NOVEL SULFONAMIDE CARBOXAMIDE COMPOUNDS

Abstract

The present invention relates to compounds of formula (I):

##STR00001##

wherein Q is selected from O or S; R.sup.1 is a non-aromatic heterocyclic group comprising at least one ring nitrogen atom, wherein R.sup.1 is attached to the sulfur atom of the sulfonylurea group by a ring carbon atom, and wherein R.sup.1 may optionally be substituted; and R.sup.2 is a cyclic group substituted at the -position, wherein R.sup.2 may optionally be further substituted.

The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP3.

Claims

1. A compound of formula (I): ##STR00589## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is selected from O or S; R.sup.1 is a non-aromatic heterocyclic group comprising at least one ring nitrogen atom, wherein R.sup.1 is attached to the sulfur atom of the sulfonylurea group by a ring carbon atom, and wherein R.sup.1 may optionally be substituted; and R.sup.2 is a cyclic group substituted at the -position, wherein R.sup.2 may optionally be further substituted.

2. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, wherein R.sup.1 is a monocyclic or bicyclic non-aromatic heterocyclic group, wherein R.sup.1 may optionally be substituted.

3. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 2, wherein R.sup.1 is a 4-, 5-, 6- or 7-membered monocyclic non-aromatic heterocyclic group or a 7-, 8-, 9- or 10-membered bicyclic non-aromatic heterocyclic group, wherein R.sup.1 may optionally be substituted.

4. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, wherein the non-aromatic heterocyclic group of R.sup.1 is fully saturated.

5. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, wherein R.sup.1 comprises one, two or three ring nitrogen, oxygen or sulfur atoms.

6. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 5, wherein R.sup.1 comprises one or two ring nitrogen or oxygen atoms.

7. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 6, wherein R.sup.1 comprises one or two ring nitrogen atoms.

8. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, wherein R.sup.1 is selected from: ##STR00590## wherein R.sup.1 is attached to the sulfur atom of the sulfonylurea group by a non-aromatic ring carbon atom, and wherein R.sup.1 may optionally be substituted or further substituted.

9. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, wherein R.sup.1 is substituted with one or more substituents independently selected from halo; CN; NO.sub.2; N.sub.3; R.sup.; OH; OR.sup.; SH; SR.sup.; SOR.sup.; SO.sub.2H; SO.sub.2R.sup.; SO.sub.2NH.sub.2; SO.sub.2NHR.sup.; SO.sub.2N(R.sup.).sub.2; R.sup.SH; R.sup.SR.sup.; R.sup.SOR.sup.; R.sup.SO.sub.2H; R.sup.SO.sub.2R.sup.; R.sup.SO.sub.2NH.sub.2; R.sup.SO.sub.2NHR.sup.; R.sup.SO.sub.2N(R.sup.).sub.2; NH.sub.2; NHR.sup.; N(R.sup.).sub.2; R.sup.NH.sub.2; R.sup.NHR.sup.; R.sup.N(R.sup.).sub.2; CHO; COR.sup.; COOH; COOR.sup.; OCOR.sup.; R.sup.CHO; R.sup.COR.sup.; R.sup.COOH; R.sup.COOR.sup.; R.sup.OCOR.sup.; NHCHO; NR.sup.CHO; NHCOR.sup.; NR.sup.COR.sup.; CONH.sub.2; CONHR.sup.; CON(R.sup.).sub.2; R.sup.NHCHO; R.sup.NR.sup.CHO; R.sup.NHCOR.sup.; R.sup.NR.sup.COR.sup.; R.sup.CONH.sub.2; R.sup.-CONHR.sup.; R.sup.CON(R.sup.).sub.2; OR.sup.OH; OR.sup.OR.sup.; OR.sup.-NH2; OR.sup.NHR.sup.; OR.sup.N(R.sup.).sub.2; NHR.sup.OH; NHR.sup.OR.sup.; NHR.sup.NH.sub.2; NHR.sup.NHR.sup.; NHR.sup.N(R.sup.).sub.2; NR.sup.R.sup.OH; NR.sup.R.sup.OR.sup.; NR.sup.R.sup.NH.sub.2; NR.sup.R.sup.NHR.sup.; NR.sup.R.sup.N(R.sup.).sub.2; a C.sub.3-C.sub.7 cycloalkyl group optionally substituted with one or more C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl groups; a C.sub.3-C.sub.7 cycloalkenyl group optionally substituted with one or more C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl groups; a 3- to 7-membered non-aromatic heterocyclic group optionally substituted with one or more C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.3 haloalkyl groups; oxo (O); or a C.sub.1-C.sub.4 alkylene bridge; wherein each R.sup. is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its backbone, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group may optionally be replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo and/or R.sup. groups; and wherein each R.sup. is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group, and wherein any R.sup. may optionally be substituted with one or more C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.3-C.sub.7 cycloalkyl, O(C.sub.1-C.sub.3 alkyl), halo, CN, CCH or oxo (O) groups.

10. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 9, wherein R.sup.1 is substituted on one or more ring nitrogen atoms with a substituent independently selected from halo; CN; NO.sub.2; N.sub.3; R.sup.; OH; OR.sup.; SH; SR.sup.; SOR.sup.; SO.sub.2H; SO.sub.2R.sup.; SO.sub.2NH.sub.2; SO.sub.2NHR.sup.; SO.sub.2N(R.sup.).sub.2; R.sup.SH; R.sup.SR.sup.; R.sup.SOR.sup.; R.sup.SO.sub.2H; R.sup.SO.sub.2R.sup.; R.sup.SO.sub.2NH.sub.2; R.sup.SO.sub.2NHR.sup.; R.sup.SO.sub.2N(R.sup.).sub.2; NH.sub.2; NHR.sup.; N(R.sup.).sub.2; R.sup.NH.sub.2; R.sup.NHR.sup.; R.sup.N(R.sup.).sub.2; CHO; COR.sup.; COOH; COOR.sup.; OCOR.sup.; R.sup.CHO; R.sup.COR.sup.; R.sup.COOH; R.sup.COOR.sup.; R.sup.OCOR.sup.; NHCHO; NR.sup.CHO; NHCOR.sup.; NR.sup.COR.sup.; CONH.sub.2; CONHR.sup.; CON(R.sup.).sub.2; R.sup.NHCHO; R.sup.NR.sup.CHO; R.sup.NHCOR.sup.; R.sup.NR.sup.COR.sup.; R.sup.CONH.sub.2; R.sup.-CONHR.sup.; R.sup.CON(R.sup.).sub.2; a C.sub.3-C.sub.7 cycloalkyl group optionally substituted with one or more C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl groups; a C.sub.3-C.sub.7 cycloalkenyl group optionally substituted with one or more C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl groups; ##STR00591## oxo (O); or a C.sub.1-C.sub.4 alkylene bridge; wherein each R.sup. is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 carbon atoms in its backbone, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo and/or R.sup. groups; wherein each R.sup. is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group, and wherein any R.sup. may optionally be substituted with one or more C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.3-C.sub.7 cycloalkyl, O(C.sub.1-C.sub.3 alkyl), halo, CN, CCH or oxo (O) groups; wherein each R.sup.5 is independently selected from a C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.3 haloalkyl group; wherein each m is independently selected from 1, 2 or 3; and wherein each n is independently selected from 1, 2 or 3.

11. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, wherein R.sup.2 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the -position, and wherein R.sup.2 may optionally be further substituted.

12. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 11, wherein R.sup.2 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the and positions, and wherein R.sup.2 may optionally be further substituted.

13. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 12, wherein R.sup.2 is a fused aryl or a fused heteroaryl group, wherein a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the , positions and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the , positions, and wherein R.sup.2 may optionally be further substituted.

14. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, wherein R.sup.2 is a cyclic group substituted at the and positions, wherein R.sup.2 may optionally be further substituted.

15. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, wherein Q is O.

16. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, selected from the group consisting of: ##STR00592## ##STR00593## ##STR00594## ##STR00595## ##STR00596## ##STR00597## ##STR00598## ##STR00599## ##STR00600## ##STR00601## ##STR00602## ##STR00603## ##STR00604## ##STR00605## ##STR00606## ##STR00607## ##STR00608## ##STR00609## ##STR00610## ##STR00611## ##STR00612## ##STR00613## ##STR00614## ##STR00615## ##STR00616## ##STR00617## ##STR00618## ##STR00619## ##STR00620## ##STR00621## ##STR00622## ##STR00623## ##STR00624## ##STR00625## ##STR00626## ##STR00627## ##STR00628## ##STR00629## or a pharmaceutically acceptable salt, solvate or prodrug thereof.

17. (canceled)

18. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, and a pharmaceutically acceptable excipient.

19. A method of treating or preventing a disease, disorder or condition in a subject, comprising the step of administering an effective amount of a compound or a pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1 to the subject, thereby treating or preventing the disease, disorder or condition.

20. The method of claim 19, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

21. The method of claim 19, wherein the disease, disorder or condition is selected from: (i) inflammation; (ii) an auto-immune disease; (iii) cancer; (iv) an infection; (v) a central nervous system disease; (vi) a metabolic disease; (vii) a cardiovascular disease; (viii) a respiratory disease; (ix) a liver disease; (x) a renal disease; (xi) an ocular disease; (xii) a skin disease; (xiii) a lymphatic condition; (xiv) a psychological disorder; (xv) graft versus host disease; (xvi) allodynia; and (xvii) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

22. The method of claim 19, wherein the disease, disorder or condition is selected from: (i) cryopyrin-associated periodic syndromes (CAPS); (ii) Muckle-Wells syndrome (MWS); (iii) familial cold autoinflammatory syndrome (FCAS); (iv) neonatal onset multisystem inflammatory disease (NOMID); (v) familial Mediterranean fever (FMF); (vi) pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA); (vii) hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); (viii) Tumour Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS); (ix) systemic juvenile idiopathic arthritis; (x) adult-onset Still's disease (AOSD); (xi) relapsing polychondritis; (xii) Schnitzler's syndrome; (xiii) Sweet's syndrome; (xiv) Behcet's disease; (xv) anti-synthetase syndrome; (xvi) deficiency of interleukin 1 receptor antagonist (DIRA); and (xvii) haploinsufficiency of A20 (HA20).

23. (canceled)

Description

EXAMPLESCOMPOUND SYNTHESIS

[0397] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0398] 2-MeTHF 2-methyltetrahydrofuran [0399] AcOH acetic acid [0400] aq aqueous [0401] Boc tert-butyloxycarbonyl [0402] br broad [0403] Cbz carboxybenzyl [0404] CDI 1,1-carbonyl-diimidazole [0405] cone concentrated [0406] d doublet [0407] DABCO 1,4-diazabicyclo[2.2.2]octane [0408] DCE 1,2-dichloroethane, also called ethylene dichloride [0409] DCM dichloromethane [0410] DIPEA N,N-diisopropylethylamine, also called Hnig's base [0411] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0412] DME dimethoxyethane [0413] DMF N,N-dimethylformamide [0414] DMSO dimethyl sulfoxide [0415] (ES+) electrospray ionization, positive mode [0416] Et ethyl [0417] EtOAc ethyl acetate [0418] EtOH ethanol [0419] h hour(s) [0420] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0421] HPLC high performance liquid chromatography [0422] LC liquid chromatography [0423] m multiplet [0424] m-CPBA 3-chloroperoxybenzoic acid [0425] Me methyl [0426] MeCN acetonitrile [0427] MeOH methanol [0428] (M+H)+ protonated molecular ion [0429] MHz megahertz [0430] min minute(s) [0431] MS mass spectrometry [0432] Ms mesyl, also called methanesulfonyl [0433] MsCl mesyl chloride, also called methanesulfonyl chloride [0434] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0435] m/z mass-to-charge ratio [0436] NaO.sup.tBu sodium tert-butoxide [0437] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0438] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0439] NMP N-methylpyrrolidine [0440] NMR nuclear magnetic resonance (spectroscopy) [0441] Pd(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o) [0442] Pd(dppf)Cl.sub.2 [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [0443] PE petroleum ether [0444] Ph phenyl [0445] PMB p-methoxybenzyl [0446] prep-HPLC preparative high performance liquid chromatography [0447] prep-TLC preparative thin layer chromatography [0448] PTSA p-toluenesulfonic acid [0449] q quartet [0450] RP reversed phase [0451] RT room temperature [0452] s singlet [0453] Sept septuplet [0454] sat saturated [0455] SCX solid supported cation exchange (resin) [0456] t triplet [0457] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0458] TEA triethylamine [0459] TFA 2,2,2-trifluoroacetic acid [0460] THF tetrahydrofuran [0461] TLC thin layer chromatography [0462] wt % weight percent or percent by weight

Experimental Methods

Analytical Methods

[0463] NMR spectra were recorded at 300 MHz or 400 MHz with chemical shifts reported in parts per million. Spectra were collected using one of the three machines below: [0464] An Agilent VNMRS 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, indirect detection probe and direct drive console including PFG module. [0465] An Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console. [0466] A Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control.

[0467] HPLC and LC-MS were recorded on an Agilent 1290 series with UV detector and HP 6130 MSD mass detector. Mobile phase A: ammonium acetate (10 mM); water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM); water/MeOH/acetonitrile (100:540:360); column, Waters XBridge BEH C18 XP (2.150 mm, 2.5 m)

TABLE-US-00001 Pump flow: 0.6 mL/min UV detection: 215, 238 nm Injection volume: 0.2 L Run time: 4.0 min Column temperature: 35 C. Mass detection: API-ES +ve and ive

[0468] Pump Program:

TABLE-US-00002 Gradient Time (min) % A % B 0.0 80 20 0.5 80 20 2.0 0 100

[0469] Alternatively, LC-MS were recorded using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC & Agilent 6110 MSD. Mobile Phase: A: 0.025% NH.sub.3.H.sub.2O in water (v/v); B: Acetonitrile. Column: Kinetex EVO C18 2.130 mm, 5 m.

Purification Method 1

[0470] Automated reversed phase column chromatography was carried out using a Buchi Sepracore X50 system driven by a C-605 pump module, C-620 Sepracore control package, C-640 UV photometer detection unit and C-660 fraction collector.

[0471] Revelis C18 reversed-phase 12 g cartridge

TABLE-US-00003 Carbon loading 18% Surface area 568 m.sup.2/g Pore diameter 65 Angstrom pH (5% slurry) 5.1 Average particle size 40 m

[0472] The column was conditioned before use with MeOH (5 min) then brought to H.sub.2O (in 5 min) and kept 5 min at H.sub.2O. Flow rate=30 mL/min.

Separation Runs:

[0473]

TABLE-US-00004 Time (min) A: water (%) B: MeOH (%) 0 100 0 5 100 0 30 30 70 30.1 0 100 35 0 100

[0474] Detection wavelength: 215, 235, 254 and 280 nm. Before each new run, the cartridge was cleaned using the conditioning method.

Purification Method 2

[0475] Alternatively, automated reversed phase column chromatography was carried out using a Gilson GX-281 system driven by a Gilson-322 pump module, Gilson-156 UV photometer detection unit and Gilson-281 fraction collector.

[0476] Phenomenex Gemini 150 mm25 mm10 m

[0477] pH (water (0.05% ammonium hydroxide v/v)acetonitrile)=10

[0478] Average particle size=10 m

[0479] The column was conditioned before use with 100% acetonitrile (2 min) then brought to 5% acetonitrile (in 1.5 min). Flow rate=25 mL/min.

Separation Runs:

[0480]

TABLE-US-00005 A: water (0.05% B: acetonitrile Time (min) ammonium hydroxide v/v) (%) 0 99 1 12 85 15 12.2 0 100 14.2 0 100 14.5 95 5 16.0 95 5

[0481] Detection wavelength: 220 and 254 nm. Before each new run, the cartridge was cleaned using the conditioning method.

Synthesis of Intermediates

Intermediate A1: 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

[0482] ##STR00135##

[0483] To a solution of phosgene (4.45 mL, 20% weight in toluene, 8.4 mmol) in EtOAc (90 mL) was added drop-wise a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in EtOAc (45 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 3 hours and upon cooling was filtered and concentrated in vacuo to afford the title compound as a brown oil (756 mg, 100% yield). The crude product was used directly in the next step without further purification.

[0484] .sup.1H NMR (CDCl.sub.3): 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m, 4H).

Intermediate A2: 2-Isocyanato-1,3-diisopropylbenzene

[0485] ##STR00136##

[0486] To a suspension of 2,6-diisopropylaniline hydrochloride (1 g, 4.7 mmol) in toluene (50 mL) was added 1 drop of pyridine and the resulting mixture was heated to near reflux whilst a solution of phosgene (7.3 mL, 20 wt % in toluene, 13.8 mmol) was added drop-wise over a period of 10 minutes. The mixture was stirred for an additional 45 minutes at 105 C. and then allowed to partially cool before being concentrated in vacuo to afford the title compound as a mobile yellow oil (1.5 g, >100% yield). The crude product was used directly in the next step without further purification.

[0487] .sup.1H NMR (CDCl.sub.3): 7.2 (m, 3H), 3.12 (m, 2H) and 1.25 (d, 12H).

Intermediate A3: 5-Fluoro-2-isocyanato-1,3-diisopropylbenzene

[0488] ##STR00137##

[0489] To a solution of 4-fluoro-2,6-diisopropylaniline (0.103 g, 0.527 mmol) in toluene (1.4 mL) was added a phosgene solution (0.69 mL, 20% weight in toluene, 1.3 mmol) and the reaction mixture was refluxed for 1 hour. Upon cooling, the mixture was concentrated in vacuo to afford the title compound as a brown oil (0.110 g, yield 100%). The crude product was used directly in the next step without further purification.

[0490] .sup.1H NMR (CDCl.sub.3): =6.80 (d, 2H), 3.20 (m, 2H), 1.24 (d, 12H).

Intermediate A4: 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

Step A: N-(5-Bromo-2,3-dihydro-1H-inden-4-yl)pivalamide

[0491] ##STR00138##

[0492] N-(2,3-Dihydro-1H-inden-4-yl)pivalamide (1 g, 4.60 mmol), p-toluenesulfonic acid monohydrate (0.45 g, 2.366 mmol), Pd(OAc).sub.2 (0.05 g, 0.223 mmol), and NBS (0.9 g, 5.06 mmol) were suspended in toluene (20 mL) and stirred for 16 hours. The dark green mixture was diluted with EtOAc (20 mL), and then washed with saturated aqueous NaHCO.sub.3 (210 mL), water (210 mL) and brine (10 mL). The organic phase was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a dark green amorphous solid. The crude product was purified by chromatography on silica gel (40 g column, 0-% EtOAc/isohexane) to afford the title compound (1.662 g, 100%) as a colourless crystalline solid that was contaminated with a small amount of reaction byproducts.

[0493] LCMS: m/z 296.3/298.3 (M+H).sup.+ (ES.sup.+).

Step B: 5-Bromo-2,3-dihydro-1F-inden-4-amine

[0494] ##STR00139##

[0495] N-(5-Bromo-2,3-dihydro-1H-inden-4-yl)pivalamide (0.632 g, 2.134 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature. H.sub.2SO.sub.4 (95% aqueous) (5 mL, 89 mmol) was slowly added to water (5 mL) and this mixture was then added to the reaction mixture. The slurry was heated to 100 C. (bath temperature) at which point the mixture became homogeneous and it was stirred at this temperature over the weekend. The mixture was cooled to room temperature and then basified with 2 M aqueous NaOH. The mixture was extracted with DCM (320 mL). The organic phase was dried by passing through a hydrophobic frit, and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-50% EtOAc/isohexane) to afford the title compound (0.14 g, 29%).

[0496] .sup.1H NMR (CDCl.sub.3) 7.23 (d, J=7.9 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.92 (s, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), 2.15 (p, J=7.5 Hz, 2H).

Step C: 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0497] ##STR00140##

[0498] 5-Bromo-2,3-dihydro-1H-inden-4-amine (280 mg, 1.320 mmol) was dissolved in dioxane (5 mL). A solution of potassium carbonate (600 mg, 4.34 mmol) in water (1 mL) and (2-methoxypyridin-4-yl)boronic acid (250 mg, 1.635 mmol) were added. The mixture was degassed with nitrogen for 15 minutes before Pd(dppf)C1.sub.2.DCM (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80 C. (bath temperature) for 2 hours. Then the mixture was cooled to room temperature and partitioned between DCM (30 mL) and water (20 mL). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to give a brown oil. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc/isohexane) to afford the title compound (0.29 g, 87%) as a pale yellow crystalline solid.

[0499] .sup.1H NMR (CDCl.sub.3) 8.26 (d, J=5.4 Hz, 1H), 7.11 (d, J=5.0 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.97 (s, 1H), 6.80 (d, J=7.6 Hz, 1H), 4.06 (s, 3H), 2.98 (t, J=7.6 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.19 (p, J=7.5 Hz, 2H). Two exchangeable protons not observed.

[0500] LCMS: m/z 241.3 (M+H).sup.+ (ES.sup.+).

Intermediate A5: 4-(4-Amino-2,3-dihydro-1H-inden-5-yl)picolinonitrile

[0501] ##STR00141##

[0502] Prepared according to the general procedure of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A4, Step C) from 5-bromo-2,3-dihydro-1H-inden-4-amine (Intermediate A4, Step B) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile to afford the title compound (215 mg, 61%) as a pale yellow solid.

[0503] .sup.1H (DMSO-d6) 8.72 (dd, J=5.1, 0.8 Hz, 1H), 8.03 (dd, J=1.8, 0.8 Hz, 1H), 7.74 (dd, J=5.1, 1.8 Hz, 1H), 6.91 (d, J=7.7 Hz, 1H), 6.61 (d, J=7.7 Hz, 1H), 4.94 (s, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.03 (p, J=7.4 Hz, 2H).

[0504] LCMS: m/z 236.3 (M+H).sup.+ (ES.sup.+).

Intermediate A6: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile

Step A: 4-Fluoro-2-(prop-1-en-2-yl)aniline

[0505] ##STR00142##

[0506] To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (36.21 g, 215.51 mmol, 1.05 eq) and K.sub.2CO.sub.3 (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H.sub.2O (40 mL) was added Pd(dppf)C1.sub.2 (7.51 g, 10.26 mmol, 0.05 eq) under a nitrogen atmosphere. Then the reaction mixture was stirred at 80 C. for 5 hours. The reaction mixture was quenched by addition of H.sub.2O (600 mL) and extracted with EtOAc (2500 mL). The combined organic layers were washed with brine (2600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate 1:0 to 100:1) to give the title compound (27 g, 77% yield, 89% purity on LCMS) as a yellow oil.

[0507] .sup.1H NMR (CDCl.sub.3) 6.81-6.76 (m, 2H), 6.66-6.62 (m, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 3.69 (br s, 2H) and 1.25 (s, 3H).

[0508] LCMS: m/z 152.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Fluoro-2-isopropylaniline

[0509] ##STR00143##

[0510] To a solution of 4-fluoro-2-(prop-1-en-2-yl)aniline (21 g, 138.91 mmol, 1 eq) in MeOH (300 mL) was added Pd/C (2.1 g, 178.59 mmol, 10 wt % loading on activated carbon) under a nitrogen atmosphere. The reaction mixture was degassed in vacuo and purged with hydrogen several times. The reaction mixture was stirred at 25 C. for 12 hours under hydrogen (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (20 g, crude) as a yellow oil.

[0511] .sup.1H NMR (CDCl.sub.3) 6.86 (dd, 1H), 6.75-6.72 (m, 1H), 6.63-6.61 (m, 1H), 3.50 (br s, 2H), 2.95-2.84 (m, 1H) and 1.25 (d, 6H).

[0512] LCMS: m/z 154.2 (M+H).sup.+ (ES.sup.+).

Step C: 2-Bromo-4-fluoro-6-isopropylaniline

[0513] ##STR00144##

[0514] To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 mL) was added NBS (23.24 g, 130.55 mmol, 1 eq) at 25 C. The reaction mixture was stirred at 25 C. for 10 minutes. The reaction mixture was poured into H.sub.2O (300 mL) and extracted with EtOAc (2250 mL). The combined organic phases were washed with brine (2400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, eluting only by using petroleum ether) to give the title compound (30 g, 99%) as a black brown oil.

[0515] .sup.1H NMR (CDCl.sub.3) 6.99 (dd, 1H), 6.78 (dd, 1H), 3.91 (br s, 2H), 2.88-2.71 (m, 1H) and 1.17 (d, 6H).

[0516] LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

Step D: 4-(2-Amino-5-fluoro-3-isopropylphenyl)picolinonitrile

[0517] ##STR00145##

[0518] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (3.6 g, 15.51 mmol, 1 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (3.60 g, 15.67 mmol, 1.01 eq) in dioxane (90 mL) and H.sub.2O (9 mL) was added Na.sub.2CO.sub.3 (4.11 g, 38.78 mmol, 2.5 eq). Then Pd(dppf)C.sub.2 (1.13 g, 1.55 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere. The resulting mixture was stirred at 80 C. for 2 hours under nitrogen. Then the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 20:1 to 5:1) and then triturated with petroleum ether (10 mL) to give the title compound (2.65 g, 65% yield, 97% purity on LCMS) as a yellow solid.

[0519] .sup.1HNMR (CDCl.sub.3) 8.79 (d, 1H), 7.86 (d, 1H), 7.65 (dd, 1H), 6.99 (dd, 1H), 6.70 (dd, 1H), 3.63 (br s, 2H), 2.98-2.87 (m, 1H) and 1.30 (d, 6H).

[0520] LCMS: m/z 256.2 (M+H).sup.+ (ES.sup.+).

Step E: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile

[0521] ##STR00146##

[0522] To a solution of 4-(2-amino-5-fluoro-3-isopropylphenyl)picolinonitrile (1 g, 3.92 mmol, 1 eq) in THF (40 mL) was added TEA (793 mg, 7.83 mmol, 2 eq). To the above mixture was added triphosgene (465 mg, 1.57 mmol, 0.4 eq) in portions at 5 C. Then the mixture was stirred at 70 C. for 1 hour. The mixture was diluted with EtOAc (200 mL) and then filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.2 g, crude) as a yellow solid, which was used directly in the next step.

Intermediate A7: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine

Step A: 4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline

[0523] ##STR00147##

[0524] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (12 g, 51.70 mmol, 1 eq) in dioxane (240 mL) and H.sub.2O (48 mL) was added (2-methoxypyridin-4-yl)boronic acid (9.49 g, 62.04 mmol, 1.2 eq) and Na.sub.2CO.sub.3 (13.70 g, 129.26 mmol, 2.5 eq). The reaction mixture was purged with nitrogen three times. Then Pd(dppf)C1.sub.2 (3.78 g, 5.17 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere. The resulting mixture was heated at 80 C. for 2 hours. The reaction mixture was quenched with H.sub.2O (800 mL) and extracted with EtOAc (2600 mL). The combined organic layers were washed with brine (2800 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 70:1 to 10:1) and then triturated with hexane (100 mL) to give the title compound (10.05 g, 72% yield, 96% purity on LCMS).

[0525] .sup.1H NMR (CDCl.sub.3) 8.24 (d, 1H), 6.97 (d, 1H), 6.93 (d, 1H), 6.83 (s, 1H), 6.73-6.70 (m, 1H), 3.99 (s, 3H), 3.66 (br s, 2H), 2.97-2.89 (m, 1H) and 1.29 (dd, 6H).

[0526] LCMS: m/z 261.1 (M+H).sup.+ (ES.sup.+).

Step B: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine

[0527] ##STR00148##

[0528] To a solution of 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (1 g, 3.84 mmol, 1 eq) in THF (40 mL) was added TEA (777 mg, 7.68 mmol, 2 eq). Then triphosgene (456 mg, 1.54 mmol, 0.4 eq) was added in portions at 5 C. The mixture was stirred at 70 C. for 1 hour. The mixture was diluted with EtOAc (200 mL) and filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.1 g, crude) as a yellow oil, which was used directly in the next step.

Intermediate A8: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

[0529] ##STR00149##

[0530] To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A4) (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50.35 mmol, 1.1 eq) in THF (275 mL) was added in portions bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) at 0 C. Then the reaction mixture was stirred at 16 C. for 0.5 hour. The reaction mixture was filtered and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacuo to give the title compound (9.04 g, 74%) as a light yellow solid.

[0531] .sup.1H NMR (CDCl.sub.3) 8.28 (d, 1H), 7.20-7.16 (m, 3H), 7.02 (s, 1H), 4.16 (s, 3H), 3.04-2.99 (m, 4H) and 2.23-2.15 (m, 2H).

Intermediate A9: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl) pyridine

Step A: 7-Fluoro-4-nitro-2,3-dihydro-1H-inden-1-one

[0532] ##STR00150##

[0533] To a mixture of 7-fluoro-2,3-dihydro-1H-inden-1-one (9.5 g, 63.27 mmol, 1 eq) in concentrated H.sub.2SO.sub.4 (100 mL) was added dropwise a solution of HNO.sub.3 (5.37 mL, 82.25 mmol, 69 wt % in water, 1.3 eq) in concentrated H.sub.2SO.sub.4 (20 mL) at 15 C. Then the reaction mixture was stirred at 0 C. for 0.5 hour. The mixture was quenched with water (500 mL) at 0 C., and then extracted with EtOAc (3300 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 3:1) to give the title compound (11.4 g, 92%) as a yellow solid.

[0534] .sup.1H NMR (CDCl.sub.3) 8.51 (dd, 1H), 7.22 (t, 1H), 3.69-3.65 (m, 2H) and 2.88-2.82 (m, 2H).

Step B: 7-Fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol

[0535] ##STR00151##

[0536] To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-one (30 g, 153.73 mmol, 1 eq) in EtOH (450 mL) was added NaBH.sub.4 (11.63 g, 307.46 mmol, 2 eq) in portions. The reaction mixture was stirred at 15 C. for 1 hour. Then the mixture was poured into water (50 mL) and extracted with DCM (2200 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (30 g, crude) as brown oil.

[0537] .sup.1H NMR (CDCl.sub.3) 8.21 (dd, 1H), 7.08 (t, 1H), 5.59-5.56 (m, 1H), 3.66-3.59 (m, 1H), 3.44-3.39 (m, 1H), 2.56-2.51 (m, 1H) and 2.22-2.17 (m, 2H).

Step C: 4-Fluoro-7-nitro-2,3-dihydro-1H-indene

[0538] ##STR00152##

[0539] To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol (4.5 g, 22.82 mmol, 1 eq) in TFA (20 mL) was added Et.sub.3SiH (7.96 g, 68.47 mmol, 3 eq) in one portion. The reaction mixture was stirred at 25 C. for 12 hours. Then the mixture was quenched with water (100 mL) and extracted with EtOAc (3100 mL). The combined organic layers were washed with saturated aqueous NaHCO.sub.3 solution (2100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (5 g, crude) as brown oil.

[0540] .sup.1H NMR (CDCl.sub.3) 8.06 (dd, 1H), 7.01 (t, 1H), 3.46 (t, 2H), 3.04 (t, 2H) and 2.25-2.20 (m, 2H).

Step D: 7-Fluoro-2,3-dihydro-1H-inden-4-amine

[0541] ##STR00153##

[0542] To a mixture of 4-fluoro-7-nitro-2,3-dihydro-1H-indene (5 g, 27.60 mmol, 1 eq) in MeOH (50 mL) was added Pd/C (0.5 g, 10 wt % loading on activated carbon) at 25 C. under a nitrogen atmosphere. Then the reaction mixture was stirred at 25 C. for 12 hours under hydrogen (15 psi). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 10:1) to give the title compound (1.8 g, 43%) as a brown solid.

[0543] .sup.1H NMR (CDCl.sub.3) 6.69 (t, 1H), 6.44 (dd, 1H), 3.47 (br s, 2H), 2.95 (t, 2H), 2.75 (t, 2H) and 2.19-2.11 (m, 2H).

Step E: 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine

[0544] ##STR00154##

[0545] To a solution of 7-fluoro-2,3-dihydro-1H-inden-4-amine (8.3 g, 54.90 mmol, 1 eq) in toluene (100 mL) was added NBS (10.26 g, 57.65 mmol, 1.05 eq) in one portion at 25 C. The reaction mixture turned dark brown immediately and then the mixture was stirred at 25 C. for 30 minutes. The reaction mixture was quenched with saturated aqueous Na.sub.2SO.sub.3 solution (200 mL) and extracted with EtOAc (2100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:o to 20:1) to give the title compound (8.51 g, 67%) as a brown solid.

[0546] .sup.1H NMR (CDCl.sub.3) 6.99 (d, 1H), 3.81 (br s, 2H), 2.92 (t, 2H), 2.78 (t, 2H) and 2.21-2.13 (m, 2H).

Step F: 7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0547] ##STR00155##

[0548] To a mixture of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (3.5 g, 15.21 mmol, 1 eq) and pyridin-4-ylboronic acid (1.96 g, 15.97 mmol, 1.05 eq) in dioxane (50 mL) and H.sub.2O (5 mL) was added K.sub.2CO.sub.3 (6.31 g, 45.64 mmol, 3 eq) and Pd(dppf)C1.sub.2 (1.11 g, 1.52 mmol, 0.1 eq) in one portion under a nitrogen atmosphere. Then the reaction mixture was heated to 80 C. for 12 hours. The reaction mixture was filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (3100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 2:1) to give the title compound (1.7 g, 45% yield, 90.98% purity on HPLC) as a brown solid.

[0549] .sup.1H NMR (CDCl.sub.3) 8.68 (dd, 2H), 7.40 (dd, 2H), 6.72 (d, 1H), 3.76 (br s, 2H), 3.01 (t, 2H), 2.80 (t, 2H) and 2.26-2.18 (m, 2H).

Step G: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

[0550] ##STR00156##

[0551] To a solution of 7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (400 mg, 1.75 mmol, 1 eq) and TEA (355 mg, 3.50 mmol, 2 eq) in THF (30 mL) was added bis(trichloromethyl) carbonate (208 mg, 700.94 mol, 0.4 eq) at 0 C. The reaction mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was filtered through a pad of silica gel and the filter cake was washed with THF (20 mL). The filtrate was concentrated in vacuo to reduce to 10 mL, which was used directly in the next step.

Intermediate A10: 3-(5-Fluoro-2-isocyanato-3-isopropylphenyl)pyridine

Step A: 4-Fluoro-2-isopropyl-6-(pyridin-3-yl)aniline

[0552] ##STR00157##

[0553] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (21 g, 90.48 mmol, 1 eq) in dioxane (450 mL) and H.sub.2O (90 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (22.26 g, 108.58 mmol, 1.2 eq) and Na.sub.2CO.sub.3 (23.98 g, 226.20 mmol, 2.5 eq). The reaction mixture was purged with nitrogen three times. Then Pd(dppf)C1.sub.2 (5.10 g, 6.97 mmol, 0.077 eq) was added under a nitrogen atmosphere. The resulting mixture was heated to 80 C. and stirred for 2 hours. The reaction mixture was quenched by addition of H.sub.2O (800 mL) and extracted with EtOAc (2600 mL). The combined organic layers were washed with brine (2800 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 1:1) and then triturated with hexane (40 mL) to give the title compound (17 g, 82%) as a grey solid.

[0554] .sup.1H NMR (CDCl.sub.3) 8.70 (d, 1H), 8.63 (dd, 1H), 7.79 (dd, 1H), 7.41-7.38 (m, 1H), 6.94 (dd, 1H), 6.71 (dd, 1H), 3.57 (s, 2H), 2.97-2.88 (m, 1H) and 1.30 (d, 6H).

[0555] LCMS: m/z 231.2 (M+H).sup.+ (ES.sup.+).

Step B: 3-(5-Fluoro-2-isocyanato-3-isopropylphenyl)pyridine

[0556] ##STR00158##

[0557] To a solution of 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (0.5 g, 2.17 mmol, 1 eq) and TEA (439 mg, 4.34 mmol, 2 eq) in THF (10 mL) was added triphosgene (257 mg, 868.51 mol, 0.4 eq) in portions at 5 C. Then the reaction mixture was heated to 70 C. and stirred for 1 hour. The reaction mixture was concentrated in vacuo. The residue was treated with EtOAc (100 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (0.2 g, crude) as a yellow oil, which was used directly in the next step.

Intermediate A11: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

Step A: 7-Fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0558] ##STR00159##

[0559] To a mixture of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (Intermediate A9, Step E) (8.5 g, 36.94 mmol, 1 eq) and (2-methoxypyridin-4-yl)boronic acid (5.93 g, 38.79 mmol, 1.05 eq) in dioxane (150 mL) and water (15 mL) were added K.sub.2CO.sub.3 (15.32 g, 110.83 mmol, 3 eq) and Pd(dppf)C1.sub.2 (2.70 g, 3.69 mmol, 0.1 eq) in one portion under nitrogen. Then the reaction mixture was heated to 80 C. and stirred for 12 hours. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (3300 mL). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:EtOAc, 1:0 to 10:1) and then purified by trituration with a mixture of TBME and n-hexane (50 mL, 1:20) to give the title compound (5.06 g, 52% yield, 97.44% purity on LCMS) as an off-white solid.

[0560] .sup.1H NMR (CDCl.sub.3) 8.23 (d, 1H), 6.99 (dd, 1H), 6.86 (s, 1H), 6.71 (d, 1H), 3.99 (s, 3H), 3.67 (br s, 2H), 3.00 (t, 2H), 2.79 (t, 2H) and 2.25-2.17 (m, 2H).

Step B: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

[0561] ##STR00160##

[0562] To a solution of phosgene (1.5 mL, 20 wt % in toluene, 2.9 mmol) in toluene (40 mL) was added dropwise a solution of 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (300 mg, 1.16 mmol) in toluene (20 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and upon cooling was concentrated in vacuo to afford the title compound as a brown oil (325 mg, 98%).

The crude product was used directly in the next step without further purification.

[0563] .sup.1H NMR (CDCl.sub.3) 8.24 (d, 1H), 6.95 (dd, 1H), 6.88 (s, 1H), 6.85-6.75 (m, 1H), 4.00 (s, 3H), 3.15-2.95 (m, 4H), 2.32-2.12 (m, 2H).

Intermediate A12: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl) picolinonitrile

[0564] ##STR00161##

[0565] To a solution of phosgene (1.7 mL, 20 wt % in toluene, 3.2 mmol) in toluene (40 mL) was added dropwise a solution of 4-(4-amino-2,3-dihydro-1H-inden-5-yl)picolinonitrile (Intermediate A5) (300 mg, 1.3 mmol) in toluene (20 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and upon cooling was concentrated in vacuo to afford the title compound as a brown oil (333 mg, 100%). The crude product was used directly in the next step without further purification.

[0566] .sup.1H NMR (CDCl.sub.3) 8.75 (dd, 1H), 7.81 (dd, 1H), 7.63 (dd, 1H), 7.22-7.08 (m, 2H), 3.04 (m, 4H), 2.23 (m, 2H).

Intermediate A13: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

Step A: 5-(Pyridin-4-yl)-2,3-dihydro-1I-inden-4-amine

[0567] ##STR00162##

[0568] 5-Bromo-2,3-dihydro-1H-inden-4-amine (1.2 g, 5.7 mmol) was dissolved in dioxane (25 mL). A solution of potassium carbonate (3.1 g, 23 mmol) in water (6 mL) and pyridin-4-ylboronic acid (0.83 g, 6.8 mmol) were added. The mixture was degassed with nitrogen for 20 minutes before Pd(dppf)Cl.sub.2.DCM (0.74 g, 0.91 mmol) was added. The reaction mixture was heated to 77 C. for 2 hours. Then the mixture was cooled to room temperature and filtered over Celite with DCM (100 mL) and water (25 mL). The organic phase was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a brown oil (3.3 g). The crude product was purified by chromatography on silica gel (80 g column, 0-100% EtOAc/heptane) to afford the title compound (0.75 g, 63%) as a pale yellow crystalline solid.

[0569] .sup.1H NMR (CDCl.sub.3) 8.72-8.54 (m, 2H), 7.50-7.37 (m, 2H), 6.97 (d, 1H), 6.78 (d, 1H), 3.72 (s, 2H), 2.96 (t, 2H), 2.77 (t, 2H), 2.18 (m, 2H).

Step B: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

[0570] ##STR00163##

[0571] To a solution of phosgene (1.1 mL, 20 wt % in toluene, 2.06 mmol) in toluene (40 mL) was added dropwise a solution of 5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (175 mg, 0.83 mmol) in toluene (20 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and upon cooling to room temperature a yellow precipitate was formed. The solid was filtered and dried in vacuo to afford the title compound as a yellow solid (145 mg, 74%). The crude product was used directly in the next step without further purification.

[0572] .sup.1H NMR (CDCl.sub.3) 8.76 (d, 2H), 8.04 (d, 2H), 7.26-7.08 (m, 2H), 3.08 (t, 4H), 2.26 (m, 2H).

Intermediate A14: 8-Isocyanato-1,2,3,5-tetrahydro-s-indacene

[0573] ##STR00164##

[0574] To a solution of phosgene (1.4 mL, 20 wt % in toluene, 2.6 mmol) in toluene (40 mL) was added dropwise a solution of 1,2,3,7-tetrahydro-s-indacen-4-amine (180 mg, 1.05 mmol) in toluene (20 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and upon cooling was concentrated in vacuo to afford the title compound as a brown oil (207 mg, 100%). The crude product was used directly in the next step without further purification.

[0575] .sup.1H NMR (CDCl.sub.3) (mixture of isomers) 7.18, 7.12 (m, 1H), 6.94, 6.80 (m, 1H), 6.52, 6.50 (s, 1H), 3.38, 3.34 (m, 2H), 2.95 (m, 4H), 2.16 (m, 2H).

Intermediate A15: 5-Chloro-2-isocyanato-1,3-diisopropylbenzene

[0576] ##STR00165##

[0577] To a solution of 4-chloro-2,6-diisopropylaniline (0.105 g, 0.496 mmol) in toluene (1 mL) was added a phosgene solution (0.65 mL, 20 wt % in toluene, 1.22 mmol) and the reaction mixture was refluxed for 1 hour. Upon cooling, the mixture was concentrated in vacuo to afford the title compound as an orange oil (0.111 g, 94%).

[0578] .sup.1H NMR (CDCl.sub.3) 7.07 (d, 2H), 3.17 (h, 2H), 1.24 (d, 12H).

Intermediate P3: 1-(Prop-2-yn-1-yl)piperidine-4-sulfonamide

[0579] ##STR00166##

[0580] To a mixture of piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol, 1.0 equiv.), potassium carbonate (4.0 equiv., 4.0 mmol, 552 mg) and acetonitrile (10 mL) was added propargyl bromide (0.1 mL, 1.0 mmol, 1.0 equiv.). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo and the crude material was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (115 mg, 56%).

[0581] .sup.1H NMR (CDCl.sub.3): 4.42 (br s, 1H), 3.38 (s, 2H), 3.05 (d, 2H), 2.95 (m, 1H), 2.12 (m, 4H) and 1.95 (m, 2H).

Intermediate P4: 1-(2,2,2-Trifluoroacetyl)piperidine-4-sulfonamide

[0582] ##STR00167##

[0583] To a suspension of piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol, 1.0 equiv.) and triethylamine (0.35 mL, 2.5 mmol, 2.5 equiv.) in acetonitrile (10 mL) was added trifluoroacetic anhydride (0.14 mL, 1.0 mmol, 1.0 equiv.). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and submitted to normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (ratio 1:1) to afford the title compound (61 mg, yield 23%).

[0584] .sup.1H NMR (CDCl.sub.3): 4.73 (d, 1H), 4.52 (s, 2H), 4.20 (d, 1H), 3.21 (t, 2H), 2.91 (t, 1H), 2.37 (d, 2H) and 1.95 (m, 2H).

Intermediate P5: N-iso-Propyl-4-sulfamoylpiperidine-1-carboxamide

[0585] ##STR00168##

[0586] To a suspension of piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol, 1.0 equiv.), 4-dimethylaminopyrimidine (12 mg, 0.1 mmol, 0.1 equiv.) and triethylamine (0.34 mL, 2.5 mmol, 2.5 equiv.) was added isopropyl isocyanate (0.1 mL, 1.0 mmol, 1.0 equiv.). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then purified by normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (ratio 1:1) as eluent to afford the title compound (55 mg, yield 22%).

[0587] .sup.1H NMR (CDCl.sub.3): 4.45 (br s, 1H), 4.22 (m, 1H), 4.10 (d, 2H), 3.98 (m, 1H), 3.10 (m, 1H), 2.81 (t, 2H), 2.20 (d, 2H), 1.80 (m, 2H) and 1.19 (d, 6H).

Intermediate P6: 1-Ethylpiperidine-4-sulfonamide

[0588] ##STR00169##

[0589] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) using ethyliodide instead of propargyl bromide. The crude product was coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and was submitted to normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (ratio 1:1) as eluent to afford the title compound contaminated with triethylamine hydrochloride (50 mg, yield 26%). The crude product was used as such in preparing examples.

[0590] .sup.1H NMR (CDCl.sub.3): 5.05 (br s, 2H), 3.10 (m, 2H), 2.95 (m, 1H), 2.45 (m, 2H), 2.20 (d, 2H), 1.95 (m, 4H) and 1.08 (t, 3H).

Intermediate P7: 1-Acetylpiperidine-4-sulfonamide

[0591] ##STR00170##

[0592] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) except that the suspension was cooled to 0 C. and then acetic anhydride was added instead of trifluoroacetic anhydride. The reaction mixture was allowed to warm to room temperature overnight. The crude product was coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and was submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol as eluent to afford the title compound as a mixture with triethylamine hydrochloride salt (139 mg, yield 67%). The crude product was used as such in the preparation of examples.

[0593] .sup.1H NMR (CDCl.sub.3): 4.90 (m, 3H), 3.99 (d, 1H), 3.10 (m, 2H), 2.60 (t, 1H), 2.10 (t, 2H), 2.05 (s, 3H) and 1.75 (m, 2H).

Intermediate P8: 1-(Cyclopropanecarbonyl)piperidine-4-sulfonamide

[0594] ##STR00171##

[0595] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) except that cyclopropanecarbonyl chloride (1.0 equiv.) was used instead of trifluoroacetic anhydride. The crude product was coated on Agilent hydromatrix and was submitted to normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (ratio 1:1) as eluent to afford the title compound (84 mg, yield 36%).

[0596] .sup.1H NMR (CDCl.sub.3): 4.80 (br s, 1H), 4.58 (s, 2H), 4.40 (br s, 1H), 3.18 (m, 2H), 2.64 (br s, 1H), 2.25 (br s, 2H), 1.78 (m, 3H), 1.00 (m, 2H) and 0.79 (m, 2H).

Intermediate P9: 1-(Cyanomethyl)piperidine-4-sulfonamide

[0597] ##STR00172##

[0598] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) using bromo acetonitrile instead of propargyl bromide to afford the title compound as a solid (40%).

[0599] .sup.1H NMR (DMSO-d6): =6.71 (s, 2H), 3.73 (s, 2H), 2.89 (d, 2H), 2.79 (m, 1H), 2.19 (t, 2H), 1.99 (d, 2H) and 1.60 (m, 2H).

Intermediate P10: 1-Propionylpiperidine-4-sulfonamide

[0600] ##STR00173##

[0601] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) using propionic anhydride instead of trifluoroacetic anhydride to afford the title compound as a solid (71%).

[0602] .sup.1H NMR (CD.sub.3OD): =4.67 (d, 1H), 4.05 (d, 1H), 3.17 (m, 2H), 2.65 (t, 1H), 2.42 (q, 2H), 2.18 (t, 2H), 1.65 (m, 2H) and 1.10 (t, 3H).

Intermediate P11: 1-iso-Butyrylpiperidine-4-sulfonamide

[0603] ##STR00174##

[0604] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) using iso-butyric anhydride instead of trifluoroacetic anhydride to afford the title compound contaminated with triethylamine hydrochloride (64%).

[0605] .sup.1H NMR (CDCl.sub.3): =4.83 (d, 1H), 4.63 (s, 2H), 4.10 (d, 1H), 3.10 (m, 2H), 2.79 (m, 1H) 2.60 (t, 1H), 2.14 (m, 2H), 2.76 (m, 2H) and 1.16 (d, 6H).

Intermediate P12: 1-(2-Methoxyacetyl)piperidine-4-sulfonamide

[0606] ##STR00175##

[0607] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) using 2-methoxyacetyl chloride instead of cyclopropanecarbonyl chloride to afford the title compound contaminated with triethylamine hydrochloride (55%).

[0608] .sup.1H NMR (CDCl.sub.3): =5.37 (bs, 2H), 4.72 (d, 1H), 4.10 (m, 3H), 3.41 (s, 3H), 3.16 (m, 2H), 2.64 (t, 1H), 2.23 (d, 2H) and 1.79 (m, 2H).

Intermediate P13: Methyl 4-sulfamoylpiperidine-1-carboxylate

[0609] ##STR00176##

[0610] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) using methyl chloroformate instead of cyclopropanecarbonyl chloride to afford the tittle compound as a solid (10%).

[0611] .sup.1H NMR (CDCl.sub.3): =4.49 (s, 2H), 4.33 (bs, 2H), 3.72 (s, 3H), 3.07 (m, 1H), 2.80 (t, 2H), 2.19 (d, 2H) and 1.77 (m, 2H).

Intermediate P14: 1-Cyclobutylpiperidine-4-sulfonamide

[0612] ##STR00177##

[0613] To a suspension of piperidine-4-sulfonamide hydrochloric acid (157 mg, 0.79 mmol, 1.0 equiv.) and triethylamine (0.12 mL, 0.86 mmol, 1.1 equiv.) in acetonitrile (10 mL) was added cyclobutanone (61 L, 0.82 mmol, 1.05 equiv.) followed by sodium triacetoxyborohydride (207 mg, 0.98 mmol, 1.25 equiv.). After being allowed to stir overnight the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated on hydromatrix and then purified by normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (1:1) as eluent to afford the title compound contaminated with trimethylamine hydrochloride (110 mg product, yield 64%).

[0614] .sup.1H NMR (CDCl.sub.3): =4.76 (bs, 2H), 2.98 (m, 3H), 2.78 (m, 1H), 2.19 (d, 2H), 2.00 (m, 2H), 1.88 (m, 6H) and 1.65 (m, 2H).

Intermediate P15: 1-Ethylpiperidine-3-sulfonamide

[0615] ##STR00178##

[0616] Piperidine-3-sulfonamide hydrochloride (0.5 g, 3.2 mmol) was suspended in acetonitrile (10 mL) and potassium carbonate (1.75 g, 12.6 mmol) was added before the mixture was allowed to stir for 30 minutes. To the resulting slurry was added ethyl bromide (0.24 mL, 0.34 g, 3.2 mmol) and the mixture was allowed to stir for 60 hours at ambient temperature. The reaction was concentrated in vacuo and then purified by column chromatography (40 g Silicycle FLH-R10030B-ISO40 cartridge, 5-25% methanol in DCM) to afford the title compound (0.11 g, 0.57 mmol, yield 18%).

[0617] .sup.1H NMR (1:1 CD.sub.3OD:CDCl.sub.3): 3.36 (m, 2H), 3.10 (m, 1H), 2.92 (bd, 1H), 2.56 (q, 2H), 2.22 (bd, 1H), 2.11 (t, 1H), 1.88 (m, 2H), 1.58 (m, 2H) and 1.10 (t, 3H).

Intermediate P16: 1-Propylpiperidine-4-sulfonamide

[0618] ##STR00179##

[0619] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from 1-bromopropane and piperidine-4-sulfonamide hydrochloric acid. This afforded the title compound impure (44 mg, yield 40%) which was used without purification.

[0620] .sup.1H NMR (CDCl.sub.3): =3.10 (m, 3H), 2.38 (m, 2H), 2.20 (m, 2H), 2.00 (m, 4H), 1.25 (m, 2H) and 0.95 (t, 3H).

Intermediate P17: 1-(Oxetan-3-yl)piperidine-4-sulfonamide

[0621] ##STR00180##

[0622] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 3-oxetanone and piperidine-4-sulfonamide hydrochloric acid (130 mg, yield 59%).

[0623] .sup.1H NMR (DMSO-d.sub.6): =6.75 (s, 2H), 4.49 (t, 2H), 4.38 (t, 2H), 3.38 (m, 2H), 2.79 (m, 2H), 1.98 (d, 2H), 1.79 (t, 2H) and 1.59 (m, 2H).

Intermediate P18: Methyl 2-(4-sulfamoylpiperidin-1-yl)acetate

[0624] ##STR00181##

[0625] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) using methyl bromoacetate instead of propargyl bromide (91 mg, yield 39%).

[0626] .sup.1H NMR (DMSO-d.sub.6): =6.70 (s, 2H), 3.60 (s, 3H), 3.19 (s, 2H), 2.93 (d, 2H), 2.76 (m, 1H), 2.18 (t, 2H), 1.93 (d, 2H) and 1.59 (m, 2H).

Intermediate P19: 1-Cyclopropylpiperidine-4-sulfonamide

[0627] ##STR00182##

[0628] Prepared as described for 1-cyclopropylpyrrolidine-3-sulfonamide (Intermediate P30) from piperidine-4-sulfonamide hydrochloric acid and triethylamine (1.1 equiv.) was added to the suspension. This afforded the title compound (150 mg, yield 73%) which was used as such without further purification.

[0629] .sup.1H NMR (DMSO-d.sub.6): =6.67 (s, 2H), 2.98 (m, 2H), 2.77 (m, 1H), 2.15 (t, 2H), 1.92 (m, 2H), 1.52 (m, 3H), 0.23 (m, 2H) and 0.39 (m, 2H).

Intermediate P20: 1-(1-Ethylazetidin-3-yl)piperidine-4-sulfonamide

[0630] ##STR00183##

[0631] A suspension of 1-(azetidin-3-yl)piperidine-4-sulfonamide dihydrochloride (145 mg, 0.45 mmol) in acetonitrile (5.8 mL) was stirred with triethylamine (0.13 mL, 95 mg, 0.94 mmol) for 30 minutes. To this was added acetaldehyde (0.03 mL, 25 mg, 0.6 mmol) and sodium triacetoxyborohydride (122 mg, 0.56 mmol). The stirring was continued for 20 hours and then the mixture concentrated in vacuo. The residue was dissolved in methanol/dichloromethane (1:1) and purified by chromatography (40 g Silicycle SiO.sub.2 cartridge through a syringe filter and eluted with 5-30% 3.5 N ammonia in methanol/dichloromethane) to afford the title compound (73 mg, 0.28 mmol, yield 63%)

[0632] .sup.1H NMR (DMSO-d.sub.6): =6.71 (br s, 2H), 3.49 (m, 4H), 2.89 (m, 3H), 2.77 (m, 3H), 1.95 (br d, 2H), 1.77 (m, 2H), 1.57 (dq, 2H) and 0.89 (t, 3H).

Intermediate P21: 1-(Cyclobutanecarbonyl)piperidine-4-sulfonamide

[0633] ##STR00184##

[0634] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) using cyclobutanecarbonyl chloride instead of trifluoroacetic anhydride to afford the title compound (158 mg, yield 64%).

[0635] .sup.1H NMR (CDCl.sub.3): =4.81 (d, 1H), 4.58 (s, 2H), 3.84 (d, 1H), 3.24 (m, 1H), 3.18 (m, 1H), 3.01 (t, 1H), 2.60 (t, 1H), 2.37 (m, 2H), 2.20 (m, 4H), 1.99 (m, 1H), 1.89 (m, 1H) and 1.72 (m, 2H).

Intermediate P22: N-Ethyl-4-sulfamoylpiperidine-1-carboxamide

[0636] ##STR00185##

[0637] To a suspension of piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol, 1.0 equiv.) and triethylamine (0.34 mL, 2.5 mmol, 2.5 equiv.) in acetonitrile (10 mL) was added ethyl isocyanate (79 L, 1.0 mmol, 1.0 equiv.). The reaction mixture was stirred overnight and then concentrated in vacuo. The crude product was coated on Agilent Hydromatrix and then submitted to normal phase flash chromatography on silica gel using dichloromethane and a mixture of methanol and triethylamine (ratio 1:1) to afford the title compound (141 mg, yield 60%) which was used without any further purification.

[0638] .sup.1H NMR (DMSO-d.sub.6): =6.78 (br s, 2H), 4.04 (d, 2H), 2.98 (m, 3H), 2.64 (t, 2H), 1.91 (d, 2H), 1.39 (m, 2H) and 0.98 (t, 3H).

Intermediate P23: N-Methyl-4-sulfamoylpiperidine-1-carboxamide

[0639] ##STR00186##

[0640] Prepared as described for N-iso-propyl-4-sulfamoylpiperidine-1-carboxamide (Intermediate P5) from piperidine-4-sulfonamide hydrochloric acid and N-methyl-1H-imidazole-1-carboxamide, but no 4-dimethylaminopyrimidine was required. The title compound (12 mg, yield 5%) was used without purification.

[0641] .sup.1H NMR (CDCl.sub.3): =4.18 (d, 2H), 3.18 (m, 1H), 2.78 (m, 5H), 2.20 (m, 2H) and 1.75 (m, 2H).

Intermediate P24: 1-(Methylsulfonyl)piperidine-4-sulfonamide

[0642] ##STR00187##

[0643] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) from piperidine-4-sulfonamide hydrochloric acid and methanesulfonic anhydride. The title compound (18 mg, yield 7%) was used without purification.

[0644] .sup.1H NMR (CD.sub.3OD): =3.90 (m, 2H), 3.08 (m, 2H), 2.82 (m, 4H), 2.23 (d, 2H) and 1.83 (m, 2H).

Intermediate P25: N-Ethyl-3-sulfamoylpyrrolidine-1-carboxamide

[0645] ##STR00188##

[0646] Prepared as described for N-iso-propyl-4-sulfamoylpiperidine-1-carboxamide (Intermediate P5) from ethyl isocyanate and pyrrolidine-3-sulfonamide, but no 4-dimethylaminopyrimidine nor triethylamine were required. The title compound (13 mg, yield 5%) was used crude without purification.

[0647] .sup.1H NMR (CD.sub.3OD): =3.81 (m, 1H), 3.57 (m, 1H), 3.39 (m, 1H), 3.19 (m, 4H), 2.38 (m, 2H) and 1.10 (t, 3H).

Intermediate P26: N-iso-Propyl-3-sulfamoylpiperidine-1-carboxamide

[0648] ##STR00189##

[0649] Prepared as described for N-iso-propyl-4-sulfamoylpiperidine-1-carboxamide (Intermediate P5) from isopropyl isocyanate and piperidine-3-sulfonamide hydrochloride to afford the title compound (0.11 g, 0.44 mmol, yield 41%).

[0650] .sup.1H NMR (CD.sub.3OD): =3.85 (m, 2H), 2.98 (m, 2H), 2.77 (br t, 1H), 2.25 (br d, 1H), 2.00 (s, 2H), 1.65-1.90 (m, 2H) and 1.13 (d, 6H).

Intermediate P27: 1-Methylpyrrolidine-3-sulfonamide

[0651] ##STR00190##

[0652] To a suspension of pyrrolidine-3-sulfonamide (150 mg, 1.0 mmol, 1.0 equiv.) and formaldehyde (37% in water stabilized with methanol; 78 L, 1.05 mmol, 1.05 equiv.) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (265 mg, 1.25 mmol, 1.25 equiv.). The reaction mixture was stirred for 5 days at room temperature and then concentrated in vacuo. The crude material was dissolved in methanol, coated on hydromatrix and then submitted for normal phase flash chromatography using dichloromethane and a mixture of triethylamine:methanol (ratio 1:1) as eluent to afford the title compound impure (80 mg, yield 49%) which was used as such in further reactions.

[0653] .sup.1H NMR (CD.sub.3OD): =3.78 (m, 1H), 3.18 (m, 3H), 2.86 (m, 2H), 2.70 (m, 1H) and 2.43 (s, 3H).

Intermediate P28: 1-Ethylpyrrolidine-3-sulfonamide

[0654] ##STR00191##

[0655] Prepared as described for 1-ethylpiperidine-4-sulfonamide (Intermediate P6) from pyrrolidine-3-sulfonamide and ethyl iodide. The title compound (75 mg, yield 42%) was used without further purification.

[0656] .sup.1H NMR (CD.sub.3OD): =3.77 (m, 1H), 3.10 (t, 1H), 2.79 (m, 2H), 2.57 (m, 3H), 2.19 (m, 2H) and 1.16 (t, 3H).

Intermediate P29: 1-Acetylpyrrolidine-3-sulfonamide

[0657] ##STR00192##

[0658] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) from acetic anhydride (1.0 equiv.) and pyrrolidine-3-sulfonamide. The title compound (75 mg, yield 39%) was used without purification.

[0659] .sup.1H NMR (CD.sub.3OD): =3.89 (m, 2H), 3.78 (m, 2H), 3.62 (m, 1H), 2.41 (m, 2H) and 2.08 (s, 3H).

Intermediate P30: 1-Cyclopropylpyrrolidine-3-sulfonamide

[0660] ##STR00193##

[0661] To a suspension of pyrrolidine-3-sulfonamide (150 mg, 1.00 mmol) and 1-(ethoxycyclopropoxy)trimethylsilane (0.4 mL, 2.0 mmol, 2.0 equiv.) in tetrahydrofuran (5 mL) and methanol (5 mL) was added acetic acid (0.12 mL, 2.2 mmol, 2.2 equiv.) followed by sodium cyanoborohydride (94 mg, 1.5 mmol, 1.5 equiv.). The reaction mixture was stirred overnight and then concentrated in vacuo. The crude was dissolved in methanol, coated on hydromatrix and then submitted for normal phase flash chromatography using dichloromethane and a mixture of triethylamine:methanol (ratio 1:1) as eluent to afford the title compound (75 mg, yield 39%).

[0662] .sup.1H NMR (DMSO-d.sub.6): =6.79 (s, 2H), 3.57 (m, 1H), 2.98 (t, 1H), 2.80 (t, 1H), 2.71 (m, 1H), 2.58 (q, 1H), 2.01 (q, 2H), 1.64 (m, 1H), 0.28 (m, 2H) and 0.38 (m, 2H).

Intermediate P31: N,N-Dimethyl-3-sulfamoylpyrrolidine-1-carboxamide

[0663] ##STR00194##

[0664] To a solution of carbonyldiimidazole (269 mg, 1.66 mmol) in acetonitrile (10 mL) was added dimethylamine hydrochloride (122 mg, 1.55 mmol, 0.9 equiv.). The resulting solution was allowed to stir for 1.5 hours at room temperature after which triethylamine (0.3 mL, 2.0 mmol, 1.2 equiv.) and pyrrolidine-3-sulfonamide (250 mg, 1.66 mmol) were added. The reaction mixture was stirred for 3 hours before extra triethylamine (0.3 mL, 2.0 mmol, 1.2 equiv.) was added to the suspension. After stirring overnight, more carbonyldiimidazole (269 mg, 1.66 mmol, 1.0 equiv.), and 2 M dimethylamine in tetrahydrofuran (0.83 mL, 1.66 mmol, 1.0 equiv.) were added. The reaction mixture was heated to 50 C. overnight, and then more dimethylamine (2 M in tetrahydrofuran; 0.83 mL, 1.66 mmol, 1.0 equiv.) was added. After heating overnight, more dimethylamine (2 M in tetrahydrofuran; 4.2 mL, 8.3 mmol, 5.0 equiv.) was added. The reaction mixture was again heated overnight. Upon cooling the reaction mixture was concentrated in vacuo. The crude was dissolved in methanol, coated on hydromatrix and then submitted for normal phase flash chromatography on silicagel using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent to afford the title compound, still not completely pure (35 mg, yield 15%). The product was used as such.

[0665] .sup.1H NMR (DMSO-d.sub.6): =7.19 (s, 2H), 3.84 (m, 2H), 3.79 (m, 1H), 3.58 (m, 2H), 2.73 (s, 6H) and 2.02 (m, 2H).

Intermediate P32: 1-iso-Propylpyrrolidine-3-sulfonamide

[0666] ##STR00195##

[0667] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from pyrrolidine-3-sulfonamide and acetone, but no triethylamine was required. The title compound (130 mg, yield 67%) was used without purification.

[0668] .sup.1H NMR (CD.sub.3OD): =3.76 (m, 1H), 3.23 (t, 1H), 2.92 (m, 1H), 2.90 (m, 1H), 2.62 (m, 1H), 2.52 (m, 1H), 2.21 (m, 2H) and 1.17 (m, 6H).

Intermediate P33: Azetidine-3-sulfonamide

Step A: Benzyl 3-sulfamoylazetidine-1-carboxylate

[0669] ##STR00196##

[0670] A solution of ammonium hydroxide (25% in water; 22 mL, 73 mmol, 10.0 equiv.) was added to benzyl 3-(chlorosulfonyl)azetidine-1-carboxylate (2.1 g, 7.3 mmol, 1.0 equiv.). The suspension was stirred at room temperature for 20 minutes to afford a clear solution and the reaction mixture was then acidified to pH 8-9, using hydrochloric acid (2 M, aqueous) and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and then concentrated in vacuo to afford the title compound (1.52 g, 5.62 mmol, yield 77%) which was used without further purification.

[0671] .sup.1H NMR (CDCl.sub.3): =7.38 (m, 5H), 5.18 (s, 4H), 4.40 (m, 4H) and 4.00 (m, 1H).

Step B: Azetidine-3-sulfonamide

[0672] ##STR00197##

[0673] A suspension of benzyl 3-sulfamoylazetidine-1-carboxylate (1.52 g, 5.62 mmol, 1.0 equiv.) in ethyl acetate (30 mL) was flushed with a flow of nitrogen before Pd/C (10 wt % loading, 595 mg, 0.56 mmol, 0.1 equiv.) was added and the flask was then flushed with hydrogen. The reaction mixture was heated to reflux for 20 hours under hydrogen atmosphere (balloon). Upon cooling the suspension was filtered over Celite 545 and the Celite was washed extensively with methanol. The filtrates were combined and concentrated in vacuo to afford the title compound (541 mg, 3.97 mmol, yield 70%) which was used without further purification.

[0674] .sup.1H NMR (DMSO-d.sub.6): =6.91 (br s, 2H), 4.08 (m, 1H), 3.74 (t, 2H) and 3.63 (t, 2H).

Intermediate P34: Quinuclidine-3-sulfonamide

Step A: (Quinuclidin-3-yl) ethanethioate

[0675] ##STR00198##

[0676] To a solution of triphenylphosphine (4.12 g, 15.7 mmol, 2.0 equiv.) in tetrahydrofuran (64 mL) cooled in an ice-bath was added di-iso-propyl azodicarboxylate (3.1 mL, 15.7 mmol, 2.0 equiv.). The clear yellow solution was stirred for to minutes during which time a precipitate appeared. 3-Quinuclidinol (1.0 g, 7.86 mmol, 1.0 equiv.) was added, followed by thioacetic acid (1.2 mL, 15.7 mmol, 2.0 equiv.) and then the ice-bath was removed and the green solution was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo and the crude material was purified by normal phase flash chromatography using dichloromethane and methanol as eluent to afford the title compound (581 mg, yield 40%).

[0677] .sup.1H NMR (CDCl.sub.3): =3.71 (m, 1H), 2.97 (m, 5H), 2.77 (dd, 1H), 2.33 (s, 3H) 1.92 (m, 1H), 1.81 (m, 3H) and 1.57 (m, 1H).

Step B: Quinuclidine-3-sulfonamide

[0678] ##STR00199##

[0679] To a suspension of N-chlorosuccinimide (1.7 g, 12.5 mmol, 4.0 equiv.) in acetonitrile (7.0 mL) was added hydrochloric acid (aqueous, 2 M, 1.2 mL, 2.50 mmol, 0.8 equiv.). The solution was cooled in an ice-bath, after which a solution of S-(quinuclidin-3-yl) ethanethioate (581 mg, 3.14 mmol, 1.0 equiv.) in acetonitrile (3.0 mL) was added and the ice-bath was removed. The reaction mixture was stirred for 45 minutes and then added drop-wise to a solution of ammonium hydroxide (25 wt % in water; 25 mL, 160 mmol, 51 equiv.). The mixture was stirred for to minutes and then concentrated in vacuo. The resulting solid was suspended in methanol, filtered and the filtrate was concentrated in vacuo. The crude was purified by reversed phase flash chromatography (see Experimental Methods, Purification Method 1) using water and methanol as eluent to afford the title compound impure (43 mg, 0.22 mmol, yield 7%).

[0680] .sup.1H NMR (DMSO-d.sub.6): =3.74 (m, 1H), 3.55 (m, 4H), 3.01 (m, 1H), 2.65 (m, 1H), 2.38 (m, 2H), 2.23 (m, 2H) and 2.01 (m, 1H).

Intermediate P35: 1-(1-Ethylpiperidin-4-yl)pyrrolidine-3-sulfonamide

[0681] ##STR00200##

[0682] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from pyrrolidine-3-sulfonamide and 1-ethyl-4-piperidone, but no triethylamine was required. The crude compound was purified by normal phase flash chromatography using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent to afford the title compound (217 mg, yield 83%).

[0683] .sup.1H NMR (DMSO-d.sub.6): =6.81 (s, 2H), 3.58 (m, 1H), 3.00 (m, 3H), 2.65 (m, 4H), 2.44 (m, 3H), 2.08 (br s, 1H), 2.03 (m, 2H), 1.82 (m, 2H), 1.49 (br s, 2H) and 1.07 (t, 3H).

Intermediate P36: (1R*,3R*,5S*)-8-iso-Propyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

Step A: tert-Butyl (1R*,3S*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0684] ##STR00201##

[0685] To a mixture of tert-butyl 3-exo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (3.0 g, 13.2 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (3.0 mL, 17.2 mmol, 1.3 equiv.) in dichloromethane (66 mL) was added methanesulfonyl chloride (1.1 mL, 14.5 mmol, 1.1 equiv.). The reaction mixture was stirred for 2.5 hours at room temperature and then the solution was washed twice with water, once with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (4.08 g, 13.2 mmol, quantitative yield).

[0686] .sup.1H NMR (CDCl.sub.3): =5.08 (m, 1H), 4.28 (br s, 2H), 3.00 (s, 3H), 2.10 (br d, 4H), 1.82 (br s, 2H), 1.63 (d, 2H) and 1.44 (s, 9H).

Step B: tert-Butyl (1R*,3R*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0687] ##STR00202##

[0688] To a solution of tert-butyl (1R*,3S*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (4.08 g, 13.2 mmol, 1.0 equiv.) in dimethylformamide (50 mL) and acetonitrile (13 mL) was added potassium thioacetate (4.52 g, 39.6 mmol, 3.0 equiv.). The reaction mixture was heated to reflux for 1 hour and then allowed to cool to room temperature. Brine and ethyl acetate were added to the solution and after thorough mixing the organic layer was separated, washed twice with brine, dried (over sodium sulfate), filtered and concentrated in vacuo. The crude material was purified by normal phase flash chromatography using ethyl acetate and heptane as eluent to afford the title compound (2.95 g, yield 78%).

[0689] .sup.1H NMR (CDCl.sub.3): =4.20 (br s, 2H), 3.98 (t, 1H), 2.42 (br s, 2H), 2.28 (S, 3H), 1.98 (m, 4H), 1.64 (m, 2H) and 1.44 (s, 9H).

Step C: tert-Butyl (1R*,3R*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylate

[0690] ##STR00203##

[0691] To a solution of tert-butyl (1R*,3R*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.95 g, 10.3 mmol, 1.0 equiv.) in water (10.3 mL) and acetic acid (103 mL) was added N-chlorosuccinimide (4.1 g, 30.9 mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature for 1 hour and then concentrated to about 20-30 mL before the resulting solution was added dropwise to a solution of ammonium hydroxide (25 wt % in water; 400 mL) and after that stirred for to minutes at room temperature. The solution was then acidified with hydrochloric acid (aqueous, 1 M) to pH 7-8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound impure (387 mg, yield 12%) which was used without further purification.

[0692] .sup.1H NMR (CDCl.sub.3): =4.33 (br s, 2H), 3.11 (m, 1H), 2.00 (m, 4H), 1.82 (m, 2H), 1.64 (m, 2H) and 1.44 (s, 9H).

Step D: (1R*,3R*,5S*)-8-Azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride

[0693] ##STR00204##

[0694] To a solution of tert-butyl (1R*,3R*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylate (387 mg, 1.33 mmol, 1.0 equiv.) in dichloromethane (10 mL) was added hydrochloric acid (4 M in dioxane, 3.3 mL, 13.3 mmol, 10.0 equiv.). The solution was stirred at room temperature for 1.5 hours. Then the solvent was decanted and dichloromethane was added and then decanted again. This afforded the title compound impure (200 mg, yield 66%) which was used without purification.

[0695] .sup.1H NMR (DMSO-d.sub.6): =9.40 (br s, 1H), 9.20 (br s, 1H), 6.93 (br s, 2H), 4.01 (m, 2H), 3.32 (m, 1H), 2.18 (m, 1H), 1.98 (m, 6H) and 1.79 (m, 1H).

Step E: (1R*,3R*,5S*)-8-iso-Propyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

[0696] ##STR00205##

[0697] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R*,3R*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride and acetone. The crude compound was purified by normal phase flash chromatography using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent to afford the title compound (22 mg, yield 21%) in a non-homogeneous state, which was used without further purification.

[0698] .sup.1H NMR (DMSO-d.sub.6): =6.61 (s, 2H), 3.50 (s, 2H), 3.12 (m, 2H), 1.82 (m, 4H), 1.50 (m, 4H) and 0.97 (d, 6H).

Intermediate P37: 1-iso-Propylazetidine-3-sulfonamide

[0699] ##STR00206##

[0700] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide (Intermediate P33) and acetone, but no triethylamine was required. The title compound (12 mg, yield 6%) was used without purification.

[0701] .sup.1H NMR (DMSO-d.sub.6): =6.87 (br s, 2H), 3.82 (m, 1H), 3.39 (m, 2H), 3.23 (t, 2H), 2.32 (m, 1H) and 0.81 (d, 6H).

Intermediate P38: 1-Ethyl-[1,4-bipiperidine]-4-sulfonamide

[0702] ##STR00207##

[0703] A suspension of 4-piperidine sulfonamide hydrochloric acid (0.35 g, 1.6 mmol) in acetonitrile (14 mL) was stirred with triethylamine (0.17 g, 0.24 mL, 1.7 mmol) for 30 minutes. To this was added 1-ethyl-4-piperidone (0.21 g, 0.23 mL, 1.6 mmol) and sodium triacetoxy-borohydride (0.43 g, 2.0 mmol). The stirring was allowed to continue for 20 hours and then the solution concentrated in vacuo. The crude material was suspended in a few mL of dichloromethane/methanol/7 N ammonia in methanol (1:1:1) and purified by chromatography (40 g Silicycle SiO.sub.2 cartridge through a syringe filter eluting with 5-30% 3.5 N ammonia/methanol in dichloromethane) to afford the title compound (290 mg, yield 90%).

[0704] .sup.1H NMR (CD3OD): =3.09 (m, 4H), 2.88 (m, 1H), 2.52 (q, 2H), 2.40 (m, 1H), 2.27 (m, 2H), 2.15 (m, 4H), 1.84 (m, 4H), 1.64 (m, 2H) and 1.13 (t, 3H).

Intermediate P39: 1-Methylazetidine-3-sulfonamide

[0705] ##STR00208##

[0706] Prepared as described for 1-methylpyrrolidine-3-sulfonamide (Intermediate P27) from azetidine-3-sulfonamide (Intermediate P33) and formaldehyde. The crude compound was purified by normal phase flash chromatography on silicagel using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent to afford the title compound (24 mg, yield 16%).

[0707] .sup.1H NMR (CD.sub.3OD): =4.08 (m, 1H), 3.91 (t, 2H), 3.87 (t, 2H) and 2.54 (s, 3H).

Intermediate P40: 2-Ethyl-2-azaspiro[3.3]heptane-6-sulfonamide

Step A: tert-Butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0708] ##STR00209##

[0709] To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (2 g, 9.4 mmol) in dichloromethane (25 mL) was added triethylamine (2.6 mL, 18.8 mmol). The solution was cooled to 0 C. and a solution of methanesulfonylchloride (0.8 mL, 10.3 mmol) in dichloromethane (5 mL) was added dropwise. The mixture was stirred for 18 hours at room temperature and then washed with water and brine, dried (sodium sulfate), filtered and evaporated to afford the title compound (2.7 g, yield 100%) as a white solid.

[0710] .sup.1H NMR (CDCl.sub.3): =4.89 (m, 1H), 3.94 (s, 4H), 2.99 (s, 3H), 2.70 (m, 2H), 2.48 (m, 2H) and 1.44 (s, 9H).

Step B: tert-Butyl 6-(acetylthio)-2-azaspiro[3.3]heptane-2-carboxylate

[0711] ##STR00210##

[0712] To a solution of tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 3.4 mmol) in acetonitrile (10 mL) and dimethylformamide (40 mL) was added potassium thioacetate (1.57 g, 13.7 mmol). The reaction was heated to reflux for 18 hours and upon cooling was poured into water (200 mL) and ethyl acetate (100 mL). The mixture was separated and the water layer was extracted with ethyl acetate. The combined organic layers were washed with water (4) and brine, before being dried (sodium sulfate), filtered and evaporated in vacuo to afford the title compound (1 g, yield 100%) as a brown oil.

[0713] .sup.1H NMR (CDCl.sub.3): =3.96 (s, 2H), 3.90 (m, 1H), 3.86 (s, 2H), 2.65 (m, 2H), 2.27 (s, 3H), 2.18 (m, 2H) and 1.42 (s, 9H).

Step C: tert-Butyl 6-sulfamoyl-2-azaspiro[3.3]heptane-2-carboxylate

[0714] ##STR00211##

[0715] A mixture of tert-butyl 6-(acetylthio)-2-azaspiro[3.3]heptane-2-carboxylate (650 mg, 2.4 mmol), acetic acid (5 mL) and water (i mL) was cooled in ice/water. N-chloro succinimide (960 mg, 7.8 mmol) was added in portions over a 10 minute period. Then the reaction mixture was stirred at room temperature for 1 hour, before being poured into cold aqueous ammonium hydroxide (50 mL, 25%). The mixture was allowed to stir for 18 hours at room temperature, before the solvents were evaporated in vacuo and the residue was triturated in tetrahydrofuran and decanted. The combined tetrahydrofuran layers were evaporated and the residue was purified over silica, using dichloromethane/methanol (9:1) as the eluent. The title compound was obtained as a white foam (240 mg, yield 36%).

[0716] .sup.1H NMR (CDCl.sub.3): =4.87 (br s, 2H), 3.96 (s, 4H), 3.72 (m, 1H), 2.62 (m, 4H) and 1.44 (s, 9H).

Step D: 2-Azaspiro[3.3]heptane-6-sulfonamide

[0717] ##STR00212##

[0718] To a solution of tert-butyl 6-sulfamoyl-2-azaspiro[3.3]heptane-2-carboxylate (240 mg, 0.87 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.26 mL, 3.5 mmol). The reaction was stirred for 48 hours and the solvents were evaporated. The residue was dissolved in methanol and purified over Amberlite 410 ion exchange resin, to afford the title compound (100 mg, yield 67%) as a pale yellow oil.

[0719] .sup.1H NMR (CD.sub.3OD): =3.93 (s, 4H), 3.66 (m, 1H) and 2.64 (m, 4H).

Step E: 2-Ethyl-2-azaspiro[3.3]heptane-6-sulfonamide

[0720] ##STR00213##

[0721] Prepared following the procedure as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from ethyliodide and 2-azaspiro[3.3]heptane-6-sulfonamide. The crude material was purified by normal phase flash chromatography using ethyl acetate and methanol (9:1) as eluent to afford the product as a mixture with triethylamine salts. The crude product was dissolved in methanol and filtered over Amberlite 410. The solvent was evaporated to afford the title compound (8 mg, yield 15%).

[0722] .sup.1H NMR (CD.sub.3 OD): =3.67 (m, 1H), 3.24 (d, 4H), 2.50 (d, 4H), 2.43 (q, 2H) and 0.95 (t, 3H).

Intermediate P41: 1-(1-iso-Propylazetidin-3-yl)pyrrolidine-3-sulfonamide

Step A: 1-(Azetidin-3-yl)pyrrolidine-3-sulfonamide dihydrochloride

[0723] ##STR00214##

[0724] To a solution of tert-butyl 3-(3-sulfamoylpyrrolidin-1-yl)azetidine-1-carboxylate (726 mg, 2.38 mmol, 1.0 equiv.) in dichloromethane (24 mL) was added hydrochloric acid in dioxane (4 M, 6.0 mL, 23.8 mmol, 10.0 equiv.). The reaction mixture was stirred for 1.5 hours and then concentrated in vacuo to afford the title compound as a dihydrochloride salt (774 mg, 2.38 mmol, yield too %) which was used without purification.

[0725] .sup.1H NMR (DMSO-d.sub.6): =9.60 (br s, 1H), 9.17 (br s, 1H), 7.24 (s, 2H), 4.34 (m, 4H), 4.11 (m, 3H), 3.91 (m, 2H) and 2.23 (m, 4H).

Step B: 1-(1-iso-Propylazetidin-3-yl)pyrrolidine-3-sulfonamide

[0726] ##STR00215##

[0727] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 1-(azetidin-3-yl)pyrrolidine-3-sulfonamide dihydrochloride and acetone, but 2.5 equivalent of triethylamine was required. The crude compound was purified by normal phase flash chromatography using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent to afford the title compound (94 mg, yield 38%).

[0728] .sup.1H NMR (DMSO-d.sub.6): =6.91 (s, 2H), 3.58 (m, 1H), 3.24 (t, 2H), 2.98 (m, 1H), 2.90 (m, 3H), 2.52 (m, 2H), 2.38 (q, 1H), 2.21 (m, 1H), 2.01 (m, 2H) and 0.81 (d, 6H).

Intermediate P42: (1R*,3R*,5S*)-8-Ethyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

[0729] ##STR00216##

[0730] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from iodoethane and (1R,3R,5S)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride. The title compound (36 mg, yield 41%) was used without further purification.

[0731] .sup.1H NMR (DMSO-d.sub.6): =6.63 (br s, 2H), 3.97 (br s, 2H), 3.10 (q, 2H), 2.98 (br s, 1H), 2.58 (m, 2H), 2.30 (m, 2H), 2.11 (m, 4H) and 1.11 (m, 3H).

Intermediate P43: 1-Ethylazetidine-3-sulfonamide

[0732] ##STR00217##

[0733] Prepared as described for 1-ethylpiperidine-4-sulfonamide (Intermediate P6) from azetidine-3-sulfonamide (Intermediate P33) and ethyl iodide. This afforded the title compound impure (15 mg, yield 9%) which was used without further purification.

[0734] .sup.1H NMR (CD.sub.3OD): =4.11 (m, 1H), 3.81 (t, 2H), 3.62 (t, 2H), 2.74 (q, 2H) and 1.02 (t, 3H).

Intermediate P44: 1-(2,2,2-Trifluoroacetyl)pyrrolidine-3-sulfonamide

[0735] ##STR00218##

[0736] Prepared as described for 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) from pyrrolidine-3-sulfonamide and bis-trifluoroacetic anhydride. This afforded the title compound (72 mg, yield 36%) which was used without purification.

[0737] .sup.1H NMR (CD.sub.3OD): =4.08 (m, 1H), 3.91 (m, 3H), 3.63 (m, 1H), 2.45 (m, 1H) and 2.38 (m, 1H).

Intermediate P45: 1-(Cyclopropylmethyl)piperidine-3-sulfonamide

[0738] ##STR00219##

[0739] Prepared as described for 1-ethylpiperidine-3-sulfonamide (Intermediate P15) using piperidine-3-sulfonamide hydrochloride (0.5 g, 3.2 mmol) and iodomethyl-cyclopropane (0.29 mL, 0.58 g, 3.2 mmol) to afford the title compound (0.28 g, 1.26 mmol, yield 40%) after column purification.

[0740] .sup.1H NMR (CDCl.sub.3): =3.41 (br d, 1H), 3.31 (m, 1H), 2.96 (br d, 1H), 2.44 (t, 1H), 2.36 (d, 2H), 2.20 (m, 2H), 1.91 (m, 1H), 1.71 (m, 2H), 0.90 (m, 1H), 0.57 (m, 2H) and 0.15 (m, 2H).

Intermediate P46: 1-Methylpiperidine-3-sulfonamide

[0741] ##STR00220##

[0742] Prepared as described for 1-ethylpiperidine-3-sulfonamide (Intermediate P15) using piperidine-3-sulfonamide hydrochloride (0.5 g, 3.2 mmol) and methyl iodide (0.20 mL, 0.45 g, 3.2 mmol) to give the title compound (0.24 g, 1.35 mmol, yield 43%). The crude product was used without further purification.

[0743] .sup.1H NMR (CD.sub.3OD): =3.2-3.4 (m, 3H), 2.97 (br d, 1H), 2.45 (s, 3H), 2.38 (br t, 1H), 2.20 (m, 1H), 1.90 (br d, 1H) and 1.5-1.8 (m, 2H).

Intermediate P47: Benzyl 3-sulfamoylazetidine-1-carboxylate

[0744] ##STR00221##

[0745] To a stirred solution of benzyl 3-(chlorosulfonyl)azetidine-1-carboxylate (2.0 g, 6.9 mmol) in dichloromethane (30 mL) at 0 C. was added ammonia (7 N in methanol, 30 mL). The resultant mixture was stirred overnight, slowly warming to room temperature and then concentrated to a white solid, triturated with THF and the resulting title compound isolated as a white solid by filtration (yield 95%) and used without further purification.

[0746] .sup.1H NMR (CD.sub.3OD): =7.3 (m, 5H), 5.05 (d, 2H), 4.25 (m, 2H), 4.13 (m, 2H) and 2.47 (m, 1H).

Intermediate P48: N,N-Dimethyl-4-sulfamoylpiperidine-1-carboxamide

[0747] ##STR00222##

[0748] To a solution of carbonyldiimidazole (162 mg, 1.0 mmol) in acetonitrile (10 mL) was added dimethylamine hydrochloride (81 mg, 1.0 mmol) and the solution was stirred overnight at room temperature. Triethylamine (0.42 mL, 3.0 mmol, 3.0 equiv.) and piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol) were added to the suspension. The reaction mixture was stirred overnight and additional portions of carbonyldiimidazole (162 mg, 1.0 mmol), triethylamine (0.42 mL, 3.0 mmol, 3.0 equiv.) and 2 M dimethylamine in tetrahydrofuran (0.5 mL, 1.0 mmol) were added.

[0749] After stirring overnight, extra 2 M dimethylamine in tetrahydrofuran (2 mL, 4.0 mmol, 4.0 equiv.) was added. The reaction mixture was then stirred at room temperature for 3 days, before being transferred to a microwave vial and additional 2 M dimethylamine in tetrahydrofuran (2.0 mL, 4.0 mmol, 4.0 equiv.) added. The vial was heated to 50 C. overnight and then concentrated in vacuo. The crude was dissolved in methanol, coated on hydromatrix and then purified by normal phase flash chromatography using dichloromethane and a mixture of triethylamine and methanol (ratio 1:1) as eluent to afford the title compound (73 mg, yield 31%).

[0750] .sup.1H NMR (DMSO-d.sub.6): =6.72 (s, 2H), 3.60 (d, 2H), 2.98 (m, 1H), 2.72 (m, 8H), 1.94 (d, 2H), 1.52 (m, 2H).

Intermediate P49: 1-(1-Isopropyl-azetidin-3-yl)piperidine-4-sulfonamide

Step A: tert-Butyl 3-(4-sulfamoylpiperidin-1-yl)azetidine-1-carboxylate

[0751] ##STR00223##

[0752] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from piperidine-4-sulfonamide hydrochloride salt (0.35 g, 1.6 mmol) and 1-Boc-azetidinone (0.28 g, 1.6 mmol) using 2 equivalents of triethylamine. The crude compound was purified by normal phase flash chromatography using dichloromethane and a mixture of 3.5 M ammonia in methanol as eluent to afford the title compound as a white waxy solid (236 mg, yield 47%).

[0753] HPLC-MS: 100% (ELSD), M 319+1 (ACPI pos.)

[0754] .sup.1H NMR (Methanol-d4): =4.37 (s, 2H), 3.94 (dd, J=8.8, 7.2 Hz, 2H), 3.77 (dd, J=9.0, 5.3 Hz, 2H), 3.09 (tt, J=7.1, 5.3 Hz, 1H), 3.00-2.81 (m, 3H), 2.22-2.08 (m, 2H), 1.98-1.70 (m, 4H), 1.41 (s, 9H).

Step B: 1-(Azetidin-3-yl)piperidine-4-sulfonamide dihydrochloride

[0755] ##STR00224##

[0756] tert-Butyl 3-(4-sulfamoylpiperidin-1-yl)azetidine-1-carboxylate (0.23 g, 0.7 mmol) from step A was suspended in HCl in dioxane (4N, 9 mL, 36 mmol) and stirred for 20 hours at ambient temperature. The solvents were evaporated in vacuo and the residue stripped once with dioxane (25 mL) to afford the crude product (250 mg, quant. yield), which was used as is in the next step.

[0757] HPLC-MS: 97% (ELSD), M 291+1 (ACPI pos.)

[0758] .sup.1H NMR (Methanol-d4): =4.72-4.57 (m, 2H), 4.44-4.28 (m, 3H), 3.61 (d, J=11.7 Hz, 2H), 3.26 (dd, J=11.1, 4.2 Hz, 2H), 3.01 (s, 1H), 2.44 (dd, J=14.3, 3.1 Hz, 2H), 2.24 (t, 1H), 1.61 (s, 1H).

Step C: 1-(1-Isopropyl-azetidin-3-yl)piperidine-4-sulfonamide

[0759] ##STR00225##

[0760] Prepared following the procedure as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 1-(azetidin-3-yl)piperidine-4-sulfonamide dihydrochloride (100 mg, 0.31 mmol) from step B and acetone (0.03 mL, 22 mg, 0.39 mmol) to yield the title compound as a white solid (70 mg, yield 87%) after column chromatography.

[0761] HPLC-MS: 59+40% (ELSD) showed two peaks both have M 262+1 (ACPI pos.) .sup.1H NMR (Methanol-d4): =3.55 (t, J=6.5 Hz, 2H), 3.02-2.82 (m, 6H), 2.49 (h, J=6.2 Hz, 1H), 2.13 (ddd, J=12.0, 4.2, 2.2 Hz, 2H), 1.88 (dd, J=11.3, 2.1 Hz, 2H), 1.77 (qd, J=12.1, 3.5 Hz, 2H), 0.97 (d, J=6.3 Hz, 6H).

Intermediate P50: 2-Isopropyl-2-azaspiro[3.3]heptane-6-sulfonamide

[0762] ##STR00226##

[0763] To a solution of 2-azaspiro[3.3]heptane-6-sulfonamide (50 mg, 0.28 mmol) and acetone (25 mg, 0.43 mmol, 1.5 equiv.) in acetonitrile (5 mL) was added sodium triacetoxyborohydride (89 mg, 0.43 mmol, 1.5 equiv.). The reaction mixture was stirred for 18 hours at room temperature and then concentrated in vacuo. The crude material was dissolved in methanol and treated with Amberlite 410 ion exchange resin. The mixture was filtered and the methanol was evaporated. The residue was triturated in THF. The mixture was filtered and the THF was evaporated to afford the title compound (40 mg, yield 65%) which was used as such.

[0764] .sup.1H NMR (CD3OD): =3.71 (m, 1H), 3.25 (m, 4H), 2.53 (m, 4H), 2.33 (m, 1H), 0.93 (d, 6H).

Intermediate P51: 2-Methyl-2-azaspiro[3.3]heptane-6-sulfonamide

[0765] ##STR00227##

[0766] To a solution of 2-azaspiro[3.3]heptane-6-sulfonamide (50 mg, 0.28 mmol) and formaldehyde (32 L, 37% in water, 0.43 mmol, 1.5 equiv.) in acetonitrile (5 mL) was added sodium triacetoxyborohydride (90 mg, 0.43 mmol, 1.5 equiv.). The reaction mixture was stirred for 18 hours at room temperature and then concentrated in vacuo. The crude material was dissolved in methanol and treated with Amberlite 410 ion exchange resin. The mixture was filtered and the methanol was evaporated. The residue was triturated in THF. The mixture was filtered and the THF was evaporated to afford the title compound (40 mg, yield 74%) which was used as such.

[0767] .sup.1H NMR (CD.sub.3OD): =3.71 (m, 1H), 3.37-3.21 (m, 4H), 2.52 (m, 4H), 2.29 (s, 3H).

Intermediate P52: 1-(Pentan-3-yl)azetidine-3-sulfonamide

[0768] ##STR00228##

[0769] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 3-pentanone. The title compound (20 mg, yield 12%) was used without further purification.

[0770] .sup.1H NMR (DMSO-d6): =6.86 (s, 2H), 3.82 (m, 1H), 3.42 (t, 2H), 3.21 (t, 2H), 2.03 (m, 1H), 1.24 (m, 4H), 0.74 (m, 6H).

Intermediate P53: 1-Ethyl-1,2,3,4-tetrahydroquinoline-3-sulfonamide

[0771] ##STR00229##

[0772] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 1,2,3,4-tetrahydroquinoline-3-sulfonamide, acetone and acetic acid, but no triethylamine was required. The title compound (27 mg, yield 11%) was used without further purification. The expected iso-propyl analog was not isolated.

[0773] .sup.1H NMR (CDCl.sub.3): =7.09 (m, 2H), 6.70 (m, 2H), 4.52 (br s, 2H), 3.60 (m, 3H), 3.44 (m, 2H), 3.26 (m, 2H), 1.17 (t, 3H).

Intermediate P54: 1-(2,2,2-Trifluoroethyl)piperidine-4-sulfonamide

Step A: 1-(2,2,2-Trifluoroacetyl)piperidine-4-sulfonamide

[0774] ##STR00230##

[0775] A suspension of piperidine-4-sulfonamide hydrochloride salt (600 mg, 2.7 mmol) was stirred with triethylamine (0.75 mL, 0.54 g, 5.4 mmol) in acetonitrile (12 mL) for 30 minutes. To this slurry was added trifluoroacetic anhydride (0.38 mL, 0.57 g, 2.7 mmol) and the stirring continued for 20 hours. The mixture was concentrated in vacuo and the residue dissolved in methanol, then applied to a silica column (40 g) and eluted with 0-30% methanol in DCM to afford 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (182 mg, yield 26%), contaminated with a bistrifluoroacetylated byproduct. This was used for the next step as such. HPLC-MS: 76% (ELSD), M 260+1 (ACPI pos.).

[0776] HPLC-MS: 23% (ELSD), M 356+1 (ACPI pos.) for the bistrifluoroacetylated byproduct.

[0777] .sup.1H NMR (Methanol-d4): =7.39 (s, 1H), 4.64-4.47 (m, 1H), 4.10 (d, J=13.1 Hz, 1H), 3.51 (tt, J=11.4, 4.0 Hz, 1H), 3.22 (dt, J=12.6, 3.5 Hz, 2H), 2.87 (td, J=13.0, 2.9 Hz, 1H), 2.21 (ddt, J=20.3, 13.9, 3.2 Hz, 2H), 1.78 (ddtt, J=24.0, 16.4, 7.6, 4.4 Hz, 2H).

Step B: 1-(2,2,2-Trifluoroethyl)piperidine-4-sulfonamide

[0778] ##STR00231##

[0779] The 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide from step A (65 mg, 0.22 mmol) was dissolved in THF (3.25 mL) and cooled to 0 C. To this solution was added dropwise borane-DMS-adduct (94%, 9.9M, 0.10 mL, 1.01 mmol) at 0 C. and then the mixture was heated to reflux for 4 hours and subsequently allowed to cool to room temperature over the weekend. This mixture was quenched with MeOH until no gas evolution was visible anymore and then evaporated in vacuo and stripped twice with methanol. Drying in vacuo gave the crude product as a clear oil (with a slight DMS smell), which was purified by ISCO 5-30% MeOH (3.5N NH3) in DCM to afford the title compound (31 mg, yield 56%).

[0780] HPLC-MS: 100% (ELSD), M 246+1 (ACPI pos.)

[0781] .sup.1H NMR (Methanol-d4): =3.16-3.00 (m, 4H), 2.88 (tt, J=12.2, 3.8 Hz, 1H), 2.42 (td, J=12.0, 2.5 Hz, 2H), 2.08 (dt, J=13.1, 2.9 Hz, 2H), 1.80 (qd, J=12.4, 4.1 Hz, 2H), 1.17 (t, J=7.1 Hz, 1H), 1.00-0.81 (m, 1H).

Intermediate P55: (1R*,3S*,5S*)-8-iso-Propyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

Step A: tert-Butyl (1R*,3R*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0782] ##STR00232##

[0783] Prepared as described for tert-butyl (1R*,3S*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1] octane-8-carboxylate (intermediate P36 step A) from tert-butyl 3-endo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate to afford the title compound (3.3 g, yield 81%).

[0784] .sup.1H NMR (CDCl.sub.3): =5.02 (t, 1H), 4.21 (br s, 2H), 3.00 (s, 3H), 2.03 (m, 8H), 1.45 (s, 9H).

Step B: tert-Butyl (1R*,3S*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0785] ##STR00233##

[0786] Prepared as described for tert-butyl (1R*,3R*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate (intermediate P36 step B) from tert-butyl (1R*,3R*,5S*)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate to afford the title compound (1.65 g, yield 53%).

[0787] .sup.1H NMR (CDCl.sub.3): =4.19 (br s, 2H), 3.87 (m, 1H), 2.28 (s, 3H), 1.98 (m, 2H), 1.79 (d, 6H), 1.45 (s, 9H).

Step C: tert-Butyl (1R*,3S*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylate

[0788] ##STR00234##

[0789] Prepared as described for tert-butyl (1R*,3R*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylate (intermediate P36 step C) from tert-butyl (1R*,3S*,5S*)-3-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate, except that the crude title compound was purified by normal phase flash chromatography using heptane and ethyl acetate to afford the title compound (235 mg, yield 14%).

[0790] .sup.1H NMR (CDCl.sub.3): =4.50 (m, 2H), 3.11 (m, 1H), 2.03 (m, 4H), 1.68 (m, 4H), 1.46 (s, 9H).

Step D: (1R*,3S*,5S*)-8-Azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride

[0791] ##STR00235##

[0792] Prepared as described for (1R*,3R*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride (intermediate P36 step D) from tert-butyl (1R*,3S*,5S*)-3-sulfamoyl-8-azabicyclo[3.2.1]octane-8-carboxylate to afford the title compound (203 mg, quantitative yield).

[0793] .sup.1H NMR (DMSO-d6): =9.28 (s, 1H), 9.11 (s, 1H), 6.90 (s, 2H), 4.04 (m, 2H), 3.95 (s, 1H), 2.07 (m, 1H), 1.96 (m, 6H), 1.82 (d, 1H).

Step E: (1R*,3S*,5S*)-8-iso-Propyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

[0794] ##STR00236##

[0795] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R*,3S*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride, except that the crude compound was purified by normal phase flash chromatography using dichloromethane and a mixture of 7M ammonia in methanol to afford the title compound (15 mg, yield 16%), which was used without further purification.

[0796] .sup.1H NMR (CD3OD): =4.24 (m, 1H), 4.14 (m, 1H), 3.53 (m, 2H), 2.49 (m, 1H), 2.20 (m, 5H), 2.00 (m, 2H), 1.37 (d, 6H).

Intermediate P56: (1R*,3S*,5S*)-8-Ethyl-8-azabicyclo[3.2.1]octane-3-sulfonamide

[0797] ##STR00237##

[0798] Prepared as described for 1-ethylpiperidine-4-sulfonamide (intermediate P6) from (1R*,3S*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride to afford the title compound (30 mg, yield 34%), which was used without further purification.

[0799] .sup.1H NMR (CD3OD): =4.10 (m, 1H), 4.00 (m, 1H), 3.53 (m, 1H), 3.08 (m, 2H), 2.58 (m, 1H), 2.24 (m, 5H), 2.02 (m, 2H), 1.34 (m, 3H).

Intermediate P57: 1-Benzylazetidine-3-sulfonamide

[0800] ##STR00238##

[0801] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (intermediate P3) from azetidine-3-sulfonamide hydrochloride and benzyl bromide. The title compound (57 mg, yield 25%) was used without further purification.

[0802] .sup.1H NMR (DMSO-d6): =7.24 (m, 5H), 6.93 (s, 2H), 3.92 (m, 1H), 3.58 (s, 2H), 3.46 (t, 2H), 3.35 (m, 2H).

Intermediate P58: 1-(1-Ethylpiperidin-4-yl)azetidine-3-sulfonamide

[0803] ##STR00239##

[0804] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1-ethyl-4-piperidone. The title compound (111 mg, yield 44%) was used without further purification.

[0805] .sup.1H NMR (DMSO-d6): =6.88 (s, 2H), 3.85 (m, 1H), 3.42 (t, 2H), 3.22 (t, 2H), 2.71 (m, 2H), 2.27 (q, 2H), 2.02 (m, 1H), 1.87 (m, 2H), 1.57 (dd, 2H), 1.09 (m, 2H), 0.95 (t, 3H).

Intermediate P59: 1-Acetylazetidine-3-sulfonamide

[0806] ##STR00240##

[0807] Prepared as described for 1-acetylpiperidine-4-sulfonamide (Intermediate P7) from azetidine-3-sulfonamide hydrochloride. The title compound (31 mg, yield 20%) was used without further purification.

[0808] .sup.1H NMR (CD3OD): =4.57 (m, 1H), 4.50 (m, 2H), 4.36 (m, 2H), 1.98 (s, 3H).

Intermediate P60: 1-(Tetrahydro-2H-pyran-4-yl)azetidine-3-sulfonamide

[0809] ##STR00241##

[0810] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and tetrahydro-4H-pyran-4-one. The title compound (112 mg, yield 50%) was used without further purification.

[0811] .sup.1H NMR (DMSO-d6): =6.89 (s, 2H), 3.86 (m, 1H), 3.77 (dt, 2H), 3.44 (t, 2H), 3.24 (m, 3H), 2.98 (q, 1H), 2.26 (tq, 1H), 1.55 (dd, 2H), 1.11 (m, 2H).

Intermediate P61: 1-Propylazetidine-3-sulfonamide

[0812] ##STR00242##

[0813] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 1-bromopropane. The title compound (15 mg, yield 8%) was used without further purification.

[0814] .sup.1H NMR (DMSO-d6): =6.88 (s, 2H), 3.87 (m, 1H), 3.44 (t, 2H), 3.22 (t, 2H), 2.32 (t, 2H), 1.24 (m, 2H), 0.80 (t, 3H).

Intermediate P62: tert-Butyl 3-sulfamoylazetidine-1-carboxylate

Step A: tert-Butyl 3-(acetylthio)azetidine-1-carboxylate

[0815] ##STR00243##

[0816] To a solution of tert-butyl 3-iodoazetidine-1-carboxylate (17.2 g, 60.8 mmol, 1.O equiv.) and thioacetic acid (8.7 mL, 121.6 mmol, 2.0 equiv.) in dimethylformamide (83 mL) was added cesium carbonate (39.6 g, 121.6 mmol, 2.0 equiv.) portionwise. The reaction was exothermic during this addition. Then the reaction mixture was heated to 70 C. for 1 hour to afford complete conversion. The mixture was diluted with water (600 mL) and then extracted with diethyl ether (600 mL). The organic layer was washed twice with water (600 mL), once with brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude was submitted to normal phase flash chromatography on silica gel using heptane and ethyl acetate as eluent to afford the title compound (8.76 g, yield 62%).

[0817] .sup.1H NMR (CDCl.sub.3): =4.35 (t, 2H), 4.10 (m, 1H), 3.78 (dd, 2H), 2.28 (s, 3H), 1.39 (s, 9H).

Step B: tert-Butyl 3-(chlorosulfonyl)azetidine-1-carboxylate

[0818] ##STR00244##

[0819] To a solution of tert-butyl 3-(acetylthio)azetidine-1-carboxylate (8.76 g, 37.9 mmol, 1.0 equiv.) in water (38 mL) and acetic acid (380 mL) was added N-chlorosuccinimide (15.2 g, 113.7 mmol, 3.0 equiv.). The suspension was stirred for 20 minutes at room temperature to afford a clear solution and complete conversion. The reaction mixture was diluted with water (600 mL), and then extracted with dichloromethane (600 mL). The organic layer was washed twice with water (600 mL), once with brine (300 mL), dried over Na2SO4, filtered and then used as such for the following reaction without further concentrating the organic layer.

[0820] .sup.1H NMR (CDCl.sub.3): =4.57 (m, 1H), 4.38 (m, 4H), 1.42 (s, 9H).

Step C: tert-Butyl 3-sulfamoylazetidine-1-carboxylate

[0821] ##STR00245##

[0822] To a solution of tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (max 37.9 mmol) in dichloromethane (600 mL) was added 7M ammonia in methanol (55 mL, 379 mmol, to equiv.). The clear solution was stirred for half an hour at room temperature. The suspension was concentrated in vacuo. The crude was dissolved in methanol, coated on hydromatrix and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol as eluent to afford the tittle compound (2.67 g, 11.3 mmol, yield over two steps 30%).

[0823] .sup.1H NMR (DMSO-d6): =7.18 (s, 2H), 4.10 (m, 2H), 3.98 (m, 3H), 1.39 (s, 9H).

Intermediate P63: Methyl 2-(3-sulfamoylazetidin-1-yl)acetate

[0824] ##STR00246##

[0825] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and methyl bromoacetate. The title compound (43 mg, yield 21%) was used without further purification.

[0826] .sup.1H NMR (DMSO-d6): =6.92 (s, 2H), 3.92 (m, 1H), 3.58 (m, 5H), 3.41 (dd, 2H), 3.29 (s, 2H).

Intermediate P64: 1-Isopropyl-2-oxopyrrolidine-3-sulfonamide

Step A: 2-Bromo-4-chlorobutanoyl chloride

[0827] ##STR00247##

[0828] To a solution of 4-chlorobutanoyl chloride (25 g, 177.31 mmol, 1 eq) in DCM (45 mL) was added NBS (47.34 g, 265.97 mmol, 1.5 eq) and SOCl.sub.2 (1.05 g, 8.87 mmol, 643.13 L, 0.05 eq) followed by HBr (1.33 g, 6.58 mmol, 892.86 L, 40% purity, 0.037 eq) at 25 C. The mixture was stirred at 50 C. for 1.5 hours. The reaction mixture was diluted with hexane (300 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (35 g, crude), which was used in the next step without further purification.

[0829] .sup.1H NMR (CDCl.sub.3): =4.87-4.80 (m, 1H), 3.76-3.74 (m, 2H) and 2.59-2.44 (m, 2H).

Step B: 2-Bromo-4-chloro-N-isopropylbutanamide

[0830] ##STR00248##

[0831] To a solution of 2-bromo-4-chlorobutanoyl chloride (20 g, 90.95 mmol, 1 eq) in DCM (50 mL) was added propan-2-amine (6.45 g, 109.14 mmol, 9.38 mL, 1.2 eq) at 0 C. The mixture was warmed to 25 C. and stirred at 25 C. for another 1 hour. The reaction mixture was diluted with DCM (200 mL) and washed with water (100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (19.1 g, 78.75 mmol, yield 87%).

Step C: 3-Bromo-1-isopropylpyrrolidin-2-one

[0832] ##STR00249##

[0833] To a solution of 2-bromo-4-chloro-N-isopropylbutanamide (19 g, 78.34 mmol, 1 eq) in THF (200 mL) was added NaH (6.27 g, 156.67 mmol, 60% purity, 2 eq) at 0 C. The mixture was stirred at 25 C. for 1 hour. Then the reaction mixture was quenched with H.sub.2O (200 mL) and extracted with ethyl acetate (2300 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=20:1 to 1:1) to give the title compound (11.5 g, 55.80 mmol, yield 71%).

[0834] .sup.1H NMR (CDCl.sub.3): =4.41-4.31 (m, 2H), 3.46-3.43 (m, 1H), 3.32-3.29 (m, 1H), 2.55-2.49 (m, 1H), 2.32-2.30 (m, 1H) and 1.16-1.14 (m, 6H).

Step D: Methyl 3-((1-isopropyl-2-oxopyrrolidin-3-yl)sulfonyl)propanoate

[0835] ##STR00250##

[0836] To a solution of 3-bromo-1-isopropylpyrrolidin-2-one (1 g, 4.85 mmol, 1 eq) in DMSO (10 mL) was added sodium 3-methoxy-3-oxo-propane-1-sulfinate (845 mg, 4.85 mmol, 1 eq). The mixture was stirred at 25 C. for 16 hours. The reaction mixture was quenched with water (80 mL) and extracted with ethyl acetate (380 mL). The combined organic layers were washed with brine (60 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=10:1 to 1:1) to give the title compound (1.1 g, 3.97 mmol, yield 82%).

[0837] .sup.1H NMR (CDCl.sub.3): =4.37-4.33 (m, 1H), 3.97-3.93 (m, 1H), 3.82-3.72 (m, 5H), 3.58-3.51 (m, 1H), 3.39-3.38 (m, 1H), 2.94-2.90 (m, 2H), 2.77-2.73 (m, 1H), 2.44-2.34 (m, 1H) and 1.18 (d, 6H).

[0838] LCMS: m/z 277.9 (M+H).sup.+ (ES.sup.+).

Step E: Sodium 1-isopropyl-2-oxopyrrolidine-3-sulfinate

[0839] ##STR00251##

[0840] To a solution of methyl 3-((1-isopropyl-2-oxopyrrolidin-3-yl)sulfonyl)propanoate (0.6 g, 2.16 mmol, 1 eq) in a mixture of MeOH (4.8 mL) and THF (4.8 mL) was added a solution of NaOMe in MeOH (6.2 M, 1.05 mL, 3 eq) at 25 C. The mixture was stirred at 25 C. for 3 hours. Then the reaction mixture was concentrated in vacuo to give the title compound (461.3 mg, crude) as a brown solid, which was used in the next step without further purification.

[0841] .sup.1H NMR (CD.sub.3OD): =4.34-4.27 (m, 1H), 3.53-3.41 (m, 1H), 3.19-3.15 (m, 2H), 2.54-2.51 (m, 1H), 2.17-2.12 (m, 1H) and 1.19-1.14 (m, 6H).

[0842] LCMS: m/z 192.0 (M+H).sup.+ (ES.sup.+).

Step F: 1-Isopropyl-2-oxopyrrolidine-3-sulfonamide

[0843] ##STR00252##

[0844] To a solution of sodium 1-isopropyl-2-oxopyrrolidine-3-sulfinate (461 mg, 2.16 mmol, 1 eq) in DMSO (6 mL) was added a solution of (aminooxy)sulfonic acid (1.22 g, 10.82 mmol, 5 eq) and AcONa (709 mg, 8.65 mmol, 4 eq) in H.sub.2O (2 mL) at 0 C. The mixture was warmed to 25 C. and stirred at 25 C. for 16 hours. The reaction mixture was filtered and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (see Experimental Methods, Purification Method 2) to give the title compound (219.8 mg, 1.07 mmol, yield 49%, 100% purity) as white solid.

[0845] .sup.1H NMR (DMSO-d.sub.6): =6.92 (br s, 2H), 4.18-4.15 (m, 1H), 3.91-3.88 (m, 1H), 3.33-3.27 (m, 2H), 2.38-2.30 (m, 2H) and 1.10-1.03 (m, 6H).

[0846] LCMS: m/z 206.9 (M+H).sup.+ (ES.sup.+).

Intermediate P65: 1-(1-Acetylazetidin-3-yl)piperidine-4-sulfonamide

[0847] ##STR00253##

[0848] A suspension of 1-(azetidin-3-yl)piperidine-4-sulfonamide dihydrochloride salt (95%, 250 mg, 0.81 mmol) and triethylamine (0.23 mL, 164 mg, 1.63 mmol) in acetonitrile (10 mL) was stirred for 30 minutes. Acetic anhydride (0.08 mL, 87 mg, 0.85 mmol) was added to this slurry and the stirring was continued for 20 hours. The mixture was concentrated in vacuo and the residue dissolved in methanol, then applied to a silica column (40 g) and eluted with 0-30% methanol in DCM to afford the title compound (93 mg, yield 43%).

[0849] HPLC-MS: 100% (ELSD), M 261+1 (ACPI pos.)

[0850] .sup.1H NMR (DMSO-d6): =6.72 (s, 2H), 4.08 (t, J=7.8 Hz, 1H), 3.91 (dd, J=8.6, 5.1 Hz, 1H), 3.81 (dd, J=9.7, 7.2 Hz, 1H), 3.61 (dd, J=9.8, 5.1 Hz, 1H), 3.13-2.98 (m, 1H), 2.94-2.72 (m, 3H), 2.04-1.92 (m, 2H), 1.90-1.73 (m, 5H), 1.59 (qt, J=12.9, 3.5 Hz, 2H).

Intermediate P66: 1-(1-Methylazetidin-3-yl)piperidine-4-sulfonamide

[0851] ##STR00254##

[0852] A suspension of 1-(azetidin-3-yl)piperidine-4-sulfonamide dihydrochloride salt (95%, 200 mg, 0.65 mmol) and triethylamine (0.19 mL, 138 mg, 1.36 mmol) in acetonitrile (8 mL) was stirred for 30 minutes. A formalin solution (37% w/w, 15% methanol, 0.09 mL, 0.81 mmol) and sodium triacetoxyborohydride (1.25 eq., 178 mg, 0.81 mmol) were added to the resulting slurry portionwise. The stirring was continued for 20 hours at ambient temperature, then the mixture was concentrated in vacuo. The residue was dissolved in 3.5N ammonia in methanol and applied to a silica cartridge (40 g, silicycle). The title compound (65 mg, yield 38%) was isolated by elution with 0-30% gradient of 3.5N (ammonia/methanol) in DCM.

[0853] HPLC-MS: 100% (ELSD), M 233+1 (ACPI pos.)

[0854] .sup.1H NMR (DMSO-d6): =6.70 (s, 2H), 3.44 (s, 2H), 2.89-2.66 (m, 6H), 2.25 (s, 2H), 1.95 (dd, J=13.0, 3.5 Hz, 2H), 1.81-1.67 (m, 3H), 1.56 (qd, J=12.2, 3.9 Hz, 2H).

Intermediate P67: 1-(Pentan-3-yl)pyrrolidine-3-sulfonamide

[0855] ##STR00255##

[0856] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from pyrrolidine-3-sulfonamide and 3-pentanone, but no triethylamine was required. The title compound (143 mg, yield 64%) was used without further purification.

[0857] .sup.1H NMR (DMSO-d6): =6.80 (s, 2H), 3.53 (m, 1H), 2.90 (dd, 1H), 2.65 (m, 2H), 2.48 (m, 1H), 2.01 (m, 3H), 1.40 (m, 4H), 0.79 (m, 6H).

Intermediate P68: 1-(sec-Butyl)pyrrolidine-3-sulfonamide

[0858] ##STR00256##

[0859] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from pyrrolidine-3-sulfonamide and 2-butanone, but no triethylamine was required. The title compound (143 mg, yield 64%) was used without further purification.

[0860] .sup.1H NMR (CD3OD): =3.78 (m, 1H), 3.33 (m, 1H), 2.99 (m, 2H), 2.78 (m, 1H), 2.51 (m, 1H), 2.25 (q, 2H), 1.74 (m, 1H), 1.40 (m, 1H), 1.15 (dd, 3H), 0.93 (t, 3H).

Intermediate P69: 1-Butylazetidine-3-sulfonamide

[0861] ##STR00257##

[0862] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and butyraldehyde. The title compound (82 mg, yield 42%) was used without further purification.

[0863] .sup.1H NMR (DMSO-d6): =6.88 (s, 2H), 3.85 (m, 1H), 3.43 (t, 2H), 3.22 (m, 2H), 2.34 (t, 2H), 1.22 (m, 4H), 0.83 (t, 3H).

Intermediate P70: 1-(2-Hydroxy-2-methylpropyl)azetidine-3-sulfonamide

[0864] ##STR00258##

[0865] To a solution of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol, 1.0 equiv.) and potassium carbonate (691 mg, 5.0 mmol, 5.0 equiv.) in water (5 mL) and ethanol (5 mL) in a microwave vial (20 mL) was added 1,2-epoxy-2-methylpropane (88 L, 1.0 mmol, 1.0 equiv.). The reaction mixture was heated in the microwave at 110 C. for 30 minutes and then concentrated in vacuo. The crude material was suspended in methanol and filtered. The filtrate was coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (38 mg, yield 18%), which was used without further purification.

[0866] .sup.1H NMR (DMSO-d6): =6.86 (s, 2H), 4.03 (s, 1H), 3.88 (m, 1H), 3.54 (t, 2H), 3.36 (m, 2H), 2.31 (s, 2H), 1.00 (s, 6H).

Intermediate P71: 1-Cyclopropylazetidine-3-sulfonamide

[0867] ##STR00259##

[0868] Prepared as described for 1-cyclopropylpyrrolidine-3-sulfonamide (Intermediate P30) from azetidine-3-sulfonamide hydrochloride, except that the reaction was stirred for 3 days at room temperature and another 8 hours at 50 C. The title compound (47 mg, yield 26%) was used without further purification.

[0869] .sup.1H NMR (DMSO-d6): =6.92 (s, 2H), 3.84 (m, 1H), 3.50 (t, 2H), 3.40 (t, 2H), 1.94 (m, 1H), 0.32 (m, 2H), 0.19 (m, 2H).

Intermediate P72: 1-(1,3-Difluoropropan-2-yl)azetidine-3-sulfonamide

[0870] ##STR00260##

[0871] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1,3-difluoroacetone. The title compound (87 mg, yield 40%) was used without further purification.

[0872] .sup.1H NMR (DMSO-d6): =6.93 (s, 2H), 4.47 (m, 2H), 4.32 (m, 2H), 3.94 (m, 1H), 3.59 (t, 2H), 3.48 (t, 2H), 2.80 (m, 1H).

Intermediate P73: 1-(Cyanomethyl)azetidine-3-sulfonamide

[0873] ##STR00261##

Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and bromoacetonitrile. The title compound (47 mg, yield 26%) was used without further purification.

[0874] .sup.1H NMR (DMSO-d6): =6.98 (s, 2H), 3.91 (m, 1H), 3.62 (s, 2H), 3.53 (m, 4H).

Intermediate P74: 1-(2-Methoxyethyl)azetidine-3-sulfonamide

[0875] ##STR00262##

[0876] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 2-bromoethyl methyl ether. The title compound (38 mg, yield 20%) was used without further purification.

[0877] .sup.1H NMR (DMSO-d6): =6.89 (s, 2H), 3.87 (m, 1H), 3.47 (t, 2H), 3.32 (m, 2H), 3.25 (m, 2H), 3.18 (s, 3H), 2.54 (m, 2H).

Intermediate P75: 1-(Cyclohexylmethyl)azetidine-3-sulfonamide

[0878] ##STR00263##

[0879] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclohexanecarboxaldehyde. The title compound (202 mg, yield 86%) was used without further purification.

[0880] .sup.1H NMR (DMSO-d6): =6.87 (s, 2H), 3.86 (m, 1H), 3.44 (t, 2H), 3.22 (t, 2H), 2.21 (d, 2H), 1.63 (m, 5H), 1.14 (m, 4H), 0.81 (m, 2H).

Intermediate P76: 1-(Pyridin-3-ylmethyl)azetidine-3-sulfonamide

[0881] ##STR00264##

[0882] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and pyridin-3-aldehyde. The title compound (131 mg, yield 58%) was used without further purification.

[0883] .sup.1H NMR (DMSO-d6): =8.44 (m, 2H), 7.65 (dt, 1H), 7.32 (dd, 1H), 6.95 (s, 2H), 3.92 (m, 1H), 3.61 (s, 2H), 3.48 (t, 2H), 3.37 (m, 2H).

Intermediate P77: N,N-Dimethyl-2-(3-sulfamoylazetidin-1-yl)acetamide

[0884] ##STR00265##

[0885] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 2-chloro-N,N-dimethylacetamide, except that potassium iodide (0.5 equiv.) was added to the reaction mixture. The title compound (40 mg, yield 18%) was used without further purification.

[0886] .sup.1H NMR (DMSO-d6): =7.17 (s, 2H), 4.07 (m, 3H), 3.90 (m, 4H), 2.88 (s, 3H), 2.80 (s, 3H).

Intermediate P78: 1-(2-Chloroethyl)azetidine-3-sulfonamide

[0887] ##STR00266##

[0888] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and chloroacetaldehyde (50 wt % in H.sub.2O). The title compound (100 mg, yield 50%) was used without further purification.

[0889] .sup.1H NMR (DMSO-d6): =6.91 (s, 2H), 3.92 (m, 1H), 3.53 (m, 4H), 3.36 (t, 2H), 2.73 (t, 2H).

Intermediate P79: 1-Cyclobutylazetidine-3-sulfonamide

[0890] ##STR00267##

[0891] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclobutanone. The title compound (127 mg, yield 66%) was used without further purification.

[0892] .sup.1H NMR (DMSO-d6): =6.91 (s, 2H), 3.86 (m, 1H), 3.39 (t, 2H), 3.30 (m, 2H), 3.09 (q, 1H), 1.87 (m, 2H), 1.67 (m, 4H).

Intermediate P80: 1-Isopropyl-N,N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide

Step A: 4-Nitrobenzyl 2-(dimethylcarbamoyl)-4-sulfamoylpyrrolidine-1-carboxylate

[0893] ##STR00268##

[0894] A suspension of 4-nitrobenzyl 2-(dimethylcarbamoyl)-4-mercaptopyrrolidine-1-carboxylate (1 g, 2.83 mmol) in acetic acid (5 mL)/water (1 mL) was cooled in an ice-bath to 0 C. N-Chlorosuccinimide (1.13 g, 8.49 mmol, 3.0 equiv.) was added in portions over a 5 minute period. The mixture was allowed to stir for another hour at room temperature. The reaction was then poured into ammonia (50 mL, 25% solution in water). The resulting solution was stirred for 18 hours at room temperature. The solvents were evaporated and the residue was triturated with ethanol (50 mL). Sodium sulphate (15 g) was added and the mixture was filtered and evaporated. The residue was dissolved in methanol (50 mL) and Amberlite 400 (OH) (20 g) was added. After 18 hours stirring, the mixture was filtered and evaporated to afford the title compound (610 mg, yield 54%) as an oil that crystallized upon standing.

[0895] .sup.1H NMR (CD.sub.3OD): =8.20 (m, 2H), 7.62 (d, 1H), 7.53 (d, 1H), 5.26 (d, 2H), 4.08-3.66 (m, 4H), 3.00 (m, 6H), 2.12 (m, 2H).

Step B: N,N-Dimethyl-4-sulfamoylpyrrolidine-2-carboxamide

[0896] ##STR00269##

[0897] 4-Nitrobenzyl 2-(dimethylcarbamoyl)-4-sulfamoylpyrrolidine-1-carboxylate (61 mg, 1.53 mmol) was dissolved in methanol (10 mL). Palladium (47 mg, 10% on charcoal) was added and the mixture was stirred for 18 hours under a hydrogen atmosphere (balloon). The mixture was filtered over Celite and evaporated. The residue was purified by reversed phase silica to yield white solids (0.5 g), which were triturated with THF. The THF layer was decanted and evaporated to afford the title compound (350 mg, yield 100%) as a white solid.

[0898] .sup.1H NMR (CD.sub.3OD): =3.79-3.55 (m, 4H), 3.00 (m, 6H), 1.90 (m, 2H).

Step C: 1-Isopropyl-N,N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide

[0899] ##STR00270##

[0900] N,N-Dimethyl-4-sulfamoylpyrrolidine-2-carboxamide (84 mg, 0.38 mmol) was dissolved in acetonitrile (10 mL). Acetone (90 mg, 1.5 mmol) was added followed by sodium triacetoxyborohydride. After 18 hours stirring at room temperature, the solvents were evaporated and the residue was purified over silica to afford the title compound (10 mg, yield to %) as an oil.

[0901] .sup.1H NMR (CD.sub.3OD): =3.92 (t, 1H), 3.73 (m, 1H), 3.46 (dd, 1H), 3.18 (s, 3H), 3.05 (m, 1H), 2.95 (s, 3H), 2.88 (m, 1H), 2.57 (m, 1H), 2.14 (m, 1H), 1.08 (d, 3H), 1.03 (d, 3H).

Intermediate P81: 1-Ethyl-5-oxopyrrolidine-3-sulfonamide

[0902] ##STR00271##

[0903] 1-Ethyl-5-oxopyrrolidine-3-sulfonyl chloride (15 mg, 0.71 mmol) was dissolved in THF (3 mL) and added dropwise to ammonia (25% solution in water, 5 mL) at 4 C. After 18 hours stirring at room temperature, the solvents were evaporated. The residue was triturated in THF. The THF layer was decanted and evaporated to afford the title compound (30 mg, yield 22%) as a brown oil.

[0904] .sup.1H NMR (CD.sub.3OD): =3.80 (m, 2H), 3.34 (m, 3H), 2.78 (m, 2H), 1.13 (t, 3H).

Intermediate P82: 1-(tert-Butyl)azetidine-3-sulfonamide

Step A: 1-(tert-Butyl)azetidin-3-yl methanesulfonate

[0905] ##STR00272##

[0906] To a suspension of N-tert-butyl-3-hydroxyazetidine hydrochloride (1.0 g, 6.0 mmol) in dichloromethane (30 mL) was added N,N-diisopropylethylamine (2.4 mL, 13.8 mmol, 2.5 equiv.). After stirring for 20 minutes at room temperature, the clear solution was cooled to 0 C. and mesyl chloride (0.5 mL, 6.6 mmol, 1.1 equiv.) was added dropwise.

[0907] The reaction mixture was stirred for 1 hour, while allowing to warm up to room temperature. Then the solvent was removed by evaporation in vacuo. The crude product was dissolved in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (456 mg, yield 37%).

[0908] .sup.1H NMR (CDCl.sub.3): =5.10 (m, 1H), 3.74 (m, 2H), 3.47 (m, 2H), 3.02 (s, 3H), 1.04 (s, 9H).

Step B: S-(1-(tert-Butyl)azetidin-3-yl) ethanethioate

[0909] ##STR00273##

[0910] To a solution of 1-(tert-butyl)azetidin-3-yl methanesulfonate (269 mg, 1.3 mmol) in acetonitrile (20 mL) was added potassium thioacetate (447 mg, 3.9 mmol, 3 equiv.). The reaction mixture was stirred overnight at room temperature, and then for another 7 hours at 50 C. The solvent was removed by evaporation in vacuo. The crude product was dissolved in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (90 mg, yield 37%).

[0911] .sup.1H NMR (CDCl.sub.3): =4.15 (m, 1H), 3.80 (m, 2H), 3.30 (m, 2H), 2.31 (s, 3H), 1.03 (s, 9H).

Step C: 1-(tert-Butyl)azetidine-3-sulfonamide

[0912] ##STR00274##

[0913] To a suspension of N-chlorosuccinimide (200 mg, 1.5 mmol, 3 equiv.) in acetonitrile (2.0 mL) was added hydrochloric acid (aqueous, 2 M, 0.2 mL, 0.38 mmol, 0.8 equiv.). The solution was cooled in an ice-bath, after which a solution of S-(1-(tert-butyl)azetidin-3-yl) ethanethioate (90 mg, 0.48 mmol, 1.0 equiv.) in acetonitrile (1.o mL) was added and the ice-bath was removed. The reaction mixture was stirred for 1 hour and then added dropwise to a solution of ammonia in methanol (7 M, 50 mL, 350 mmol, 729 equiv.). The mixture was stirred for 30 minutes and then concentrated in vacuo. The crude product was dissolved in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (11 mg, yield to %).

[0914] .sup.1H NMR (CD.sub.3OD): =3.97 (m, 1H), 3.68 (m, 2H), 3.51 (m, 2H), 1.02 (S, 9H).

Intermediate P83: 1-(Cyclopropylmethyl)azetidine-3-sulfonamide

[0915] ##STR00275##

[0916] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclopropane carboxaldehyde. The crude product was dissolved in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (180 mg, yield 94%) which was used without further purification.

[0917] .sup.1H NMR (DMSO-d.sub.6): =6.90 (s, 2H), 3.90 (m, 1H), 3.49 (t, 2H), 3.30 (t, 2H), 2.26 (d, 2H), 0.69 (m, 1H), 0.37 (m, 2H), 0.07 (m, 2H).

Intermediate P84: 1-Isobutylazetidine-3-sulfonamide

[0918] ##STR00276##

[0919] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and isobutyraldehyde. The title compound (138 mg, yield 71%) was used without further purification.

[0920] .sup.1H NMR (DMSO-d.sub.6): =6.88 (s, 2H), 3.88 (m, 1H), 3.46 (t, 2H), 3.23 (m, 2H), 2.18 (d, 2H), 1.47 (m, 1H), 0.80 (d, 6H).

Intermediate P85: 1-(2-Azidoethyl)azetidine-3-sulfonamide

[0921] ##STR00277##

[0922] To a solution of 1-(2-chloroethyl)azetidine-3-sulfonamide (45 mg, 0.22 mmol, 1.0 equiv.) in acetonitrile (5 mL) was added sodium azide (14 mg, 0.22 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature over the weekend. Extra sodium azide (56 mg, 0.88 mmol, 4.0 equiv.) was added and the reaction mixture was heated to 50 C. After stirring overnight, water (0.4 mL) was added and the reaction mixture was stirred for 2 more days. The solution was concentrated in vacuo. The residue was suspended in methanol, filtered and the filtrate was concentrated in vacuo to afford the crude title compound (45 mg, 0.22 mmol, quantitative yield). The crude title compound was used without further purification.

[0923] .sup.1H NMR (DMSO-d.sub.6): =6.93 (s, 2H), 3.92 (m, 1H), 3.53 (t, 2H), 3.34 (m, 2H), 3.21 (dd, 2H), 2.59 (dd, 2H).

Intermediate P86: 1-(2,2,2-Trifluoroethyl)azetidine-3-sulfonamide

[0924] ##STR00278##

[0925] To a suspension of azetidine-3-sulfonamide hydrochloride (333 mg, 1.92 mmol) and triethylamine (0.67 mL, 4.8 mmol, 2.5 equiv.) in acetonitrile (20 mL) was added trifluoroacetic anhydride (0.24 mL, 1.73 mmol, 0.9 equiv.). After stirring for 4 hours at room temperature, the reaction mixture was concentrated in vacuo. The crude intermediate 1-(2,2,2-trifluoroacetyl)azetidine-3-sulfonamide was dissolved in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol. The impure intermediate (max 1.92 mmol) was dissolved in tetrahydrofuran (20 mL) and then cooled to 0 C. To this solution, borane dimethyl sulfide (0.85 mL, 9.0 mmol, 4.5 equiv.) was added dropwise. The reaction mixture was refluxed overnight, and then cooled to room temperature. Methanol was added to the reaction mixture until no more gas evolution was observed and then the reaction mixture was concentrated in vacuo. The crude product was dissolved in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (20 mg, yield 5%). The title compound was used without further purification.

[0926] .sup.1H NMR (DMSO-d.sub.6): =7.07 (s, 2H), 4.24-4.08 (m, 1H), 3.65 (t, 2H), 3.52 (dd, 2H), 3.31-3.16 (m, 2H).

Intermediate P87: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)azetidine-3-sulfonamide

[0927] ##STR00279##

[0928] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (intermediate P3) from azetidine-3-sulfonamide hydrochloride and (2-bromoethoxy)-tert-butyldimethylsilane. The title compound (44 mg, yield 16%) was used without further purification.

[0929] .sup.1H NMR (DMSO-d.sub.6): =6.89 (s, 2H), 3.88 (q, 1H), 3.50 (m, 4H), 3.31 (m, 2H), 0.84 (s, 9H), 0.01 (s, 6H).

Intermediate P88: 1-Cyclohexylazetidine-3-sulfonamide

[0930] ##STR00280##

[0931] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclohexanone. The title compound (218 mg, quantitative yield) was used without further purification.

[0932] .sup.1H NMR (DMSO-d6): =6.86 (s, 2H), 3.83 (p, 1H), 3.41 (t, 2H), 3.21 (dd, 2H), 2.00 (m, 1H), 1.59 (m, 6H), 1.15 (q, 2H), 0.93 (m, 2H).

Intermediate P89: 1-Cyclopentylazetidine-3-sulfonamide

[0933] ##STR00281##

[0934] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclopentanone. The title compound (204 mg, quantitative yield) was used without further purification.

[0935] .sup.1H NMR (DMSO-d.sub.6): =6.86 (s, 2H), 3.82 (m, 1H), 3.41 (t, 2H), 3.18 (m, 2H), 2.72 (m, 1H), 1.49 (m, 6H), 1.24 (m, 2H).

Intermediate P90: 1-(1-Iminoethyl)azetidine-3-sulfonamide

[0936] ##STR00282##

[0937] To a suspension of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol, 1.0 equiv.) and triethylamine (0.49 mL, 3.5 mmol, 3.5 equiv.) in acetonitrile (10 mL) was added ethyl acetimidate hydrochloride (123 mg, 1.0 mmol, 1.0 equiv.). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude compound (approx. 300 mg) was dissolved in water/methanol (ratio 1:1) (3 mL). 1 mL of this solution was purified by reversed phase flash chromatography to afford the title compound (30 mg, yield 9%).

[0938] .sup.1H NMR (DMSO-d.sub.6): =10.25 (s, 1H), 7.41 (s, 2H), 4.61 (dd, 1H), 4.44 (m, 2H), 4.21 (m, 2H), 2.08 (s, 3H).

Intermediate P91: 1-(Oxetan-3-ylmethyl)azetidine-3-sulfonamide

[0939] ##STR00283##

[0940] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 3-oxetanecarboxaldehyde. The title compound (156 mg, yield 75%) was used without further purification.

[0941] .sup.1H NMR (DMSO-d.sub.6): =6.91 (s, 2H), 4.57 (dd, 2H), 4.22 (t, 2H), 3.90 (m, 1H), 3.47 (t, 2H), 3.28 (m, 2H), 2.90 (m, 1H), 2.68 (d, 2H).

Intermediate P92: 1-(2-(Dimethylamino)ethyl)azetidine-3-sulfonamide

[0942] ##STR00284##

[0943] To a solution of 1-(cyanomethyl)azetidine-3-sulfonamide (220 mg, 1.25 mmol) in tetrahydrofuran (15 mL), cooled to 0 C., was added borane dimethyl sulfide (0.16 mL, 1.63 mmol, 1.3 equiv.). The reaction mixture was refluxed overnight, and then quenched with methanol. The solution was concentrated in vacuo. The crude intermediate was suspended in acetonitrile (20 mL) and formaldehyde (37% in water stabilized with methanol, 186 L, 2.5 mmol, 2.1 equiv.) followed by sodium triacetoxyborohydride (688 mg, 3.25 mmol, 2.6 equiv.) was added. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude product was dissolved in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (28 mg, yield 14%).

[0944] .sup.1H NMR (CD.sub.3OD): =4.02 (m, 1H), 3.67 (m, 2H), 3.55 (m, 2H), 2.74 (dt, 4H), 2.56 (s, 6H).

Intermediate P93: 1-(Pyridin-4-ylmethyl)azetidine-3-sulfonamide

[0945] ##STR00285##

[0946] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 4-pyridinecarboxaldehyde. The title compound (130 mg, yield 57%) was used without further purification.

[0947] .sup.1H NMR (DMSO-d.sub.6): =8.47 (d, 2H), 7.26 (d, 2H), 6.97 (s, 2H), 3.94 (m, 1H), 3.64 (s, 2H), 3.52 (t, 2H), 3.39 (t, 2H).

Intermediate P94: 1-(Pyridin-2-ylmethyl)azetidine-3-sulfonamide

[0948] ##STR00286##

[0949] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 2-pyridinecarboxaldehyde. The title compound (196 mg, yield 86%) was used without further purification.

[0950] .sup.1H NMR (DMSO-d.sub.6): =8.46 (dd, 1H), 7.73 (td, 1H), 7.32 (d, 1H), 7.24 (m, 1H), 6.95 (s, 2H), 3.94 (tt, 1H), 3.70 (s, 2H), 3.55 (t, 2H), 3.44 (t, 2H).

Intermediate P95: 1-((2-Bromopyridin-3-yl)methyl)azetidine-3-sulfonamide

[0951] ##STR00287##

[0952] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 2-bromo-3-pyridinecarboxaldehyde. The title compound (137 mg, yield 45%) was used without further purification.

[0953] .sup.1H NMR (DMSO-d.sub.6): =8.27 (dd, 1H), 7.79 (dd, 1H), 7.44 (dd, 1H), 7.02 (S, 2H), 3.97 (m, 1H), 3.67 (s, 2H), 3.61 (t, 2H), 3.49 (dd, 2H).

Intermediate P96: tert-butyl 3-sulfamoyl-[1,3-biazetidine]-1-carboxylate

[0954] ##STR00288##

[0955] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and tert-butyl-3-oxoazetidine-1-carboxylate. The title compound (350 mg, yield 24%) was used without further purification.

[0956] .sup.1H NMR (DMSO-d.sub.6): =6.95 (s, 2H), 3.92 (m, 1H), 3.80 (t, 2H), 3.57 (d, 2H), 3.48 (t, 2H), 3.36 (m, 3H), 1.35 (s, 9H).

Intermediate P97: 1-Methyl-[1,3-biazetidine]-3-sulfonamide

Step A: [1,3-Biazetidine]-3-sulfonamide dihydrochloride

[0957] ##STR00289##

[0958] To a solution of tert-butyl 3-sulfamoyl-[1,3-biazetidine]-1-carboxylate (intermediate P96; 315 mg, 1.08 mmol) in dichloromethane (10 mL) was added 4M hydrochloric acid in dioxane (2.7 mL, 10.8 mmol). After stirring for 2 hours at room temperature, the reaction mixture was concentrated in vacuo to afford the title compound (285 mg, quantitative yield), which was used without further purification.

[0959] .sup.1H NMR (DMSO-d.sub.6): =9.50 (bs, 1H), 9.18 (bs, 1H), 7.42 (s, 2H), 4.57-4.31 (m, 3H), 4.31-4.00 (m, 8H).

Step B: 1-Methyl-[1,3-biazetidine]-3-sulfonamide

[0960] ##STR00290##

[0961] Prepared as described for 1-methylazetidine-3-sulfonamide (intermediate P39) from [1,3-biazetidine]-3-sulfonamide dihydrochloride. The title compound (63 mg, yield 61%) was used without further purification.

[0962] .sup.1H NMR (CD.sub.3OD): =4.10-3.94 (m, 1H), 3.75-3.60 (m, 4H), 3.59-3.51 (m, 2H), 3.51-3.44 (m, 1H), 3.41-3.32 (m, 2H), 2.55 (s, 3H).

Intermediate P98: 1-(2-(Methylthio)ethyl)azetidine-3-sulfonamide

[0963] ##STR00291##

[0964] To a solution of 0.5M hydrochloric acid in water (6.0 mL, 3.0 mmol) was added (methylthio)acetaldehyde dimethyl acetal (0.4 mL, 3.0 mmol). After heating the reaction for 1 hour at 50 C., the reaction mixture was cooled to room temperature and then extracted with dichloromethane (10 mL). The organic layer was added to a suspension of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol) and triethylamine (0.17 mL, 1.2 mmol) in acetonitrile. After that, sodium triacetoxyborohydride (265 mg, 1.25 mmol) was added. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude product was dissolved in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (89 mg, yield 42%).

[0965] .sup.1H NMR (DMSO-d.sub.6): =6.91 (s, 2H), 3.89 (p, 1H), 3.49 (t, 2H), 3.33-3.25 (m, 2H), 2.59 (dd, 2H), 2.37 (dd, 2H), 2.03 (s, 3H).

Intermediate P99: 1-(2-Fluoroethyl)azetidine-3-sulfonamide

[0966] ##STR00292##

[0967] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 1-bromo-2-fluoroethane. The title compound (yield 10%) was used without further purification.

[0968] .sup.1H NMR (DMSO-d.sub.6): =6.91 (s, 2H), 4.44 (t, 1H), 4.29 (t, 1H), 3.90 (q, 1H), 3.53 (t, 2H), 3.36 (t, 2H), 2.79-2.69 (m, 1H), 2.64 (t, 1H).

Intermediate P100: 1-(Thietan-3-yl)azetidine-3-sulfonamide

[0969] ##STR00293##

[0970] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and thietan-3-one. The title compound (54 mg, yield 26%) was used without further purification.

[0971] .sup.1H NMR (DMSO-d.sub.6): =6.95 (s, 2H), 3.98-3.83 (m, 2H), 3.43 (P, 4H), 3.19 (t, 2H), 2.97 (t, 2H).

Intermediate P101: 1-(2-(3-(But-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)azetidine-3-sulfonamide

[0972] ##STR00294##

[0973] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and (3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-diazirine (0.8 equiv.) except that a more diluted solution was used (0.02 M solution). The title compound (yield 10%) was used without further purification.

[0974] .sup.1H NMR (CD.sub.3OD): =4.09-3.92 (m, 1H), 3.61 (td, 2H), 3.47-3.35 (m, 2H), 2.37 (dd, 2H), 2.27 (t, 1H), 2.02 (td, 2H), 1.60 (t, 2H), 1.51-1.39 (m, 2H).

Intermediate P102: tert-Butyl (Z)-(((tert-butoxycarbonyl)amino)(3-sulfamoylazetidin-1-yl) methylene)carbamate

[0975] ##STR00295##

[0976] To a suspension of azetidine-3-sulfonamide hydrochloride (172 mg, 1.0 mmol), triethylamine (0.49 mmol, 3.5 mmol) and 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (290 mg, 1.0 mmol) in acetonitrile (10 mL) was added mercury dichloride (271 mg, 1.0 mmol). After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (216 mg, yield 57%).

[0977] .sup.1H NMR (DMSO-d.sub.6): =10.24 (s, 1H), 7.16 (s, 2H), 4.41-3.94 (m, 5H), 1.41 (s, 9H), 1.35 (s, 9H).

Intermediate P103: 1-(3-Methylcyclobutyl)azetidine-3-sulfonamide

[0978] ##STR00296##

[0979] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 3-methylcyclobutan-1-one. The title compound (79 mg, yield 39%) was used without further purification.

[0980] .sup.1H NMR (DMSO-d.sub.6): =6.88 (s, 2H), 3.84 (td, 1H), 3.44-3.18 (m, 4H), 2.92 (m, 1H), 2.10-1.96 (m, 1H), 1.91-1.78 (m, 2H), 1.59-1.45 (m, 1H), 1.39-1.24 (m, 1H), 1.00 (S, 3H).

Intermediate P104: 1-(3,3-Dimethylcyclobutyl)azetidine-3-sulfonamide

[0981] ##STR00297##

[0982] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 3,3-dimethylcyclobutan-1-one. The title compound (96 mg, yield 44%) was used without further purification.

[0983] .sup.1H NMR (DMSO-d.sub.6): =6.88 (s, 2H), 3.84 (m, 1H), 3.34 (t, 2H), 3.29-3.19 (m, 2H), 3.08 (dq, 1H), 1.77-1.62 (m, 2H), 1.58-1.43 (m, 2H), 1.03 (td, 6H).

Intermediate P105: 1-(Pyrimidin-5-ylmethyl)azetidine-3-sulfonamide

[0984] ##STR00298##

[0985] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and pyrimidine-5-carboxyaldehyde. The title compound (98 mg, yield 43%) was used without further purification.

[0986] .sup.1H NMR (DMSO-d.sub.6): =9.07 (s, 1H), 8.69 (s, 2H), 6.96 (s, 2H), 3.93 (m, 1H), 3.64 (s, 2H), 3.52 (t, 2H), 3.40 (t, 2H).

Intermediate P106: 1-(Tetrahydrofuran-3-yl)azetidine-3-sulfonamide

[0987] ##STR00299##

[0988] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and tetrahydrofuran-3-one. The title compound (31 mg, yield 15%) was used without further purification.

[0989] .sup.1H NMR (DMSO-d.sub.6): =6.90 (s, 2H), 3.86 (m, 1H), 3.70-3.54 (m, 2H), 3.54-3.34 (m, 4H), 3.29-3.19 (m, 2H), 3.08-2.98 (m, 1H), 1.83-1.67 (m, 1H), 1.62-1.49 (m, 1H).

Intermediate P107: 1-(sec-Butyl)azetidine-3-sulfonamide

[0990] ##STR00300##

[0991] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 2-butanone. The title compound (191 mg, yield 85%) was used without further purification.

[0992] .sup.1H NMR (DMSO-d.sub.6): =6.87 (s, 2H), 3.81 (m, 1H), 3.41 (td, 2H), 3.21 (t, 2H), 2.45-2.34 (m, 1H), 2.18-2.03 (m, 1H), 1.42-1.25 (m, 1H), 1.01 (t, 3H), 0.78 (d, 3H).

Intermediate P108: 1-((1-Methyl-1H-imidazol-2-yl)methyl)azetidine-3-sulfonamide

[0993] ##STR00301##

[0994] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1-methylimidazole-2-carbaldehyde. The title compound (144 mg, yield 63%) was used without further purification.

[0995] .sup.1H NMR (DMSO-d.sub.6): =7.03 (d, 1H), 6.91 (s, 2H), 6.71 (d, 1H), 3.96-3.80 (m, 1H), 3.61 (s, 2H), 3.57 (s, 3H), 3.45 (t, 2H), 3.37 (dd, 2H).

Intermediate P109: 1-(2,2-Dimethylcyclobutyl)azetidine-3-sulfonamide

[0996] ##STR00302##

[0997] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 2,2-dimethylcyclobutanone. The title compound (24 mg, yield 11%) was used without further purification.

[0998] .sup.1H NMR (DMSO-d.sub.6): =6.87 (s, 2H), 3.90 (p, 1H), 3.40 (dd, 2H), 3.20 (dt, 2H), 2.57 (d, 1H), 1.86-1.72 (m, 1H), 1.56-1.33 (m, 3H), 1.00 (s, 3H), 0.92 (s, 3H).

Intermediate P110: tert-Butyl (E)-(((tert-butoxycarbonyl)imino)(3-sulfamoylazetidin-1-yl)methyl)(methyl)carbamate

Step A: 1-Methyl-1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea

[0999] ##STR00303##

[1000] A solution of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (435 mg, 1.5 mmol) in dimethylformamide (5 mL) was cooled to 0 C. in a cooling bath and then sodium hydride (60% dispersion in mineral oil, 72 mg, 1.8 mmol) was added. The cooling bath was removed. After stirring for 1 hour at room temperature, methyl iodide (0.19 mL, 3.0 mmol) was added. After stirring overnight, the reaction mixture was poured into water and then extracted once with dichloromethane and once with ethyl acetate. The organic layers were combined, washed twice with water, once with brine, dried over sodium sulphate, filtered and then concentrated in vacuo to afford the title compound (230 mg, yield 50%), which was used without further purification.

[1001] .sup.1H NMR (CDCl.sub.3): =3.12 (s, 3H), 2.39 (s, 3H), 1.51 (s, 9H), 1.48 (s, 9H).

Step B: tert-Butyl (E)-(((tert-butoxycarbonyl)imino)(3-sulfamoylazetidin-1-yl) methyl)(methyl)carbamate

[1002] ##STR00304##

[1003] Prepared as described for tert-butyl (Z)-(((tert-butoxycarbonyl)amino)(3-sulfamoylazetidin-1-yl)methylene)carbamate (Intermediate P102) from 1-methyl-1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea, except that after stirring over the weekend, water was added to the reaction mixture. The mixture was extracted three times with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (48 mg, yield 16%).

[1004] .sup.1H NMR (DMSO-d.sub.6): =7.23 (s, 2H), 4.20 (bs, 1H), 4.09 (P, 4H), 2.84 (s, 3H), 1.41 (s, 9H), 1.36 (s, 9H).

Intermediate P111: 1-(Cyclobutylmethyl)azetidine-3-sulfonamide

[1005] ##STR00305##

[1006] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and cyclobutane carboxaldehyde. The title compound (145 mg, yield 11%) was used without further purification.

[1007] .sup.1H NMR (DMSO-d.sub.6): =6.88 (s, 2H), 3.87 (m, 1H), 3.43 (t, 2H), 3.29-3.18 (m, 2H), 2.39 (d, 2H), 2.22 (dt, 1H), 1.98-1.85 (m, 2H), 1.77 (m, 2H), 1.67-1.49 (m, 2H).

Intermediate P112: 1-(2-(Hydroxyimino)propyl)azetidine-3-sulfonamide

Step A: 1-(2-Oxopropyl)azetidine-3-sulfonamide

[1008] ##STR00306##

[1009] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and chloroacetone to afford the title compound (125 mg, yield 21%).

[1010] .sup.1H NMR (CD.sub.3OD): =4.06 (m, 1H), 3.75 (td, 2H), 3.60-3.49 (m, 4H), 2.07 (s, 3H).

Step B: 1-(2-(Hydroxyimino)propyl)azetidine-3-sulfonamide

[1011] ##STR00307##

[1012] A solution of 1-(2-oxopropyl)azetidine-3-sulfonamide (138 mg, 0.72 mmol) and 7M ammonia in methanol (4.1 mL, 28.7 mmol) was cooled to 0 C. and then hydroxylamine-O-sulfonic acid (81 mg, 0.72 mmol) was added. After stirring for 3 hours, the reaction mixture was filtered over cotton and the residue was washed extensively with methanol. The filtrates were combined and then concentrated in vacuo. The residue was dissolved in methanol (10 mL) and then triethylamine (0.1 mL, 0.72 mmol) was added. The mixture was cooled in an ice bath and iodine (183 mg, 0.72 mmol) was added in small portions. After stirring for 5 minutes, the mixture was concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (18 mg, yield 12%).

[1013] .sup.1H NMR (CD.sub.3OD): =4.16-4.01 (m, 1H), 3.82-3.72 (m, 2H), 3.60 (dd, 2H), 3.33 (p, 2H), 1.85 (s, 3H).

Intermediate P113: 1-(1-Hydroxypropan-2-yl)azetidine-3-sulfonamide

[1014] ##STR00308##

[1015] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and hydroxyacetone. The title compound (36 mg, yield 18%) was used without further purification.

[1016] .sup.1H NMR (DMSO-d.sub.6): =6.85 (s, 2H), 4.41 (t, 1H), 3.83 (t, 1H), 3.45 (dt, 2H), 3.27-3.17 (m, 3H), 3.05 (dd, 2H), 0.78 (d, 3H).

Intermediate P114: 1-(1,1-Difluoropropan-2-yl)azetidine-3-sulfonamide

[1017] ##STR00309##

[1018] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1,1-difluoroacetone. The title compound (81 mg, yield 38%) was used without further purification.

[1019] .sup.1H NMR (DMSO-d.sub.6): =6.93 (s, 2H), 5.73 (td, 1H), 3.90 (m, 1H), 3.55 (q, 2H), 3.44 (dd, J 2H), 2.68-2.57 (m, 1H), 0.90 (d, 3H).

Intermediate P115: 1-Allylazetidine-3-sulfonamide

[1020] ##STR00310##

[1021] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and allylbromide to afford the title compound (56 mg, yield 32%).

[1022] .sup.1H NMR (DMSO-d.sub.6): =6.90 (s, 2H), 5.77-5.57 (m, 1H), 5.22-4.96 (m, 2H), 3.96-3.82 (m, 1H), 3.44 (t, 2H), 3.31-3.22 (m, 2H), 3.01 (dt, 2H).

Intermediate P116: 1-(Prop-2-yn-1-yl)azetidine-3-sulfonamide

[1023] ##STR00311##

[1024] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and propargyl bromide (80 wt % in toluene) to afford the title compound (21 mg, yield 15%).

[1025] .sup.1H NMR (DMSO-d.sub.6): =6.91 (s, 2H), 3.86 (m, 1H), 3.43 (dt, 4H), 3.20 (d, 2H), 3.16-3.12 (m, 1H).

Intermediate P117: 1-(3-Hydroxypropyl)azetidine-3-sulfonamide

[1026] ##STR00312##

[1027] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 3-bromo-1-propanol to afford the title compound (60 mg, yield 38%).

[1028] .sup.1H NMR (DMSO-d.sub.6): =6.91 (s, 2H), 3.89 (m, 1H), 3.49 (t, 2H), 3.37 (t, 2H), 3.32-3.24 (m, 2H), 2.47-2.41 (m, 2H), 1.39 (p, 2H).

Intermediate P118: 1-Neopentylazetidine-3-sulfonamide

[1029] ##STR00313##

[1030] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and pivalaldehyde. The title compound (71 mg, yield 35%) was used without further purification.

[1031] .sup.1H NMR (DMSO-d.sub.6): =6.90 (s, 2H), 3.92 (m, 1H), 3.57 (t, 2H), 3.39-3.29 (m, 2H), 2.20 (s, 2H), 0.80 (s, 9H).

Intermediate P119: 1-((Trimethylsilyl)methyl)azetidine-3-sulfonamide

[1032] ##STR00314##

[1033] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and (iodomethyl)trimethylsilane to afford the title compound (60 mg, yield 33%).

[1034] .sup.1H NMR (DMSO-d.sub.6): =6.92 (s, 2H), 3.89 (t, 1H), 3.61 (bs, 2H), 3.31 (bs, 2H), 2.07 (s, 2H), 0.01 (s, 9H).

Intermediate P120: 1-(2-Hydroxypropyl)azetidine-3-sulfonamide

[1035] ##STR00315##

[1036] To a solution of 1-(2-oxopropyl)azetidine-3-sulfonamide (Intermediate P112 step A, 125 mg, 0.65 mmol) in methanol (10 mL) was added sodium borohydride (29 mg, 0.78 mmol). After stirring for 4 hours at room temperature, more sodium borohydride (7.4 mg, 0.2 mmol) was added. After stirring overnight, the reaction mixture was quenched with water (1.0 mL) and then concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (11 mg, yield 8%).

[1037] .sup.1H NMR (CD.sub.3OD): =4.09-3.96 (m, 1H), 3.77-3.64 (m, 3H), 3.61-3.48 (m, 2H), 2.55-2.44 (m, 2H), 1.12 (d, 3H).

Intermediate P121: 1-(4-Hydroxybutyl)azetidine-3-sulfonamide

[1038] ##STR00316##

[1039] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3) from azetidine-3-sulfonamide hydrochloride and 4-bromo-1-butanol to afford the title compound (41 mg, yield 20%).

[1040] .sup.1H NMR (DMSO-d.sub.6): =6.98 (s, 2H), 3.93 (m, 1H), 3.57 (t, 2H), 3.36 (t, 4H), 3.16 (d, 1H), 2.50-2.42 (m, 2H), 1.47-1.21 (m, 4H).

Intermediate P122: 1-(2-(3-Methyl-3H-diazirin-3-yl)ethyl)azetidine-3-sulfonamide

Step A: 2-(3-Methyl-3H-diazirin-3-yl)ethan-1-ol

[1041] ##STR00317##

[1042] To cooled liquid ammonia (78 C., 30 mL) was added 4-hydroxy-2-butanone (5.3 mL, 60.5 mmol). The solution was stirred at 40 C. for 4 hours, and then cooled back to 78 C. To the cooled mixture was added dropwise a solution of hydroxylamine-O-sulfonic acid (7.6 g, 67 mmol) in methanol (60 mL). The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. The suspension was filtered and the residue was washed with methanol extensively. The filtrates were combined and concentrated in vacuo to about 100 mL, and then degassed by passing nitrogen through the filtrates for 20 minutes. The solution was cooled in an ice bath and then triethylamine (7.5 mL, 53.8 mmol) was added followed by iodine (5.0 g, 19.7 mmol). After stirring for 1 hour, another batch of iodine (4.0 g, 15.8 mmol) was added. After 5 minutes, the reaction mixture was concentrated in vacuo to about 100 mL, then brine was added. The aqueous solution was extracted three times with diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated in vacuo. Vacuum distillation (90 C., 10.sup.2 mbar) provided the title compound as a yellow oil (226 mg, yield 3%).

[1043] .sup.1H NMR (CDCl.sub.3): =3.53 (t, 2H), 1.73 (s, 1H), 1.64 (t, 2H), 1.07 (s, 3H).

Step B: 2-(3-Methyl-3H-diazirin-3-yl)ethyl methanesulfonate

[1044] ##STR00318##

[1045] A solution of 2-(3-methyl-3H-diazirin-3-yl)ethan-1-ol (100 mg, 1.0 mmol) and triethylamine (160 L, 1.15 mmol) in dichloromethane (5 mL) was cooled in an ice bath. To the cooled solution was added methanesulfonyl chloride (93 L, 1.2 mmol). The reaction mixture was stirred for 1.5 hours in the ice bath, then saturated ammonium chloride was added and the organic layer was separated. The aqueous layer was extracted once with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated in vacuo to afford the title compound (178 mg, quantitative yield) which was used without further purification.

[1046] .sup.1H NMR (CDCl.sub.3): =4.13 (t, 2H), 3.05 (s, 3H), 1.79 (t, 2H), 1.09 (s, 3H).

Step C: 1-(2-(3-Methyl-3H-diazirin-3-yl)ethyl)azetidine-3-sulfonamide

[1047] ##STR00319##

[1048] To a solution of 2-(3-methyl-3H-diazirin-3-yl)ethyl methanesulfonate (178 mg, 1.0 mmol) in acetonitrile (20 mL) was added azetidine-3-sulfonamide hydrochloride (344 mg, 2.0 mmol) and then potassium carbonate (1.1 g, 8.0 mmol). The reaction mixture was stirred overnight at 55 C., and then potassium iodide (158 mg, 1.0 mmol) and N,N-dimethylformamide (2 mL) were added. The reaction mixture was stirred for 6 hours at 60 C., then filtered over a glass filter. The residue was washed with methanol. The filtrates were combined and concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (16 mg, yield 7%).

[1049] .sup.1H NMR (DMSO-d.sub.6): =6.90 (s, 2H), 3.92-3.82 (m, 1H), 3.44 (t, 2H), 3.21 (t, 2H), 2.27 (t, 2H), 1.25 (t, 2H), 0.97 (s, 3H).

Intermediate P123: 1-((1-Methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl) azetidine-3-sulfonamide

[1050] ##STR00320##

[1051] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde. The title compound (116 mg, yield 62%) was used without further purification.

[1052] .sup.1H NMR (DMSO-d.sub.6): =7.54 (s, 1H), 7.29 (d, 1H), 6.93 (s, 2H), 6.32 (d, 1H), 3.97-3.79 (m, 1H), 3.43 (t, 2H), 3.37 (s, 3H), 3.31-3.24 (m, 4H).

Intermediate P124: 1-((1-Methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl) azetidine-3-sulfonamide

[1053] ##STR00321##

[1054] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 1-methyl-2-oxo-1,2-dihydropyridine-4-carbaldehyde. The title compound (51 mg, yield 27%) was used without further purification.

[1055] .sup.1H NMR (DMSO-d.sub.6): =7.57 (d, 1H), 6.98 (s, 2H), 6.23 (s, 1H), 6.07 (d, 1H), 4.00-3.79 (m, 1H), 3.49 (t, 2H), 3.42 (s, 3H), 3.40-3.33 (m, 4H).

Intermediate P125: 1-(2-(Tetrahydrofuran-3-yl)ethyl)azetidine-3-sulfonamide

[1056] ##STR00322##

[1057] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and 2-(oxolan-3-yl)acetaldehyde. The title compound (90 mg, yield 27%) was used without further purification.

[1058] .sup.1H NMR (DMSO-d.sub.6): =6.93 (s, 2H), 3.90 (m, 1H), 3.75 (t, 1H), 3.68 (dt, 1H), 3.59 (q, 1H), 3.47 (t, 2H), 3.26 (t, 3H), 2.45-2.33 (m, 2H), 2.09 (m, 1H), 2.00-1.86 (m, 1H), 1.42 (dt, 1H), 1.30 (q, 2H).

Intermediate P126: 1-((Tetrahydrofuran-3-yl)methyl)azetidine-3-sulfonamide

[1059] ##STR00323##

[1060] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from azetidine-3-sulfonamide hydrochloride and tetrahydrofuran-3-carbaldehyde. The title compound (85 mg, yield 39%) was used without further purification.

[1061] .sup.1H NMR (CD.sub.3OD): =4.06 (t, 1H), 3.88-3.66 (m, 5H), 3.59 (t, 2H), 3.43 (dd, 1H), 2.66 (d, 2H), 2.35-2.22 (m, 1H), 2.12-1.97 (m, 1H), 1.65-1.52 (m, 1H).

Intermediate P127: 1-((Tetrahydrofuran-2-yl)methyl)azetidine-3-sulfonamide

[1062] ##STR00324##

[1063] To a solution of (tetrahydrofuran-2-yl)methanol (291 L, 3.00 mmol) in dichloromethane (30 mL) was added Dess-Martin periodinane (1.40 g, 3.30 mmol). The reaction mixture was stirred at room temperature. After stirring for 1 hour, the solution was washed once with saturated sodium bicarbonate. To the organic solution was added acetonitrile (10 mL), azetidine-3-sulfonamide hydrochloride (172 mg, 1.00 mmol), triethylamine (0.17 mL, 1.20 mmol), and then sodium triacetoxyborohydride (265 mg, 1.25 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (77 mg, yield 35%).

[1064] .sup.1H NMR (DMSO-d.sub.6): =6.90 (s, 2H), 3.90 (m, 1H), 3.69 (q, 2H), 3.60-3.46 (m, 3 H), 3.43-3.33 (m, 2H), 2.44 (d, 2H), 1.89-1.68 (m, 3H), 1.47 (q, 1H).

Intermediate P128: (1R,3R,5S)-8-(1-Methylazetidin-3-yl)-8-azabicyclo[3.2.1] octane-3-sulfonamide

Step A: tert-Butyl 3-((1R,3R,5S)-3-sulfamoyl-8-azabicyclo[3.2.1]octan-8-yl)azetidine-1-carboxylate

[1065] ##STR00325##

[1066] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R*,3R*,5S*)-8-azabicyclo[3.2.1]octane-3-sulfonamide hydrochloride and 1-Boc-3-azetidinone. The title compound (286 mg, yield 41%) was used without further purification.

[1067] .sup.1H NMR (DMSO-d.sub.6): =6.62 (s, 2H), 3.82 (s, 2H), 3.49 (s, 2H), 3.20-3.04 (m, 4H), 2.36-2.18 (m, 2H), 1.85-1.74 (m, 2H), 1.72-1.64 (m, 2H), 1.58 (dd, 2H), 1.35 (s, 9H).

Step B: (1R,3R,5S)-8-(Azetidin-3-yl)-8-azabicyclo[3.2.1]octane-3-sulfonamide dihydrochloride

[1068] ##STR00326##

[1069] To a solution of tert-butyl 3-((1R,3R,5S)-3-sulfamoyl-8-azabicyclo[3.2.1]octan-8-yl)azetidine-1-carboxylate (286 mg, 0.83 mmol) in dichloromethane (10 mL) was added hydrochloric acid (4 M in dioxane, 2.1 mL, 8.3 mmol). After stirring for 2 hours, the reaction mixture was concentrated in vacuo to afford the tittle compound (237 mg, yield 89%), which was used without further purification.

[1070] .sup.1H NMR (DMSO-d.sub.6): =9.86 (bs, 1H), 9.01 (bs, 1H), 6.95 (d, J=6.1 Hz, 2H), 4.46 (bs, 2H), 4.21-3.84 (m, 6H), 3.42-3.25 (m, 1H), 2.83 (bs, 2H), 2.30 (t, 2H), 2.20-1.97 (m, 4H).

Step C: (1R,3R,5S)-8-(1-Methylazetidin-3-yl)-8-azabicyclo[3.2.1]octane-3-sulfonamide

[1071] ##STR00327##

[1072] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from (1R,3R,5S)-8-(azetidin-3-yl)-8-azabicyclo[3.2.1]octane-3-sulfonamide dihydrochloride and formaldehyde (37 wt % in water). The title compound (37 mg, yield 35%) was used without further purification.

[1073] .sup.1H NMR (CD.sub.3OD): =4.15 (bs, 3H), 3.92 (bs, 3H), 2.93 (s, 3H), 2.61-2.39 (m, 2H), 2.03-1.89 (m, 4H), 1.89-1.63 (m, 4H).

Intermediate P129: 4-Methoxy-1-methylpyrrolidine-3-sulfonamide

Step A: Benzyl 3-methoxy-4-sulfamoylpyrrolidine-1-carboxylate

[1074] ##STR00328##

[1075] To a solution of ammonia in methanol (7M, 42 mL) was added dropwise a solution of benzyl 3-(chlorosulfonyl)-4-methoxypyrrolidine-1-carboxylate (500 mg, 1.49 mmol) in dichloromethane (10 mL). After stirring for 1.5 hours at room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and then washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and then concentrated in vacuo to afford the title compound (236 mg, yield 50%).

[1076] .sup.1H NMR (DMSO-d.sub.6): =7.43-7.28 (m, 5H), 7.21 (S, 2H), 5.08 (s, 2H), 4.24 (bs, 1H), 3.82-3.64 (m, 3H), 3.66-3.55 (m, 1H), 3.46 (d, 1H), 3.29 (s, 3H).

Step B: 4-Methoxypyrrolidine-3-sulfonamide

[1077] ##STR00329##

[1078] Prepared as described for azetidine-3-sulfonamide (Intermediate P33) from benzyl 3-methoxy-4-sulfamoylpyrrolidine-1-carboxylate to afford the title compound (91 mg, yield 67%) which was used without further purification.

[1079] .sup.1H NMR (DMSO-d.sub.6): =6.98 (s, 2H), 4.08 (dt, 1H), 3.76-3.62 (m, 1H), 3.56-3.33 (m, 3H), 3.30-3.15 (m, 3H), 2.99 (dd, 1H), 2.83 (t, 1H).

Step C: 4-Methoxy-1-methylpyrrolidine-3-sulfonamide

[1080] ##STR00330##

[1081] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 4-methoxypyrrolidine-3-sulfonamide and formaldehyde (37 wt % in water). The title compound (mixture of diastereomers, 17 mg, yield 35%) was used without further purification.

[1082] .sup.1H NMR (CD.sub.3OD) of the major diastereomer: 6=4.21-4.11 (m, 1H), 3.65 (td, 1H), 3.40-3.35 (m, 2H), 3.27-3.18 (m, 1H), 2.90 (d, 1H), 2.81 (dd, 1H), 2.70-2.52 (m, 2H), 2.35 (s, 3H).

Intermediate P130: 1-Ethyl-4-methoxypyrrolidine-3-sulfonamide

[1083] ##STR00331##

[1084] Prepared as described for 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) from 4-methoxypyrrolidine-3-sulfonamide and acetaldehyde. The title compound (mixture of diastereomers, 12 mg, yield 23%) was used without further purification.

[1085] .sup.1H NMR (CD.sub.3OD) of the major diastereomer: 6=4.18 (d, 1H), 3.75-3.56 (m, 1H), 3.38 (s, 3H), 3.13-2.94 (m, 2H), 2.72 (dd, 2H), 2.66-2.50 (m, 2H), 1.14 (dd, 3H).

Intermediate P131: 1-(Oxetan-3-yl)azetidine-3-sulfonamide

[1086] ##STR00332##

[1087] To a solution of azetidine-3-sulfonamide (22 mg, 0.16 mmol) in methanol (5 mL) was added oxetan-3-one (23 mg, 0.32 mmol) and 2 drops of acetic acid. Next, sodium cyanoborohydride (20 mg, 0.32 mmol) was added. The reaction mixture was stirred for 18 hours at room temperature. Then the solvents were evaporated to afford the crude title compound (80 mg) as an oil, which was used without further purification.

[1088] NMR data of the crude product was very complex. LCMS showed the desired mass.

[1089] LCMS: m/z 193 (M+H).sup.+ (ES.sup.+); 191 (MH) (ES.sup.).

Intermediate P132: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

Step A: 6-Chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

[1090] ##STR00333##

[1091] Bis(4-methoxybenzyl)amine (3.71 g, 14.4 mmol) was added to a solution of 2-chloropyridine-5-sulfonyl chloride (3.00 g, 13.7 mmol) and triethylamine (2.49 mL, 17.8 mmol) in DCM (50 mL) at 0 C. The reaction was stirred at 0 C. for 15 minutes and then allowed to warm up to room temperature and stirred for 20 hours. Then the reaction mixture was diluted with DCM (150 mL), washed with a saturated aqueous NH.sub.4Cl solution (340 mL) and brine (40 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give the crude product as a cream solid. The crude product was triturated with TBME (70 mL), filtered and rinsed with TBME (240 mL) to afford the title compound (4.97 g, 83%) as an off-white solid.

[1092] .sup.1H NMR (DMSO-d6) 8.76 (dd, J=2.6, 0.7 Hz, 1H), 8.19 (dd, J=8.4, 2.6 Hz, 1H), 7.69 (dd, J=8.4, 0.7 Hz, 1H), 7.08-7.02 (m, 4H), 6.83-6.76 (m, 4H), 4.29 (s, 4H), 3.71 (s, 6H).

[1093] LCMS: m/z 433.3 (M+H).sup.+ (ES.sup.+).

Step B: 6-Hydroxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

[1094] ##STR00334##

[1095] A suspension of 6-chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (0.508 g, 1.17 mmol) in ethane-1,2-diol (10 mL) was treated with 2 M KOH (aq) (2.4 mL, 4.80 mmol). The resultant suspension was stirred at 140 C. for 18 hours. Then the reaction mixture was treated with further 2 M KOH (aq) (0.6 mL, 1.2 mmol, 1 eq) and heated at 140 C. for another 6 hours, and further 2 M KOH (aq) (0.6 mL, 1.2 mmol, 1 eq) and heated at 140 C. for another 18 hours. Then the reaction mixture was diluted with water (40 mL) and DCM (30 mL). Brine (5 mL) was added and the organic layer was collected. The aqueous phase was extracted with DCM (530 mL). The combined organic extracts were washed with water (10 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was dried under reduced pressure at 50 C. overnight to afford the title compound (542 mg, 100%).

[1096] .sup.1H NMR (DMSO-d6) 12.17 (S, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.63 (dd, J=9.6, 2.9 Hz, 1H), 7.11-7.02 (m, 4H), 6.87-6.79 (m, 4H), 6.37 (d, J=9.6 Hz, 1H), 4.21 (s, 4H), 3.72 (s, 6H).

[1097] LCMS: m/z 415.4 (M+H).sup.+ (ES.sup.+), 413.4 (MH).sup. (ES.sup.).

Step C: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide and 6-isopropoxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

[1098] ##STR00335##

[1099] Sodium hydride (60 wt % dispersion in mineral oil) (36 mg, 0.91 mmol) was added to a mixture of 6-hydroxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (0.40 g, 0.869 mmol) and lithium bromide (0.154 g, 1.737 mmol) in DME:DMF (5 mL, 4:1) at 0 C.

[1100] The mixture was stirred at 0 C. for 10 minutes and then at room temperature for a further 10 minutes. Then 2-iodopropane (0.10 mL, 1.04 mmol) was added and the mixture was stirred at room temperature for 46 hours. The reaction mixture was heated to 65 C. for 17 hours, cooled to room temperature and quenched with saturated aqueous NH.sub.4Cl (5 mL) and diluted with EtOAc (100 mL). The organic layer was washed with water (15 mL) and brine (315 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-100% EtOAc/isohexane) to afford 1-isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.28 g, 70%) as a white solid and 6-isopropoxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (0.11 g, 27%).

1-Isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1101] .sup.1H NMR (CDCl.sub.3) 7.91 (d, J=2.7 Hz, 1H), 7.41 (dd, J=9.6, 2.6 Hz, 1H), 7.09-7.04 (m, 4H), 6.84-6.79 (m, 4H), 6.54 (dd, J=9.6, 0.5 Hz, 1H), 5.17 (sept, J=6.8 Hz, 1H), 4.26 (s, 4H), 3.79 (s, 6H), 1.34 (d, J=6.8 Hz, 6H).

[1102] LCMS: m/z 457.4 (M+H).sup.+ (ES.sup.+).

6-Isopropoxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

[1103] .sup.1H NMR (CDCl.sub.3) 8.60-8.55 (m, 1H), 7.84-7.79 (m, 1H), 7.06-6.99 (m, 4H), 6.81-6.75 (m, 4H), 6.72-6.67 (m, 1H), 5.43-5.33 (m, 1H), 4.26 (s, 4H), 3.78 (s, 6H), 1.37 (d, J=6.2 Hz, 6H).

[1104] LCMS: m/z 457.4 (M+H).sup.+ (ES.sup.+).

Step D: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1105] ##STR00336##

[1106] TFA (0.43 ml, 5.64 mmol) was added to a solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.26 g, 0.564 mmol) in DCM (3 mL) at room temperature and the mixture was stirred for 66 hours. Then the reaction was concentrated in vacuo and the residue was redissolved in DCM (5 mL). The product was purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford the title compound (60 mg, 49%) as a white solid.

[1107] LCMS: m/z 217.3 (M+H).sup.+ (ES.sup.+).

Intermediate P133: 4-Isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide

Step A: 2-(Benzylthio)-5-chloropyrazine

[1108] ##STR00337##

[1109] To a solution of NaH (0.755 g, 18.88 mmol) in THF (55 mL) was added benzyl mercaptan (1.5 mL, 12.68 mmol) at 0 C. The reaction mixture was diluted with THF (20 mL) and stirred at 0 C. for 10 minutes. Then a solution of 2,5-dichloropyrazine (1.370 mL, 13.42 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 0 C. for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0 C., MeOH (1 mL) was added carefully and stirred for 5 minutes. Water (20 mL), then DCM (150 mL) was added and the biphasic mixture was passed through a phase separator. The organic phase was concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-3% EtOAc/isohexane) to afford the title compound (2.373 g, 72%) as a clear yellow oil.

[1110] .sup.1H NMR (DMSO-d6) 8.68 (d, J=1.5 Hz, 1H), 8.49 (d, J=1.5 Hz, 1H), 7.43-7.39 (m, 2H), 7.34-7.29 (m, 2H), 7.28-7.23 (m, 1H), 4.46 (s, 2H).

Step B: 5-Chloro-N,N-bis(4-methoxybenzyl)pyrazine-2-sulfonamide

[1111] ##STR00338##

[1112] A solution of 2-(benzylthio)-5-chloropyrazine (0.916 g, 3.87 mmol) in DCM (15 mL, 233 mmol) was treated with water (1.5 mL) and the resultant suspension was cooled to between 5 and 0 C. Sulfuryl chloride (2.2 mL, 26.2 mmol) was added and the reaction mixture was stirred for 2 hours maintaining the temperature between 5 and 0 C. A slurry of ice/water (10 mL) was added and the organic phase was collected. The aqueous phase was extracted with DCM (210 mL) and the combined organic extracts were dried (MgSO.sub.4) and concentrated in vacuo to afford crude intermediate 5-chloropyrazine-2-sulfonyl chloride as a pale yellow liquid (1.198 g).

[1113] A suspension of bis(4-methoxybenzyl)amine hydrochloride (1.198 g, 4.08 mmol) and TEA (1.2 mL, 8.61 mmol) in DCM (15 mL) at 0 C. was treated with a solution of 5-chloropyrazine-2-sulfonyl chloride (0.824 g, 3.87 mmol) in DCM (5 mL) dropwise. The resultant solution was stirred at 0 C. for 15 minutes and then allowed to warm to room temperature for 16 hours. A saturated aqueous NH.sub.4Cl solution (10 mL) was added and the organic phase was collected. The aqueous phase was extracted with DCM (210 mL) and the combined organic extracts were dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-30% EtOAc/isohexane) to afford the title compound (1.312 g, 77%) as a white solid.

[1114] .sup.1H NMR (CDCl.sub.3) 8.78 (d, J=1.4 Hz, 1H), 8.46 (d, J=1.4 Hz, 1H), 7.11-7.07 (m, 4H), 6.79-6.75 (m, 4H), 4.43 (s, 4H), 3.79 (s, 6H).

Step C: N,N-Bis(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazine-2-sulfonamide

[1115] ##STR00339##

[1116] A suspension of 5-chloro-N,N-bis(4-methoxybenzyl)pyrazine-2-sulfonamide (1.31 g, 2.99 mmol) in glycol (15 mL) was treated with 2 M KOH (aq) (7.5 mL, 15 mmol). The resultant suspension was stirred at 140 C. for 18 hours. Then the reaction mixture was allowed to cool to room temperature, diluted with water (100 mL) and neutralised with saturated aqueous NH.sub.4Cl solution (30 mL). The white precipitate was collected by filtration, washed with water and dried at 60 C. under vacuum to afford the title compound (1.094 g, 79%) as a pale yellow solid.

[1117] .sup.1H NMR (DMSO-d6) 7.94 (d, J=1.2 Hz, 1H), 7.89 (br s, 1H), 7.10-7.06 (m, 4H), 6.84-6.79 (m, 4H), 4.28 (s, 4H), 3.71 (s, 6H). One exchangeable proton not observed.

[1118] LCMS: m/z 438.2 (M+Na).sup.+ (ES.sup.+); 414.2 (MH).sup. (ES.sup.).

Step D: 4-Isopropyl-N,N-bis(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazine-2-sulfonamide

[1119] ##STR00340##

[1120] A suspension of N,N-bis(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.503 g, 1.090 mmol) and lithium bromide (0.192 g, 2.167 mmol) in DME:DMF (6 mL, 4:1) at 0 C. was treated with NaH (0.053 g, 1.325 mmol). The resultant suspension was stirred at 0 C. for 10 minutes, treated with 2-iodopropane (0.218 ml, 2.136 mmol) and then stirred at 65 C. for 64 hours. A saturated aqueous NH.sub.4Cl solution (6 mL) and EtOAc (10 mL) were added and the organic layer was collected. The aqueous layer was extracted with EtOAc (210 mL) and the combined organic extracts were washed with water (10 mL) and brine (210 mL), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g column, 0-100% EtOAc/isohexane) to afford the title compound (0.293 g, 53%) as a clear yellow oil.

[1121] .sup.1H NMR (DMSO-d6) 8.07 (d, J=1.0 Hz, 1H), 7.96 (d, J=0.9 Hz, 1H), 7.13-7.09 (m, 4H), 6.83-6.79 (m, 4H), 4.78 (sept, J=6.5 Hz, 1H), 4.33 (s, 4H), 3.71 (s, 6H), 1.34 (d, J=6.8 Hz, 6H).

[1122] LCMS: m/z 480.3 (100, [M+Na]+), 458.5 (9, [M+H].sup.+) (ES.sup.+).

Step E: 4-Isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide

[1123] ##STR00341##

[1124] A solution of 4-isopropyl-N,N-bis(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.287 g, 0.565 mmol) in DCM (1 mL) was treated with TFA (1 mL, 12.98 mmol) at room temperature. The resultant solution was stirred for 28 hours. Then the reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (4 g column, 0-10% MeOH/DCM) to afford the title compound (0.116 g, 94%) as a white solid.

[1125] .sup.1H NMR (DMSO-d6) 8.14 (d, J=1.0 Hz, 1H), 8.08 (d, J=1.0 Hz, 1H), 7.40 (s, 2H), 4.88 (sept, J=6.7 Hz, 1H), 1.36 (d, J=6.8 Hz, 6H).

[1126] LCMS: 216.1 (MH).sup. (ES.sup.).

Intermediate P134: 1-Isopropylazetidine-3-sulfonamide

Step A: tert-Butyl 3-hydroxyazetidine-1-carboxylate

[1127] ##STR00342##

[1128] To a solution of azetidin-3-ol hydrochloride (45 g, 410.75 mmol, 1 eq) in MeOH (1.2 L) was added TEA (83.13 g, 821.51 mmol, 2 eq) and di-tert-butyl dicarbonate (89.65 g, 410.75 mmol, 1 eq). The mixture was stirred at 25 C. for 16 hours. Then the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtOAc (1 L). The mixture was washed with H.sub.2O (3500 mL) and brine (3500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (65 g, 91%) as a yellow oil, which was used directly in the next step.

[1129] .sup.1H NMR (CDCl.sub.3) 4.59 (s, 1H), 4.19-4.12 (m, 2H), 3.84-3.79 (m, 2H), 1.45 (s, 9H).

Step B: tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate

[1130] ##STR00343##

[1131] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (65 g, 375.27 mmol, 1 eq) and TEA (113.92 g, 3 eq) in THF (650 mL) was added methanesulfonyl chloride (51.58 g, 450.32 mmol, 1.2 eq) at 0 C. Then the mixture was stirred at 25 C. for 12 hours. The reaction mixture was diluted with EtOAc (2 L), washed with water (31.5 L) and brine (31.5 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (90 g, 95%) as a yellow oil, which was used directly in the next step.

[1132] .sup.1H NMR (CDCl.sub.3) 5.25-5.20 (m, 1H), 4.32-4.27 (m, 2H), 4.14-4.10 (m, 2H), 3.08 (s, 3H) and 1.46 (s, 9H).

Step C: tert-Butyl 3-(acetylthio)azetidine-1-carboxylate

[1133] ##STR00344##

[1134] To a solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (90 g, 358.14 mmol, 1 eq) in DMF (1.5 L) was added potassium ethanethioate (49.08 g, 429.77 mmol, 1.2 eq). The mixture was stirred at 80 C. for 12 hours. Then the reaction mixture was diluted with EtOAc (3 L), washed with saturated aqueous NH.sub.4Cl solution (32 L) and brine (32 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 100:1 to 20:1) to give the title compound (54 g, 65%) as a yellow oil.

[1135] .sup.1H NMR (CDCl.sub.3) 4.37 (t, 2H), 4.17-4.14 (m, 1H), 3.82 (dd, 2H), 2.34 (s, 3H) and 1.44 (s, 9H).

Step D: tert-Butyl 3-(chlorosulfonyl)azetidine-1-carboxylate

[1136] ##STR00345##

[1137] To a solution of tert-butyl 3-(acetylthio)azetidine-1-carboxylate (5 g, 21.62 mmol, 1 eq) in AcOH (200 mL) and H.sub.2O (20 mL) was added NCS (8.66 g, 64.85 mmol, 3 eq). The reaction mixture was stirred at 25 C. for 1 hour. Then the reaction mixture was diluted with DCM (300 mL), washed with water (3300 mL) and brine (3300 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solution was used directly in the next step.

Step E: tert-Butyl 3-sulfamoylazetidine-1-carboxylate

[1138] ##STR00346##

[1139] Through a solution of tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (55.28 g, crude) in DCM (1.5 L) was bubbled NH.sub.3 for 30 minutes at 0 C. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and EtOAc (21 mL, 20: 1) to give the title compound (27 g, 53%) as a white solid.

[1140] .sup.1H NMR (DMSO-d.sub.6) 7.16 (br s, 2H), 4.18-4.03 (m, 2H), 4.03-3.90 (m, 3H) and 1.38 (s, 9H).

Step F: tert-Butyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)azetidine-1-carboxylate

[1141] ##STR00347##

[1142] To a solution of tert-butyl 3-sulfamoylazetidine-1-carboxylate (1 g, 4.23 mmol, 1 eq) in DMF (10 mL) was added NaH (507 mg, 12.69 mmol, 60 wt % in mineral oil, 3 eq) at 0 C. The mixture was stirred at 0 C. for 30 minutes. Then 1-(chloromethyl)-4-methoxybenzene (1.99 g, 12.69 mmol, 3 eq) was added. The mixture was stirred at 25 C. for 14 hours. Then the reaction mixture was diluted with EtOAc (50 mL), washed with a saturated aqueous NH.sub.4Cl solution (330 mL) and brine (330 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was triturated with MeOH (10 mL) to give the title compound (1 g, 50%) as a white solid.

[1143] .sup.1H NMR (CDCl.sub.3) 7.17 (d, 4H), 6.91-6.88 (m, 4H), 4.30 (s, 4H), 4.22 (dd, 2H), 4.01 (t, 2H), 3.83 (s, 6H), 3.75-3.62 (m, 1H) and 1.44 (s, 9H).

[1144] LCMS: m/z 499.2 (M+Na).sup.+ (ES.sup.+).

Step G: N,N-Bis(4-methoxybenzyl)azetidine-3-sulfonamide

[1145] ##STR00348##

[1146] To a solution of tert-butyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)azetidine-1-carboxylate (7 g, 14.69 mmol, 1 eq) and 2,6-lutidine (4.72 g, 44.06 mmol, 3 eq) in DCM (80 mL) was added trimethylsilyl trifluoromethanesulfonate (9.79 g, 44.06 mmol, 3 eq) at 0 C. Then the reaction mixture was stirred at 0 C. for 1 hour. The reaction mixture was quenched with a saturated aqueous NH.sub.4Cl solution (20 mL) and extracted with DCM (350 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (40 mL, 1:1) to give the title compound (4 g, 72%) as a white solid.

[1147] .sup.1H NMR (CD.sub.3OD) 7.21 (d, 4H), 6.94-6.85 (m, 4H), 4.35 (s, 4H), 4.28-4.11 (m, 5H) and 3.81 (s, 6H).

[1148] LCMS: m/z 377.2 (M+H).sup.+ (ES.sup.+).

Step H: 1-Isopropyl-N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide

[1149] ##STR00349##

[1150] To a solution of N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide (2.5 g, 6.64 mmol, 1 eq) and K.sub.2CO.sub.3 (1.38 g, 9.96 mmol, 1.5 eq) in MeCN (5 mL) was added 2-bromopropane (1.63 g, 13.28 mmol, 2 eq). The mixture was stirred at 70 C. for 12 hours. Then H.sub.2O (10 mL) was added and the reaction mixture was extracted with EtOAc (330 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (2.5 g, 90%).

[1151] .sup.1H NMR (CDCl.sub.3) 7.12-7.07 (m, 4H), 6.83-6.76 (m, 4H), 4.16 (s, 4H), 3.74 (s, 6H), 3.68-3.64 (m, 1H), 3.43 (t, 2H), 3.28 (t, 2H), 2.38-2.29 (m, 1H) and 0.82 (d, 6H).

[1152] LCMS: m/z 419.2 (M+H).sup.+ (ES.sup.+).

Step I: 1-Isopropylazetidine-3-sulfonamide

[1153] ##STR00350##

[1154] A solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide (1 g, 2.39 mmol, 1 eq) in TFA (7.70 g, 67.53 mmol, 28.27 eq) was stirred at 25 C. for 12 hours. Then the reaction mixture was concentrated in vacuo. The residue was treated with MeOH (10 mL), filtered and the filtrate was adjusted with NH.sub.3.H.sub.2O (30% of NH.sub.3.H.sub.2O in water) to pH=8-9. The resulting mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.1% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (220 mg, 52%) as a white solid.

[1155] .sup.1H NMR (CD.sub.3OD) 4.05-3.98 (m, 1H), 3.67 (t, 2H), 3.46 (t, 2H), 2.59-2.48 (m, 1H) and 0.97 (d, 6H). Two exchangeable protons not observed.

[1156] LCMS: m/z 179.1 (M+H).sup.+ (ES.sup.+).

Intermediate P135: 1-Cyclobutylazetidine-3-sulfonamide

Step A: Azetidine-3-sulfonamide

[1157] ##STR00351##

[1158] To a solution of tert-butyl 3-sulfamoylazetidine-1-carboxylate (3 g, 12.70 mmol, 1 eq, obtained according to Step E of the synthesis of intermediate P134) in DCM (10 mL) was added HCl/EtOAc (12.70 mmol, 20 mL, 1 eq). The mixture was stirred at 25 C. for 1 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (0.8 g, 46%) as a white solid.

[1159] .sup.1H NMR (DMSO-d.sub.6) 6.92 (s, 1H), 4.23-4.19 (m, 2H) and 3.77-3.70 (m, 3H). Two exchangeable protons not observed.

[1160] LCMS: m/z 137.1 (M+H).sup.+ (ES.sup.+).

Step B: 1-Cyclobutylazetidine-3-sulfonamide

[1161] ##STR00352##

[1162] To a solution of azetidine-3-sulfonamide (50 mg, 367.18 mol, 1 eq) in MeOH (1 mL) was added cyclobutanone (31 mg, 440.62 mol, 1.2 eq) and NaBH(OAc).sub.3 (97 mg, 458.98 mol, 1.25 eq). The reaction mixture was stirred at 20 C. for 2 hours. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (12.25 mg, 18%) as a white solid.

[1163] .sup.1H NMR (DMSO-d.sub.6) 6.92 (s, 2H), 3.88-3.85 (m, 1H), 3.41-3.33 (m, 2H), 3.32-3.29 (m, 2H), 3.12-3.09 (m, 1H), 1.89-1.86 (m, 2H) and 1.77-1.60 (m, 4H).

[1164] LCMS: m/z 191.1 (M+H).sup.+ (ES.sup.+).

Intermediate P136: 1-Ethylazetidine-3-sulfonamide

Step A: 1-Ethyl-N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide

[1165] ##STR00353##

[1166] To a solution of N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide (1 g, 2.66 mmol, 1 eq, obtained according to Step G of the synthesis of intermediate P134) and K.sub.2CO.sub.3 (367 mg, 2.66 mmol, 1 eq) in MeCN (2 mL) was added iodoethane (414 mg, 2.66 mmol, 1 eq). The mixture was stirred at 70 C. for 1 hour. Then the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (350 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.1% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (0.7 g, 22% yield, 100% purity on LCMS) as a white solid.

[1167] .sup.1H NMR (CD.sub.3OD) 7.20 (d, 4H), 6.90 (d, 4H), 4.28 (S, 4H), 4.00-3.93 (m, 1H), 3.81 (s, 6H), 3.51 (t, 2H), 3.40 (t, 2H), 2.53 (q, 2H) and 0.96 (t, 3H).

[1168] LCMS: m/z 405.2 (M+H).sup.+ (ES.sup.+).

Step B: 1-Ethylazetidine-3-sulfonamide

[1169] ##STR00354##

[1170] A solution of 1-ethyl-N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide (800 mg, 1.98 mmol, 1 eq) in TFA (82.13 g, 720.32 mmol, 364 eq) was stirred at 50 C. for 1 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.1% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (160 mg, 47% yield, 95% purity on LCMS) as a white solid.

[1171] .sup.1H NMR (DMSO-d.sub.6) 6.94 (s, 2H), 3.95-3.86 (m, 1H), 3.47 (t, 2H), 3.31-3.25 (m, 2 H), 2.43 (q, 2H) and 0.86 (t, 3H).

[1172] LCMS: m/z 165.1 (M+H).sup.+ (ES.sup.+).

Intermediate P137: 1-(Pyridin-3-ylmethyl)azetidine-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide

[1173] ##STR00355##

[1174] To a solution of N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide (1 g, 2.66 mmol, 1 eq, obtained according to Step G of the synthesis of intermediate P134) in MeCN (20 mL) was added nicotinaldehyde (341 mg, 3.19 mmol, 1.2 eq) and NaBH(OAc).sub.3 (1.13 g, 5.31 mmol, 2 eq). The mixture was stirred at 15 C. for 1 hour. Then the reaction mixture was quenched with water (80 mL) and extracted with EtOAc (6100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:1 to 0:1) to give the title compound (1.1 g, 89%) as a yellow oil.

[1175] .sup.1H NMR (DMSO-d.sub.6) 8.53 (s, 1H), 8.46 (s, 1H), 7.72 (d, 1H), 7.37-7.33 (m, 1H), 7.13 (d, 4H), 6.88 (d, 4H), 4.21-4.17 (m, 5H), 3.73 (s, 6H), 3.61 (s, 2H), 3.47-3.41 (m, 2H) and 3.33-3.31 (m, 2H).

Step B: 1-(Pyridin-3-ylmethyl)azetidine-3-sulfonamide

[1176] ##STR00356##

[1177] A solution of N,N-bis(4-methoxybenzyl)-1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (1 g, 2.14 mmol, 1 eq) in TFA (10 mL) was stirred at 10 C. for 36 hours. Then the reaction mixture was concentrated in vacuo. The residue was treated with MeOH (80 mL) and the mixture was stirred for another 1 hour. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.1% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (240 mg, 49%) as a white solid.

[1178] .sup.1H NMR (DMSO-d.sub.6) 8.52-8.45 (m, 2H), 7.67 (d, 1H), 7.35 (dd, 1H), 6.98 (s, 2H), 3.99-3.94 (m, 1H), 3.64 (s, 2H), 3.54-3.49 (m, 2H) and 3.44-3.35 (m, 2H).

[1179] LCMS: m/z 228.1 (M+H).sup.+ (ES.sup.+).

Intermediate P138: 1-Isopropylpiperidine-4-sulfonamide

Step A: Benzyl 4-hydroxypiperidine-1-carboxylate

[1180] ##STR00357##

[1181] To a solution of piperidin-4-ol (100 g, 988.66 mmol, 1 eq) in DCM (1 L) was added TEA (100.04 g, 988.66 mmol, 1 eq) and benzyl chloroformate (168.66 g, 988.66 mmol, 1 eq) at 0 C. The mixture was warmed to 25 C. and stirred for 12 hours. Then the reaction mixture was diluted with DCM (500 mL), washed with brine (3500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (220 g, 95%) as a yellow oil, which was used in the next step without further purification.

[1182] .sup.1H NMR (CDCl.sub.3) 7.36-7.29 (m, 5H), 5.10 (s, 2H), 3.90-3.81 (m, 3H), 3.15-3.08 (m, 2H), 1.83-1.81 (m, 2H) and 1.47-1.45 (m, 2H). One exchangeable proton not observed.

[1183] LCMS: m/z 258.1 (M+Na).sup.+ (ES.sup.+).

Step B: Benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[1184] ##STR00358##

[1185] To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (220 g, 935.06 mmol, 1 eq) in DCM (1.7 L) was added TEA (189.24 g, 1.87 mol, 2 eq). Then mesyl chloride (128.54 g, 1.12 mol, 1.2 eq) was added dropwise at 0 C. The solution was heated to 25 C. and stirred for 1 hour. Then the reaction mixture was quenched with saturated aqueous NaHCO.sub.3 solution (1.2 L) and the two layers were separated. The organic layer was washed with saturated aqueous NaHCO.sub.3 solution (1.2 L) and brine (21 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (293 g, 100%), which was used directly in the next step.

Step C: Benzyl 4-(acetylthio)piperidine-1-carboxylate

[1186] ##STR00359##

[1187] To a solution of benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (290 g, 925.43 mmol, 1 eq) in DMF (1.4 L) was added Cs.sub.2CO.sub.3 (331.67 g, 1.02 mol, 1.1 eq) and ethanethioic S-acid (77.49 g, 1.02 mol, 1.1 eq). The mixture was stirred at 80 C. for 12 hours. Some solid was precipitated. The reaction mixture was filtered. The filtrate was concentrated in vacuo to remove most of the DMF. The residue was diluted with EtOAc (1.5 L), washed with H.sub.2O (31 L) and brine (21 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 40:1) to give the title compound (146 g, crude) as a yellow oil.

[1188] .sup.1H NMR (CDCl.sub.3) 7.37-7.35 (m, 5H), 5.13 (s, 2H), 4.07-3.93 (m, 2H), 3.66-3.61 (m, 1H), 3.19-3.12 (m, 2H), 2.33 (s, 3H), 1.94-1.91 (m, 2H) and 1.59-1.56 (m, 2H).

[1189] LCMS: m/z 294.1 (M+H).sup.+ (ES.sup.+).

Step D: Benzyl 4-(chlorosulfonyl)piperidine-1-carboxylate

[1190] ##STR00360##

[1191] To a solution of benzyl 4-(acetylthio)piperidine-1-carboxylate (30.00 g, 102.26 mmol, 1 eq) in AcOH (1 L) and H.sub.2O (100 mL) was added NCS (40.96 g, 306.77 mmol, 3 eq). The reaction mixture was stirred at 25 C. for 40 minutes. Then the reaction mixture was poured into water (1 L) and extracted with DCM (1 L). The organic layer was washed with water (31 L) and brine (1 L), dried over Na.sub.2SO.sub.4, and filtered to give the title compound in DCM (1 L) solution (theoretical amount: 32.4 g, crude), which was used in the next step without further purification.

Step E: Benzyl 4-sulfamoylpiperidine-1-carboxylate

[1192] ##STR00361##

[1193] NH.sub.3 was bubbled into a solution of benzyl 4-(chlorosulfonyl)piperidine-1-carboxylate (theoretical amount: 30 g, crude) in DCM (1 L) at 0 C. for 20 minutes. Then the reaction mixture was stirred at 25 C. for 40 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of EtOAc (50 mL) and petroleum ether (40 mL) to give the title compound (21 g, 75%) as a yellow solid.

[1194] .sup.1H NMR (DMSO-d.sub.6) 7.38-7.32 (m, 5H), 6.79 (br s, 2H), 5.10 (s, 2H), 4.12-4.01 (m, 2H), 3.09-3.02 (m, 1H), 3.01-2.75 (m, 2H), 2.02-1.96 (m, 2H) and 1.51-1.41 (m, 2H).

Step F: Piperidine-4-sulfonamide

[1195] ##STR00362##

[1196] To a solution of benzyl 4-sulfamoylpiperidine-1-carboxylate (21 g, 70.39 mmol, 1 eq) in MeOH (200 mL) was added Pd/C (10 wt % loading on activated carbon, 4 g) under nitrogen. The suspension was degassed in vacuo and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 25 C. for 30 hours. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with EtOAc (200 mL) to give the title compound (11.2 g, 97% yield, 100% purity on LCMS) as a white solid.

[1197] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O) 3.06-2.90 (m, 2H), 2.89-2.86 (m, 1H), 2.50-2.46 (m, 2H), 1.95-1.91 (m, 2H) and 1.53-1.46 (m, 2H). Three exchangeable protons not observed.

[1198] LCMS: m/z 165.1 (M+H).sup.+ (ES.sup.+).

Step G: 1-Isopropylpiperidine-4-sulfonamide

[1199] ##STR00363##

[1200] To a solution of piperidine-4-sulfonamide (1.2 g, 7.31 mmol, 1 eq) in acetonitrile (20 mL) was added 2-bromopropane (3.59 g, 29.23 mmol, 4 eq) and NaHCO.sub.3 (1.84 g, 21.92 mmol, 3 eq). Then the reaction mixture was stirred at 70 C. for 18 hours. The hot mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.05 g, 69% yield, 98.5% purity on LCMS) as a white solid.

[1201] .sup.1H NMR (DMSO-d.sub.6) 6.61 (s, 2H), 2.81-2.77 (m, 2H), 2.66-2.61 (m, 2H), 2.05-1.99 (m, 2H), 1.91-1.87 (m, 2H), 1.50-1.45 (m, 2H) and 0.89 (dd, 6H).

[1202] LCMS: m/z 207.1 (M+H).sup.+ (ES.sup.+).

Intermediate P139: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-2-oxo-1,2-dihydropyrimidin-5-yl)sulfonyl)amide

Step A: 5-Bromo-1-isopropylpyrimidin-2(1H)-one

[1203] ##STR00364##

[1204] A suspension of 5-bromopyrimidin-2(1H)-one (10.07 g, 57.5 mmol) and K.sub.2CO.sub.3 (8.35 g, 60.4 mmol) in DMF (200 mL) was treated with 2-iodopropane (6.4 ml, 62.7 mmol) under nitrogen. The resultant suspension was stirred at room temperature for 40 hours, concentrated in vacuo and the residue was partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (350 mL). The combined organic extracts were washed with 20% v/v brine (350 mL), brine (50 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford crude product as a yellow oil (4.71 g). The crude product was purified by chromatography on silica gel (dry load) (40 g cartridge, 0-5% MeOH/DCM) to afford the title compound (1.34 g, 10%) as a clear yellow oil that solidified on standing.

[1205] .sup.1H NMR (CDCl.sub.3) 8.52 (dd, J=3.3, 1.6 Hz, 1H), 7.76 (d, J=3.2 Hz, 1H), 4.99 (pd, J=6.8, 1.6 Hz, 1H), 1.40 (dd, J=6.8, 1.0 Hz, 6H).

[1206] LCMS: m/z 217.0 (MBr.sup.79+H).sup.+ (ES.sup.+).

Step B: 5-(Benzylthio)-1-isopropylpyrimidin-2(1H)-one

[1207] ##STR00365##

[1208] A solution of 5-bromo-1-isopropylpyrimidin-2(1H)-one (1.217 g, 5.05 mmol), DIPEA (1.8 ml, 10.31 mmol) and benzyl mercaptan (0.6 ml, 5.07 mmol) in dioxane (25 mL) was sparged with nitrogen for 15 minutes before Pd.sub.2(dba).sub.3 (0.233 g, 0.254 mmol) and Xantphos (0.294 g, 0.508 mmol) were added. The reaction mixture was heated at 100 C. for 22 hours and then concentrated in vacuo. The residue was partitioned between EtOAc (30 mL) and saturated aqueous NaHCO.sub.3 (20 mL). The aqueous layer was extracted with EtOAc (330 mL) and the combined organic extracts were washed with brine (30 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford crude product as a brown oil (2.3 g). The crude product was purified by chromatography on silica gel (dry load) (40 g cartridge, 0-5% MeOH/DCM) to afford the title compound (1.49 g, 99%) as a brown oil.

[1209] .sup.1H NMR (CDCl.sub.3) 8.46 (d, J=3.1 Hz, 1H), 7.30-7.22 (m, 3H), 7.15 (d, J=3.2 Hz, 1H), 7.09-7.06 (m, 2H), 4.84 (sept, J=6.8 Hz, 1H), 3.80 (s, 2H), 1.13 (d, J=6.8 Hz, 6H).

[1210] LCMS; m/z 261.1 (M+H).sup.+ (ES.sup.+).

Step C: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyrimidine-5-sulfonamide

[1211] ##STR00366##

[1212] A suspension of 5-(benzylthio)-1-isopropylpyrimidin-2(1H)-one (1.012 g, 3.69 mmol) in DCM (15 mL) and water (1.5 mL) at 0 C. was treated with SO.sub.2C1.sub.2 (2 ml, 23.86 mmol) dropwise. The resultant yellow suspension was stirred at 0 C. for 1 hour. A slurry of ice/water (20 mL) was added and the organic phase was collected and retained. The aqueous layer was extracted with DCM (210 mL) and the combined organic extracts were dried (MgSO.sub.4) and concentrated in vacuo to afford crude sulfonyl chloride intermediate as a pale yellow liquid (1.024 g) which was used without further purification. A solution of bis(4-methoxybenzyl)amine (1.007 g, 3.91 mmol) and Et.sub.3N (0.6 ml, 4.30 mmol) in DCM (20 mL) at 0 C. was treated with a solution of the crude sulfonyl chloride intermediate in DCM (10 mL). The resultant solution was allowed to warm to room temperature, stirred for 1 hour and then diluted with DCM (20 mL) and saturated aqueous NH.sub.4Cl (20 mL). The organic layer was collected and washed with saturated aqueous NH.sub.4Cl (20 mL) and water (20 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford crude product as an orange oil (2.0 g). The crude product was triturated with TBME (30 mL), filtered, rinsing with TBME, and dried in vacuo to afford crude product which was purified by chromatography on silica gel (24 g cartridge, 0-5% MeOH/DCM) to afford the title compound (0.941 g, 44%) as a sticky orange oil.

[1213] .sup.1H NMR (CDCl.sub.3) 8.65 (d, J=3.3 Hz, 1H), 7.96 (d, J=3.3 Hz, 1H), 7.15-7.10 (m, 4H), 6.85-6.82 (m, 4H), 4.88 (sept, J=6.8 Hz, 1H), 4.32 (s, 4H), 3.79 (s, 6H), 1.34 (d, J=6.8 Hz, 6H).

[1214] LCMS: m/z 458.1 (M+H).sup.+ (ES.sup.+).

Step D: 1-Isopropyl-2-oxo-1,2-dihydropyrimidine-5-sulfonamide

[1215] ##STR00367##

[1216] 1-Isopropyl-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyrimidine-5-sulfonamide (0.941 g, 1.625 mmol) was treated with TFA (15 ml, 195 mmol) and the resultant solution was stirred at room temperature for 64 hours. Then the reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (dry load) (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (0.350 g, 94%) as a tan solid.

[1217] .sup.1H NMR (DMSO-d6) 8.81 (d, J=3.2 Hz, 1H), 8.51 (d, J=3.3 Hz, 1H), 7.45 (s, 2H), 4.77 (sept, J=6.8 Hz, 1H), 1.37 (d, J=6.8 Hz, 6H).

[1218] LCMS; m/z 218.1 (M+H).sup.+ (ES.sup.+); 215.8 (MH).sup. (ES.sup.).

Step E: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-2-oxo-1,2-dihydropyrimidin-5-yl) sulfonyl)amide

[1219] ##STR00368##

[1220] A suspension of 1-isopropyl-2-oxo-1,2-dihydropyrimidine-5-sulfonamide (0.150 g, 0.690 mmol) and DMAP (0.169 g, 1.383 mmol) in dry MeCN (2 mL) was stirred at room temperature for to minutes before diphenyl carbonate (0.163 g, 0.761 mmol) was added in one portion. The reaction was stirred for 18 hours, diluted with TBME (20 mL) and DCM (2 mL), and the precipitate was collected by filtration and used crude in the next step.

Intermediate P140: 1-Isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide

Step A: Lithium 2-chloropyridine-4-sulfinate

[1221] ##STR00369##

[1222] A solution of 4-bromo-2-chloropyridine (5.8 ml, 52.3 mmol) in dry THF (100 mL) at 78 C. was treated with 2.5 M BuLi (in hexanes) (22 ml, 55.0 mmol) dropwise under nitrogen. The resultant solution was stirred at 78 C. for to minutes and then SO.sub.2 gas was bubbled through the solution for 20 minutes. The reaction was allowed to warm to room temperature and then concentrated in vacuo. The residue was triturated with TBME (100 mL). The resultant solid was filtered, rinsing with TBME, and dried in vacuo to afford the title compound (8.80 g, 92%) as a dark purple solid that was used crude in the next step.

Step B: 2-Chloro-N,N-bis(4-methoxybenzyl)pyridine-4-sulfonamide

[1223] ##STR00370##

[1224] A suspension of lithium 2-chloropyridine-4-sulfinate (6.55 g, 35.7 mmol) in DCM (100 mL) at 0 C. was treated with NCS (4.862 g, 35.7 mmol) in one portion. The resultant suspension was stirred at 0 C. for 2 hours, quenched with water (50 mL) and the organic layer was collected. The aqueous layer was extracted with DCM (250 mL) and the combined organic extracts were washed with water (50 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford the crude sulfonyl chloride intermediate. A solution of the sulfonyl chloride intermediate in DCM (10 mL) was added dropwise to a suspension of bis(4-methoxybenzyl)amine (9.42 g, 36.6 mmol) and triethylamine (15.92 ml, 114 mmol) in DCM (100 mL) at 0 C. The reaction mixture was allowed to warm to room temperature, stirred for 16 hours and then water (100 mL) was added. The organic layer was collected and the aqueous layer was extracted with DCM (250 mL). The combined organic extracts were washed with water (100 mL), 1 M HCl (aq) (2100 mL), water (100 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford crude product which was purified by chromatography on silica gel (dry load) (80 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.677 g, 4%) as an orange solid.

[1225] .sup.1H NMR (CDCl.sub.3) 8.51 (dd, J=4.8, 1.9 Hz, 1H), 8.30 (dd, J=7.8, 1.9 Hz, 1H), 7.30 (dd, J=7.8, 4.8 Hz, 1H), 7.04-6.99 (m, 4H), 6.81-6.75 (m, 4H), 4.38 (s, 4H), 3.78 (s, 6H).

[1226] LCMS: m/z 433 (MCl.sup.35+H).sup.+ (ES.sup.+).

Step C: N,N-Bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-4-sulfonamide

[1227] ##STR00371##

[1228] A suspension of 2-chloro-N,N-bis(4-methoxybenzyl)pyridine-4-sulfonamide (0.365 g, 0.759 mmol) in ethane-1,2-diol (5 ml, 0.759 mmol) was treated with 2 M KOH (aq) (1.9 ml, 3.80 mmol). The resultant suspension was stirred at 140 C. for 72 hours, allowed to cool to room temperature and then diluted with saturated aqueous NH.sub.4Cl(30 mL) and EtOAc (20 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (220 mL). The combined organic extracts were dried (MgSO.sub.4) and concentrated in vacuo to afford crude product as a yellow solid (510 mg). The crude product was purified by chromatography on silica gel (dry load) (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.437 g, 68%) as a pale yellow solid.

[1229] LCMS: m/z 437.3 (M+Na).sup.+ (ES.sup.+); 413.1 (MH).sup. (ES.sup.).

Step D: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-4-sulfonamide

[1230] ##STR00372##

[1231] A suspension of N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-4-sulfonamide (0.437 g, 0.949 mmol) and lithium bromide (0.171 g, 1.930 mmol) in DME:DMF (7.5 mL, 4:1) at 0 C. was treated with NaH in one portion. The resultant suspension was stirred at 0 C. for 15 minutes, treated with 2-iodopropane (0.194 ml, 1.898 mmol) and heated to 65 C. for 65 hours. Further lithium bromide (0.171 g, 1.930 mmol) followed by NaH (0.053 g, 1.328 mmol) were added and the reaction mixture was stirred at 65 C. for 10 minutes. Then further 2-iodopropane (0.194 ml, 1.898 mmol) was added and the reaction mixture was stirred at 65 C. for 18 hours. EtOAc (10 mL) and saturated aqueous NH.sub.4Cl (5 mL) were added and the organic layer was collected. The aqueous layer was extracted with EtOAc (210 mL) and the combined organic extracts were washed with 20% v/v brine (310 mL) and brine (10 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford crude product as a yellow oil. The crude product was purified by chromatography on silica gel (dry load) (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.385 g, 77%) as a pale yellow oil.

[1232] .sup.1H NMR (DMSO-d6) 8.06 (dd, J=6.8, 2.1 Hz, 1H), 7.99 (dd, J=7.2, 2.0 Hz, 1H), 7.07-7.03 (m, 4H), 6.82-6.78 (m, 4H), 6.39 (t, J=7.0 Hz, 1H), 4.99 (sept, J=6.8 Hz, 1H), 4.34 (s, 4H), 3.71 (s, 6H), 1.28 (d, J=6.8 Hz, 6H).

[1233] LCMS; m/z 479.3 (M+Na).sup.+ (ES.sup.+).

Step E: 1-Isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide

[1234] ##STR00373##

[1235] 1-Isopropyl-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-4-sulfonamide (0.375 g, 0.715 mmol) was treated with TFA (2 ml, 26.o mmol) and the resultant red solution was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo, azeotroped with DCM (25 mL) and the crude product was purified by chromatography on silica gel (dry load) (4 g cartridge, 0-10% MeOH/DCM) to afford the title compound (0.160 g, 100%) as a white solid.

[1236] .sup.1H NMR (CDCl.sub.3) 8.09 (dd, J=7.1, 2.1 Hz, 1H), 7.61 (dd, J=6.9, 2.1 Hz, 1H), 6.42 (t, J=7.0 Hz, 1H), 5.38 (br s, 2H), 5.32 (sept, J=7.0 Hz, 1H), 1.41 (d, J=6.8 Hz, 6H).

[1237] LCMS: m/z 217.3 (M+H).sup.+ (ES.sup.+); 215.1 (MH).sup. (ES.sup.).

Intermediate P141: 1-Isopropyl-2-oxo-1,2-dihydropyridine-3-sulfonamide

Step A: 2-Chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

[1238] ##STR00374##

[1239] Bis(4-methoxybenzyl)amine (3.78 g, 14.41 mmol) and triethylamine (2.49 ml, 17.8 mmol) in anhydrous DCM (15 mL) were added to a solution of 2-chloropyridine-3-sulfonyl chloride (3.00 g, 13.72 mmol) in anhydrous DCM (35 mL) at 0 C. The mixture was stirred at 0 C. for 0.5 hour, then warmed to room temperature. After 19 hours the reaction mixture was diluted with a further portion of DCM (150 mL), washed with saturated aqueous NH.sub.4Cl (250 mL), water (50 mL), and brine (50 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give crude product as a pale orange solid. The crude product was triturated with TBME (50 mL), filtered, rinsing with TBME (240 mL), to afford the title compound (5.10 g, 80%) as a cream coloured solid.

[1240] .sup.1H NMR (DMSO-d6) 8.61 (dd, J=4.8, 1.8 Hz, 1H), 8.27 (dd, J=7.8, 1.8 Hz, 1H), 7.55 (dd, J=7.8, 4.8 Hz, 1H), 7.05-6.98 (m, 4H), 6.86-6.78 (m, 4H), 4.37 (s, 4H), 3.72 (s, 6H).

[1241] LCMS: m/z 433.3 (M+H).sup.+ (ES.sup.+).

Step B: 2-Hydroxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

[1242] ##STR00375##

[1243] 2 M KOH (aq) (2.15 ml, 4.30 mmol) was added to a suspension of 2-chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (0.50 g, 1.074 mmol) in ethane-1,2-diol (10 mL). The reaction mixture was stirred at 140 C. for 66 hours, cooled to room temperature and neutralised with saturated aqueous NH.sub.4Cl (10 mL). The mixture was then extracted with DCM (540 mL) and the combined organics were washed with brine (20 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo to give a cream solid, which was triturated with TBME (15 mL) to afford the title compound (0.38 g, 84%) as a pale cream solid.

[1244] .sup.1H NMR (DMSO-d6) 12.29 (br s, 1H), 8.03 (dd, J=7.2, 2.2, 1H), 7.70 (dd, J=6.3, 2.2, 1H), 7.07-7.02 (m, 4H), 6.82-6.77 (m, 4H), 6.29 (dd, J=7.2, 6.3, 1H), 4.32 (s, 4H), 3.71 (s, 6H).

[1245] LCMS: m/z 437.4 (M+Na).sup.+ (ES.sup.+).

Step C: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-sulfonamide

[1246] ##STR00376##

[1247] Sodium hydride (60% dispersion in mineral oil) (0.026 g, 0.645 mmol) was added at o C. to a mixture of 2-hydroxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (0.26 g, 0.615 mmol) and lithium bromide (0.109 g, 1.230 mmol) in a mixture of anhydrous DME/anhydrous DMF (3 mL, 4:1). The reaction mixture was stirred at room temperature for 15 minutes before 2-iodopropane (0.07 ml, 0.74 mmol) was added and the reaction mixture was stirred at 60 C. for 27 hours. The reaction was quenched with saturated aqueous NH.sub.4Cl (5 mL) and diluted with EtOAc (100 mL). The organic layer was washed with water (15 mL) and brine (315 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give crude product as a yellow oil. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.25 g, 88%) as a colourless oil.

[1248] .sup.1H NMR (CDCl.sub.3) 8.06 (dd, J=7.2, 2.1 Hz, 1H), 7.50 (dd, J=6.8, 2.1 Hz, 1H), 7.11-7.06 (m, 4H), 6.77-6.72 (m, 4H), 6.26 (t, J=7.0 Hz, 1H), 5.21 (sept, J=6.8 Hz, 1H), 4.47 (s, 4H), 3.76 (s, 6H), 1.34 (d, J=6.8 Hz, 6H).

[1249] LCMS: m/z 479.4 (M+Na).sup.+ (ES.sup.+).

Step D: 1-Isopropyl-2-oxo-1,2-dihydropyridine-3-sulfonamide

[1250] ##STR00377##

[1251] TFA (0.43 ml, 5.64 mmol) was added to a solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-sulfonamide (0.27 g, 0.591 mmol) in anhydrous DCM (3 mL) at room temperature. The reaction mixture was stirred for 66 hours, concentrated in vacuo, then redissolved in DCM (5 mL), pre-adsorbed onto silica and purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (0.11 g, 82%) as a pale brown solid.

[1252] LCMS: m/z 217.1 (M+H).sup.+ (ES.sup.+).

Intermediate P142: (R)-1-(2-Hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

Step A: 6-Chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

[1253] ##STR00378##

[1254] Bis(4-methoxybenzyl)amine (3.71 g, 14.41 mmol) was added to a solution of 2-chloropyridine-5-sulfonyl chloride (3.00 g, 13.72 mmol) and triethylamine (2.49 ml, 17.8 mmol) in anhydrous DCM (50 mL) at 0 C. The reaction mixture was stirred at 0 C. for 15 minutes, then at room temperature for 20 hours. The reaction mixture was diluted with a further portion of DCM (150 mL), washed with saturated aqueous NH.sub.4Cl (340 mL) and brine (40 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give crude product as a cream solid. Trituration with TBME (70 mL) and collection of the solid by filtration followed by rinsing with TBME (240 mL) gave the title compound (4.97 g, 83%) as an off-white solid.

[1255] .sup.1H NMR (DMSO-d6) 8.76 (dd, J=2.6, 0.7 Hz, 1H), 8.19 (dd, J=8.4, 2.6 Hz, 1H), 7.69 (dd, J=8.4, 0.7 Hz, 1H), 7.08-7.02 (m, 4H), 6.83-6.76 (m, 4H), 4.29 (s, 4H), 3.71 (s, 6H).

[1256] LCMS: m/z 433.3 (M+H).sup.+ (ES.sup.+).

Step B: N,N-Bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1257] ##STR00379##

[1258] A suspension of 6-chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (4.07 g, 9.40 mmol) in ethane-1,2-diol (90 ml, 9.40 mmol) was treated with 2 M KOH (aq) (23.50 ml, 47.0 mmol) and the resultant suspension was stirred at 140 C. for 42 hours. Then the reaction mixture was diluted with water (200 mL) and DCM (300 mL). Brine (5 mL) was added and the organic layer was collected. The aqueous layer was extracted with DCM (5100 mL) and the combined organic extracts were washed with water (100 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (2.764 g, 61%) as a white solid.

[1259] .sup.1H NMR (DMSO-d6) 7.87 (d, J=2.8 Hz, 1H), 7.60 (dd, J=9.6, 2.9 Hz, 1H), 7.09-7.03 (m, 4H), 6.84-6.79 (m, 4H), 6.34 (d, J=9.6 Hz, 1H), 4.19 (s, 4H), 3.71 (s, 6H).

[1260] One exchangeable proton not observed.

[1261] LCMS: m/z 415.4 (M+H).sup.+ (ES.sup.+); 413.3 (MH).sup. (ES.sup.).

Step C: (R)-1-(2-Hydroxypropyl)-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1262] ##STR00380##

[1263] A mixture of N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.206 g, 0.427 mmol) and lithium bromide (0.076 g, 0.855 mmol) in a mixture of DME:DMF (2 mL, 4:1) at 0 C. was treated with NaH (0.026 g, 0.641 mmol). The reaction mixture was stirred at 0 C. for to minutes, then at room temperature for to minutes. (R.sup.)-2-methyloxirane (0.3 ml, 4.24 mmol) was added, and the reaction mixture was heated to 30 C. and stirred for 16 hours. A further portion of (R.sup.)-2-methyloxirane (0.3 ml, 4.24 mmol) was added and the reaction was stirred at 30 C. for 6 hours. Further lithium bromide (0.076 g, 0.855 mmol) followed by NaH (0.026 g, 0.641 mmol) were added and the reaction mixture was stirred at 30 C. for 5 minutes.

[1264] Further (R.sup.)-2-methyloxirane (0.3 ml, 4.24 mmol) was added and the reaction mixture was stirred at 30 C. for 16 hours. Saturated aqueous NH.sub.4Cl (4 mL) was added, followed by EtOAc (10 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford crude product which was purified by chromatography on silica gel (dry load) (4 g cartridge, 50-100% EtOAc/isohexane) to afford the title compound (0.189 g, 89%) as a white solid.

[1265] .sup.1H NMR (CDCl.sub.3) 7.86 (d, J=2.6 Hz, 1H), 7.47 (dd, J=9.6, 2.7 Hz, 1H), 7.09-7.06 (m, 4H), 6.83-6.80 (m, 4H), 6.55 (d, J=9.7 Hz, 1H), 4.26 (s, 4H), 4.17-4.07 (m, 2H), 3.79 (s, 6H), 3.62 (dd, J=13.3, 8.1 Hz, 1H), 1.25 (d, J=6.3 Hz, 3H). One exchangeable proton not observed.

[1266] LCMS: m/z 473.4 (M+H).sup.+ (ES.sup.+); 471.3 (MH).sup. (ES.sup.).

Step D: (R)-1-(2-Hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1267] ##STR00381##

[1268] (R)-1-(2-Hydroxypropyl)-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.182 g, 0.366 mmol) was suspended in DCM (1 ml, 15.54 mmol) and then treated with TFA (1 ml, 12.98 mmol). The resultant solution was stirred at room temperature for 24 hours. The DCM was evaporated and the reaction mixture was stirred at room temperature for 24 hours, then at 40 C. for 21 hours. The reaction mixture was concentrated in vacuo and azeotroped with DCM (35 mL) to afford crude product as a brown foam (0.241 g). The crude product was purified by chromatography on silica gel (dry load) (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (0.049 g, 56%) as a white solid.

[1269] .sup.1H NMR (DMSO-d6) 8.10 (d, J=2.7 Hz, 1H), 7.69 (dd, J=9.6, 2.7 Hz, 1H), 7.33 (s, 2H), 6.53 (d, J=9.5 Hz, 1H), 4.92 (d, J=5.5 Hz, 1H), 4.07 (dd, J=13.0, 3.3 Hz, 1H), 3.91-3.81 (m, 1H), 3.62 (dd, J=13.0, 8.4 Hz, 1H), 1.08 (d, J=6.3 Hz, 3H).

[1270] LCMS: m/z 233.0 (M+H).sup.+ (ES.sup.+); 230.9 (MH).sup. (ES.sup.).

Intermediate P143: 1-(2-(Dimethylamino)ethyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

Step A: 1-(2-Hydroxyethyl)-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1271] ##STR00382##

[1272] A mixture of N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P142, Step B) (0.15 g, 0.355 mmol) and lithium bromide (0.063 g, 0.709 mmol) in DME:DMF (2 mL, 4:1) at room temperature was treated with sodium hydride (0.021 g, 0.532 mmol). The reaction mixture was stirred for 10 minutes, treated with 2-bromoethanol (0.030 ml, 0.426 mmol) and then stirred at 50 C. for 69 hours. The reaction was quenched with saturated aqueous NH.sub.4Cl (2 mL) and diluted with EtOAc (10 mL). The organic layer was collected, washed with water (25 mL) and brine (25 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford crude product which was purified by chromatography on silica gel (dry load) (4 g cartridge, 50-100% EtOAc/isohexane) to afford the title compound (0.124 g, 75%) as a white solid.

[1273] .sup.1H NMR (DMSO-d6) 8.16 (d, J=2.7 Hz, 1H), 7.63 (dd, J=9.6, 2.8 Hz, 1H), 7.10-7.05 (m, 4H), 6.84-6.80 (m, 4H), 6.44 (d, J=9.6 Hz, 1H), 4.95 (t, J=5.4 Hz, 1H), 4.21 (s, 4H), 3.99 (t, J=5.2 Hz, 2H), 3.71 (s, 6H), 3.62 (app. q, J=5.3 Hz, 2H).

[1274] LCMS: m/z 459.4 (M+H).sup.+ (ES.sup.+).

Step B: N,N-Bis(4-methoxybenzyl)-6-oxo-1-(2-oxoethyl)-1,6-dihydropyridine-3-sulfonamide

[1275] ##STR00383##

[1276] A solution of 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.177 g, 0.363 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (0.18 g, 0.424 mmol) and stirred at room temperature for 1 hour. Further Dess-Martin periodinane (0.09 g, 0.212 mmol) was added and the reaction mixture stirred for 0.5 hour. Saturated aqueous NaHCO.sub.3 (5 mL) and DCM (5 mL) were added and the reaction mixture was stirred vigorously for 10 minutes. The organic layer was collected and the aqueous layer was extracted with DCM (10 mL). The combined organic extracts were washed with saturated aqueous sodium thiosulfate (10 mL) and water (10 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford the title compound as a yellow oil (183 mg, 94%).

[1277] .sup.1H NMR (CDCl.sub.3) 9.65 (s, 1H), 7.61-7.58 (m, 1H), 7.47 (dd, J=9.7, 2.6 Hz, 1H), 7.13-7.09 (m, 4H), 6.86-6.82 (m, 4H), 6.57 (d, J=9.7 Hz, 1H), 4.67 (s, 2H), 4.29 (s, 4H), 3.80 (s, 6H).

Step C: 1-(2-(Dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1278] ##STR00384##

[1279] A solution of N,N-bis(4-methoxybenzyl)-6-oxo-1-(2-oxoethyl)-1,6-dihydropyridine-3-sulfonamide (0.183 g, 0.341 mmol) in 1,2-dichloroethane (3 ml, 38.1 mmol) was treated with 2M dimethylamine (in THF) (0.35 ml, 0.700 mmol). The resultant yellow/green solution was stirred for 30 minutes, before sodium triacetoxyborohydride (0.15 g, 0.708 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 16 hours, then saturated aqueous NaHCO.sub.3 (5 mL) was added and the organic layer was collected. The aqueous layer was extracted with DCM (25 mL) and the combined organic extracts were washed with water (5 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford crude product as a yellow oil (196 mg). The crude product was loaded onto a column of SCX (1.8 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (0.162 g, 96%) as a clear yellow oil.

[1280] .sup.1H NMR (DMSO-d6) 8.23 (d, J=2.7 Hz, 1H), 7.61 (dd, J=9.6, 2.8 Hz, 1H), 7.08-7.03 (m, 4H), 6.85-6.79 (m, 4H), 6.43 (d, J=9.6 Hz, 1H), 4.21 (s, 4H), 4.03 (t, J=6.0 Hz, 2H), 3.71 (s, 6H), 2.51-2.45 (m, 2H), 2.15 (s, 6H). Multiplet at 2.51-2.45 is obscured by the DMSO-d6 solvent signal.

Step D: 1-(2-(Dimethylamino)ethyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1281] ##STR00385##

[1282] A solution of 1-(2-(dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.159 g, 0.321 mmol) in DCM (3 ml, 46.6 mmol) was treated with TFA (0.25 ml, 3.24 mmol) dropwise at room temperature and the reaction mixture was stirred for 16 hours. Further TFA (0.25 ml, 3.24 mmol) was added. The reaction mixture was stirred for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (0.5 mL) and TFA (0.5 mL). The reaction mixture was stirred for 4 hours and then concentrated in vacuo. The residue was treated with TFA (2 mL) and water (0.2 mL). The reaction mixture was stirred for 24 hours at room temperature and then heated to 40 C. for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was loaded onto a column of SCX (1.9 g) in DCM. The column was washed with DCM and then the product was eluted with 0.7 M ammonia in MeOH/DCM (1:1). The resultant mixture was concentrated in vacuo to afford the title compound (0.038 g, 35%) as a pale brown solid.

[1283] LCMS: m/z 246.1 (M+H).sup.+ (ES.sup.+); 244.0 (MH).sup. (ES.sup.).

Intermediate P144: 1-Ethylazepane-4-sulfonamide

Step A: tert-Butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate

[1284] ##STR00386##

[1285] To a solution of tert-butyl 4-hydroxyazepane-1-carboxylate (3.0 g, 14.0 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (3.2 mL, 18.0 mmol, 1.3 equiv.) in dichloromethane (70 mL) was added methanesulfonyl chloride (1.2 mL, 15.0 mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 1 hour and then water was added. The organic layer was separated and then washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (3.87 g, 95%).

[1286] .sup.1H NMR (CDCl.sub.3) 4.97-4.76 (m, 1H), 3.62-3.24 (m, 4H), 3.00 (s, 3H), 2.14-1.83 (m, 4H), 1.68 (q, 2H), 1.45 (s, 9H).

Step B: tert-Butyl 4-(acetylthio)azepane-1-carboxylate

[1287] ##STR00387##

[1288] To a solution of tert-butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate (3.87 g, 13.2 mmol, 1.0 equiv.) in dimethylformamide (50 mL) and acetonitrile (13 mL) was added potassium thioacetate (4.52 g, 39.6 mmol, 3.0 equiv.). The reaction mixture was heated to 90 C. for 50 minutes and then cooled to room temperature. To the suspension was added brine and ethyl acetate. The organic layer was separated, then washed three times with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was submitted for normal phase flash column chromatography using heptane and ethyl acetate as eluent to give the title compound (2.3 g, 64%).

[1289] LC-MS: m/z 174.4 (M+HC.sub.5H.sub.9O.sub.2).sup.+ (ES.sup.+).

Step C: tert-Butyl 4-sulfamoylazepane-1-carboxylate

[1290] ##STR00388##

[1291] To a solution of tert-butyl 4-(acetylthio)azepane-1-carboxylate (2.2 g, 8.o mmol, 1.0 equiv.) in water (8.0 ml) and acetic acid (80 mL) was added N-chlorosuccinimide (3.2 g, 24.1 mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature for one hour and then added dropwise to a solution of ammonia in water (25 wt %, 500 mL) cooled in an ice bath. The mixture was adjusted to pH 9 by adding concentrated hydrochloric acid and then extracted twice with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was submitted for normal phase flash column chromatography using dichloromethane and methanol as eluent to give the title compound (250 mg, 11%).

[1292] .sup.1H NMR (CDCl.sub.3) 4.47 (s, 2H), 3.71-3.46 (m, 2H), 3.48-3.35 (m, 1H), 3.36-3.16 (m, 1H), 2.97 (dt, 1H), 2.55-2.36 (m, 2H), 2.07-1.96 (m, 1H), 1.94-1.80 (m, 1H), 1.70-1.60 (m, 2H), 1.46 (s, 9H).

Step D: Azepane-4-sulfonamide hydrochloride

[1293] ##STR00389##

[1294] To a solution of tert-butyl 4-sulfamoylazepane-1-carboxylate (252 mg, 0.9 mmol, 1.0 equiv.) in dichloromethane (10 mL) was added 4M hydrochloric acid in dioxane (5.0 mL, 18.1 mmol, 20.0 equiv.). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo to give the title compound (194 mg, quantitative yield).

[1295] .sup.1H NMR (CD.sub.3OD) 3.47 (ddd, 1H), 3.29-3.16 (m, 4H), 2.57-2.34 (m, 2H), 2.31-2.08 (m, 2H), 2.06-1.80 (m, 2H).

Step E: 1-Ethylazepane-4-sulfonamide

[1296] ##STR00390##

[1297] To a suspension of azepane-4-sulfonamide hydrochloride (97 mg, 0.45 mmol, 1.0 equiv.) in acetonitrile (10 mL) was added acetaldehyde (28 L, 0.5 mmol, 1.1 equiv.), triethylamine (69 L, 0.5 mmol, 1.1 equiv.) and then sodium triacetoxyborohydride (120 mg, 0.56 mmol, 1.25 equiv.). The suspension was stirred overnight at room temperature and then concentrated in vacuo. The crude product was dissolved in methanol, coated on Agilient hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted for normal phase flash column chromatography to give the title compound (29 mg, 31%).

[1298] .sup.1H NMR (DMSO-d.sub.6) 6.69 (s, 2H), 3.07-2.93 (m, 1H), 2.81-2.51 (m, 4H), 2.22-2.00 (m, 2H), 1.91-1.42 (m, 6H), 1.00 (t, J=7.1 Hz, 3H).

Intermediate P145: 1-(Ethyl-d5)piperidine-4-sulfonamide

[1299] ##STR00391##

[1300] To a solution of piperidine-4-sulfonamide hydrochloride (733 mg, 3.65 mmol, 1 eq) and K.sub.2CO.sub.3 (2.02 g, 14.6 mmol, 4 eq) in acetonitrile (30 mL) was added 1-iodoethane-1,1,2,2,2-d5 (588 mg, 3.65 mmol, 1 eq) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo. The residue was suspended in methanol, coated on Agilient hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to give the title compound (63 mg, 9%) as an off-white solid.

[1301] LCMS: m/z 198 (M+H).sup.+ (ES.sup.+).

PREPARATION OF EXAMPLES

Example 1: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methylpiperidine-4-sulfonamide, Potassium Salt

[1302] ##STR00392##

[1303] To a cooled (0 C.) solution of 1-methylpiperidine-4-sulfonamide (55 mg, 0.31 mmol) in THF (2 mL) was added potassium tert-butoxide (38 mg, 0.34 mmol). The reaction mixture was stirred and allowed to warm to room temperature over 40 minutes and then a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1; 68 mg, 0.34 mmol) in THF (1 mL) was added. The mixture was stirred overnight at room temperature and the resulting precipitate was isolated by filtration and washed with THF (1 mL). The solid was triturated with EtOAc (2 mL) for 1 hour, filtered and dried in vacuo to afford the title compound (17 mg; 13%) as a white solid.

[1304] .sup.1H NMR (CD.sub.3OD) 6.83 (s, 1H), 4.58 (br s, 2H), 3.2 (m, 1H), 3.02 (m, 2H), 2.82 (m, 8H), 2.3 (s, 3H) and 1.82-2.1 (m, 10H).

[1305] LCMS: m/z 378 (M+H).sup.+ (ES.sup.+); 376 (MH).sup. (ES.sup.).

Example 2: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, Potassium Salt

[1306] ##STR00393##

[1307] To a cooled (0 C.) solution of 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P3; 64 mg, 0.31 mmol) in THF (3 mL) was added potassium tert-butoxide (39 mg, 0.35 mmol). The ice bath was removed and the reaction mixture was stirred whilst being allowed to warm to room temperature over 40 minutes. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1; 69 mg, 0.35 mmol) in THF (1 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and water (2 mL) was added. The suspension was filtered over cotton wool and subsequently submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (95 mg; 75%) as a white solid.

[1308] .sup.1H NMR (CD.sub.3OD) 6.83 (s, 1H), 3.38 (m, 1H), 3.02 (m, 2H), 2.82 (m, 10H), 2.63 (s, 1H), 2.27 (m, 2H), 2.16 (m, 2H), 2.02 (m, 4H) and 1.88 (m, 2H).

[1309] LCMS: m/z 402 (M+H).sup.+ (ES.sup.+); 400 (MH).sup. (ES.sup.).

Example 3: 1-Acetyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) piperidine-4-sulfonamide, Potassium Salt

[1310] ##STR00394##

[1311] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (example 2) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-acetylpiperidine-4-sulfonamide (Intermediate P7) to afford the title compound (73%) as a white solid.

[1312] .sup.1H NMR (CD.sub.3OD) 6.84 (s, 1H), 4.6 (m, 2H), 4.02 (m, 1H), 3.62 (m, 1H), 3.15 (m, 1H), 2.82 (m, 8H), 2.64 (m, 1H), 2.17 (m, 1H), 2.09 (s, 3H), 2.02 (m, 4H) and 1.6-1.85 (m, 2H).

[1313] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+); 404 (MH).sup. (ES.sup.).

Example 4: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-4-sulfonamide, Potassium Salt

[1314] ##STR00395##

[1315] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (example 2) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) to afford the deprotected title compound (11%) as a white solid.

[1316] .sup.1H NMR (CD.sub.3OD) 6.83 (s, 1H), 4.6 (br s, 1H), 3.6 (m, 1H), 2.82 (m, 10H), 2.21 (m, 2H), 2.02 (m, 4H) and 1.86 (m, 4H).

[1317] LCMS: m/z 364 (M+H).sup.+ (ES.sup.+); 362 (MH).sup. (ES.sup.).

Example 5: 4-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-isopropylpiperidine-1-carboxamide, Potassium Salt

[1318] ##STR00396##

[1319] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (example 2) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-iso-propyl-4-sulfamoylpiperidine-1-carboxamide (Intermediate P5) to afford the title compound (39%) as a white solid.

[1320] .sup.1H NMR (CD.sub.3OD) 6.84 (s, 1H), 4.14 (m, 2H), 3.85 (m, 1H), 3.53 (m, 1H), 2.82 (m, 10H), 2.05 (m, 6H), 1.7 (m, 2H) and 1.12 (d, 6H).

[1321] LCMS: m/z 449 (M+H).sup.+ (ES.sup.+); 447 (MH).sup. (ES.sup.).

Example 6: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[1322] ##STR00397##

[1323] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (example 2) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethylpiperidine-4-sulfonamide (Intermediate P6) to afford the title compound (14%) as a white solid.

[1324] .sup.1H NMR (CD.sub.3OD) 6.83 (s, 1H), 4.6 (br s, 1H), 3.18 (m, 2H), 2.82 (m, 8H), 2.55 (q, 2H), 2.17 (m, 4H), 1.85-2.08 (m, 6H) and 1.16 (t, 3H).

[1325] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+); 390 (MH).sup. (ES.sup.).

Example 7: 1-(Cyclopropanecarbonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[1326] ##STR00398##

Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (example 2) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(cyclopropanecarbonyl)piperidine-4-sulfonamide (Intermediate P8) to afford the title compound (72%) as a white solid.

[1327] .sup.1H NMR (CD.sub.3OD) 6.84 (s, 1H), 4.58 (m, 1H), 4.42 (m, 1H), 3.6 (m, 1H), 3.18 (m, 1H), 2.82 (m, 8H), 2.64 (m, 1H), 2.08 (m, 1H), 2.02 (m, 6H), 1.8-1.94 (m, 2H) and 0.92 (m, 4H).

[1328] LCMS: m/z 432 (M+H).sup.+ (ES.sup.+); 430 (MH).sup. (ES.sup.). Example 8: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide, Potassium Salt

##STR00399##

[1329] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (example 2) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide (Intermediate P4) to afford the title compound (19%) as a white solid.

[1330] .sup.1H NMR (CD.sub.3OD) 6.84 (s, 1H), 4.51 (m, 2H), 4.09 (m, 1H), 3.7 (m, 1H), 2.92 (m, 1H), 2.82 (m, 8H), 2.12 (m, 2H), 2.02 (m, 4H) and 1.8 (m, 2H).

[1331] LCMS: m/z 460 (M+H).sup.+ (ES.sup.+); 458 (MH).sup. (ES.sup.).

Example 9: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-3-sulfonamide, Potassium Salt

[1332] ##STR00400##

[1333] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (example 2) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethylpiperidine-3-sulfonamide (Intermediate P15) to afford the afford the title compound (23%) as a white solid.

[1334] .sup.1H NMR (CD.sub.3OD) 6.83 (s, 1H), 3.61 (m, 1H), 3.45 (m, 1H), 2.94 (m, 1H), 2.82 (m, 8 H), 2.55 (q, 2H), 2.23 (m, 2H), 2.03 (m, 6H), 1.83 (m, 1H), 1.63 (m, 2H) and 1.16 (t, 3H).

[1335] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+); 390 (MH).sup. (ES.sup.).

Example 10: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-propionylpiperidine-4-sulfonamide, Potassium Salt

[1336] ##STR00401##

[1337] Prepared as described for 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-3-sulfonamide, potassium salt (example 9) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-propionylpiperidine-4-sulfonamide (Intermediate P10) to afford the title compound (32%) as a white solid.

[1338] .sup.1H NMR (CD.sub.3OD) 6.83 (s, 1H), 4.62 (m, 1H), 4.04 (m, 1H), 3.61 (m, 1H), 3.09 (m, 1H), 2.82 (m, 8H), 2.65 (m, 1H), 2.42 (q, 2H), 2.17 (m, 2H), 2.02 (m, 4H), 1.7 (m, 2H) and 1.12 (t, 3H).

[1339] LCMS: m/z 420 (M+H).sup.+ (ES.sup.+); 418 (MH).sup. (ES.sup.).

Example 11: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isobutyrylpiperidine-4-sulfonamide, Potassium Salt

[1340] ##STR00402##

[1341] Prepared as described for 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-3-sulfonamide, potassium salt (example 9) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-iso-butyrylpiperidine-4-sulfonamide (Intermediate P11) to afford the title compound (9%) as a white solid.

[1342] .sup.1H NMR (CD.sub.3OD) 6.83 (s, 1H), 4.62 (m, 1H), 4.18 (m, 1H), 3.65 (m, 1H), 3.07 (m, 1H), 2.96 (m, 1H), 2.82 (m, 8H), 2.65 (m, 1H), 2.17 (m, 2H), 2.02 (m, 4H), 1.7 (m, 2H) and 1.09 (t, 6H).

[1343] LCMS: m/z 434 (M+H).sup.+ (ES.sup.+).

Example 12: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-methoxyacetyl)piperidine-4-sulfonamide, Potassium Salt

[1344] ##STR00403##

[1345] Prepared as described for 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-3-sulfonamide, potassium salt (example 9) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-methoxyacetyl)piperidine-4-sulfonamide (Intermediate P12) to afford the title compound (5%) as a white solid.

[1346] .sup.1H NMR (CD.sub.3OD) 6.91 (s, 1H), 4.19 (q, 2H), 4.0 (m, 1H), 3.7 (m, 1H), 3.41 (s, 3H), 3.23-3.03 (m, 2H), 2.82 (m, 8H), 2.7 (m, 1H), 2.19 (m, 2H), 2.02 (m, 4H) and 1.77 (m, 2H).

[1347] LCMS: m/z 436 (M+H).sup.+ (ES.sup.+).

Example 13: Methyl 4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)piperidine-1-carboxylate, Potassium Salt

[1348] ##STR00404##

[1349] Prepared as described for 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-3-sulfonamide, potassium salt (example 9) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and methyl 4-sulfamoylpiperidine-1-carboxylate (Intermediate P13) to afford the title compound (32%) as a white solid.

[1350] .sup.1H NMR (CD.sub.3OD) 6.85 (s, 1H), 4.2 (m, 2H), 3.68 (s, 3H), 3.55 (m, 1H), 2.82 (m, 10H), 2.03 (m, 6H) and 1.7 (m, 2H).

[1351] LCMS: m/z 422 (M+H).sup.+ (ES.sup.+); 420 (MH).sup. (ES.sup.).

Example 14: 1-(Cyanomethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[1352] ##STR00405##

[1353] Prepared as described for 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-3-sulfonamide, potassium salt (example 9) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(cyanomethyl)piperidine-4-sulfonamide_(Intermediate P9) to afford the title compound (51%) as a white solid.

[1354] .sup.1H NMR (CD.sub.3OD) 6.87 (s, 1H), 3.64 (s, 2H), 3.38 (m, 1H), 2.96 (m, 2H), 2.82 (m, 8H), 2.3 (m, 2H), 2.18 (m, 2H), 2.02 (m, 5H) and 1.88 (m, 2H).

[1355] LCMS: m/z 403 (M+H).sup.+ (ES.sup.+); 401 (MH).sup. (ES.sup.).

Example 15: 1-Cyclobutyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[1356] ##STR00406##

[1357] Prepared as described for 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-3-sulfonamide, potassium salt (example 9) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclobutylpiperidine-4-sulfonamide (Intermediate P14) to afford the title compound (20%) as a white solid.

[1358] .sup.1H NMR (CD.sub.3OD) 6.87 (s, 1H), 5.2 (S, 1H), 3.47 (q, 2H), 3.02 (m, 2H), 2.82 (m, 8H), 2.18-1.97 (m, 6H), 1.97-1.82 (m, 4H), 1.72 (m, 2H) and 1.35 (m, 4H).

[1359] LCMS: m/z 418 (M+H).sup.+ (ES.sup.+); 416 (MH).sup. (ES.sup.).

Example 16: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonamide, Potassium Salt

[1360] ##STR00407##

[1361] Prepared as described for 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-3-sulfonamide, potassium salt (example 9) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxo-pyrimidine-5-sulfonate to afford the title compound (50%) as a white solid.

[1362] .sup.1H NMR (CD.sub.3OD) 8.22 (s, 1H), 6.83 (s, 1H), 3.43 (s, 3H), 3.35 (s, 3H), 2.8 (t, 4H), 2.75 (t, 4H) and 2.0 (m, 4H).

[1363] LCMS: m/z 419 (M+H).sup.+ (ES.sup.+); 417 (MH).sup. (ES.sup.).

Example 17: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-hexyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonamide, Potassium Salt

[1364] ##STR00408##

[1365] Prepared as described for 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-3-sulfonamide, potassium salt (example 9) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-hexyl-1,2,3,4-tetrahydro-2,4-dioxo-pyrimidine-5-sulfonamide to afford the title compound (30%) as a white solid.

[1366] .sup.1H NMR (CD.sub.3OD) 8.19 (s, 1H), 6.83 (s, 1H), 3.78 (t, 2H), 2.8 (t, 4H), 2.7 (t, 4H), 1.98 (m, 4H), 1.67 (m, 2H), 1.29 (m, 6H) and 0.88 (t, 3H) LCMS: m/z 475 (M+H).sup.+ (ES.sup.+); 473 (MH).sup. (ES.sup.).

Example 18: 1-Cyclobutyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1367] ##STR00409##

[1368] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclobutylazetidine-3-sulfonamide (Intermediate P79) to afford the title compound (25%) as a white solid.

[1369] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.34 (t, 1H), 3.63 (dd, 4H), 2.81 (m, 11H), 2.02 (m, 4H), 1.95-1.82 (m, 2H), 1.82-1.65 (m, 2H).

[1370] LCMS: m/z 390 (M+H).sup.+ (ES.sup.+); 388 (MH).sup. (ES.sup.).

Example 19: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-propyl piperidine-4-sulfonamide, Potassium Salt

[1371] ##STR00410##

[1372] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-propylpiperidine-4-sulfonamide (Intermediate P16) to afford the title compound (2%) as a white solid.

[1373] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+); 404 (MH).sup. (ES.sup.).

Example 20: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(oxetan-3-yl)piperidine-4-sulfonamide, Potassium Salt

[1374] ##STR00411##

[1375] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(oxetan-3-yl)piperidine-4-sulfonamide (Intermediate P17) to afford the title compound (12%) as a white solid.

[1376] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.62 (m, 4H), 3.47 (m, 1H), 3.4 (m, 1H), 2.82 (m, 10H), 2.18 (m, 2H), 2.02 (m, 4H) and 1.87 (m, 4H).

[1377] LCMS: m/z 420 (M+H).sup.+ (ES.sup.+); 418 (MH).sup. (ES.sup.).

Example 21: Methyl 2-(4-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)piperidin-1-yl)acetate, Potassium Salt

[1378] ##STR00412##

[1379] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and methyl 2-(4-sulfamoylpiperidin-1-yl)acetate (Intermediate P18) to afford the title compound (46%) as a white solid.

[1380] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.69 (s, 3H), 3.3 (m, 2H), 3.24 (s, 2H), 3.03 (m, 2H), 2.82 (m, 8H), 2.22 (m, 2H) and 2.03 (m, 8H).

[1381] LCMS: m/z 436 (M+H).sup.+ (ES.sup.+); 434 (MH).sup. (ES.sup.).

Example 22: 1-(2-Fluoroethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[1382] ##STR00413##

[1383] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-fluoroethyl)piperidine-4-sulfonamide to afford the title compound (14%) as a white solid.

[1384] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.65 (m, 1H), 4.48 (m, 1H), 3.4 (m, 1H), 3.08 (m, 2H), 2.82 (m, 8H), 2.74 (m, 1H), 2.64 (m, 1H), 2.13 (m, 4H), 2.02 (m, 4H) and 1.9 (m, 2H).

[1385] LCMS: m/z 410 (M+H).sup.+ (ES.sup.+).

Example 23: 1-Cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[1386] ##STR00414##

[1387] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclopropylpiperidine-4-sulfonamide (Intermediate P19) to afford the title compound (17%) as a white solid.

[1388] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.43 (m, 1H), 3.15 (m, 2H), 2.82 (m, 8H), 2.25 (m, 2H), 2.04 (m, 6H), 1.82 (m, 2H), 1.64 (m, 1H) and 0.44 (m, 4H).

[1389] LCMS: m/z 404 (M+H).sup.+ (ES.sup.+); 402 (MH).sup. (ES.sup.).

Example 24: 1-(1-Ethylazetidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[1390] ##STR00415##

[1391] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(1-ethylazetidin-3-yl)piperidine-4-sulfonamide (Intermediate P20) to afford the title compound (34%) as a white solid.

[1392] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.65 (m, 2H), 3.33 (m, 1H), 3.05 (m, 3), 2.82 (m, 10H), 2.63 (m, 2H), 2.14 (m, 2H), 2.02 (m, 4H), 1.83 (m, 4H), and 1.01 (t, 3H).

[1393] LCMS: m/z 447 (M+H).sup.+ (ES.sup.+); 445 (MH).sup. (ES.sup.).

Example 25: 1-(Cyclobutanecarbonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[1394] ##STR00416##

[1395] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(cyclobutanecarbonyl)piperidine-4-sulfonamide (Intermediate P21) to afford the title compound (29%) as a white solid.

[1396] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.58 (m, 1H), 3.91 (m, 1H), 3.40 (m, 1H), 3.02 (m, 1H), 2.82 (m, 8H), 2.63 (m, 1H), 2.2 (m, 6H), 2.02 (m, 6H), 1.83 (m, 1H) and 1.67 (m, 2H).

[1397] LCMS: m/z 446 (M+H).sup.+ (ES.sup.+); 444 (MH).sup. (ES.sup.).

Example 26: N-Ethyl-4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)piperidine-1-carboxamide, Potassium Salt

[1398] ##STR00417##

[1399] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-ethyl-4-sulfamoylpiperidine-1-carboxamide (Intermediate P22) to afford the title compound (5%) as a white solid.

[1400] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.13 (m, 2H), 3.56 (m, 1H), 3.18 (m, 2H), 2.82 (m, 10H), 2.02 (m, 6H), 1.7 (m, 2H) and 1.1 (t, 3H).

[1401] LCMS: m/z 435 (M+H).sup.+ (ES.sup.+).

Example 27: N-Cyclobutyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)piperidine-1-carboxamide, Potassium Salt

[1402] ##STR00418##

[1403] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-cyclobutyl-3-sulfamoylpiperidine-1-carboxamide to afford the title compound (11%) as a white solid.

[1404] .sup.1H NMR (CD.sub.30OD) 6.86 (s, 1H), 4.3 (m, 2H), 4.03 (m, 2H), 3.46 (m, 1H), 2.99 (m, 2H), 2.82 (m, 8H), 2.65 (m, 2H), 2.27 (m, 1H), 2.02 (m, 4H), 1.8 (m, 4H), 1.6 (m, 2H), 1.44 (m, 1H).

[1405] LCMS: m/z 461 (M+H).sup.+ (ES.sup.+).

Example 28: 4-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-methylpiperidine-1-carboxamide, Potassium Salt

[1406] ##STR00419##

[1407] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-methyl-4-sulfamoylpiperidine-1-carboxamide (Intermediate P23) to afford the title compound (9%) as a white solid.

[1408] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.11 (m, 2H), 3.55 (m, 1H), 3.02 (m, 1H), 2.82 (m, 9H), 2.73 (m, 1H), 2.7 (s, 3H), 2.02 (m, 6H) and 1.7 (m, 2H).

[1409] LCMS: m/z 421 (M+H).sup.+ (ES.sup.+).

Example 29: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(methylsulfonyl)piperidine-4-sulfonamide, Potassium Salt

[1410] ##STR00420##

[1411] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(methylsulfonyl)piperidine-4-sulfonamide (Intermediate P24) to afford the title compound (33%) as a white solid.

[1412] .sup.1H NMR (CD.sub.3OD) rotamer mixture 6 6.86 (s, 1H), 3.92 (m, 2H, rotamer a), 3.82 (m, 2H, rotamer b), 3.55 (m, 1H), 3.0 (m, 1H) 2.82 (m, 12H), 2.22 (m, 2H), 2.02 (m, 4H), 1.87 (m, 2H).

[1413] LCMS: m/z 442 (M+H).sup.+ (ES.sup.+).

Example 30: N-Ethyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)pyrrolidine-1-carboxamide, Potassium Salt

[1414] ##STR00421##

[1415] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-ethyl-3-sulfamoylpyrrolidine-1-carboxamide (Intermediate P25) to afford the title compound (48%) as a white solid.

[1416] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.25 (m, 1H), 3.63 (m, 3H), 3.18 (m, 2H), 2.82 (m, 10H), 2.39 (m, 1H), 2.23 (m, 1H), 2.02 (m, 4H) and 1.08 (t, 3H).

[1417] LCMS: m/z 421 (M+H).sup.+ (ES.sup.+); 419 (MH).sup. (ES.sup.).

Example 31: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-piperidine-3-sulfonamide, Potassium Salt

[1418] ##STR00422##

[1419] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropylpiperidine-3-sulfonamide to afford the title compound (18%) as a white solid.

[1420] .sup.1H NMR (CD.sub.3OD) 6.89 (s, 1H), 3.78 (m, 1H), 3.5 (m, 1H), 3.05 (m, 1H), 2.8 (m, 8H), 2.7 (m, 2H), 2.45 (m, 1H), 2.21 (m, 1H), 2.02 (m, 4H), 1.86 (m, 1H), 1.67 (m, 2H) and 1.17 (d, 6H).

[1421] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+).

Example 32: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-propionylpiperidine-3-sulfonamide, Potassium Salt

[1422] ##STR00423##

[1423] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-propionylpiperidine-3-sulfonamide to afford the title compound (2.sub.7%) as a white solid.

[1424] .sup.1H NMR (CD.sub.3OD) rotamer mixture 6 6.87 (s, 1H), 4.96 (m, 1H, rotamer a), 4.4 (m, 1H, rotamer b), 4.28 (m, 1H, rotamer a), 3.87 (m, 1H, rotamer b), 3.52 (m, 1H), 3.01 (m, 1H), 2.82 (m, 8H), 2.64 (m, 1H), 2.42 (m, 2H), 2.28 (m, 1H), 2.02 (m, 4H), 1.85 (m, 2H), 1.5 (m, 1H) and 1.1 (t, 3H).

[1425] LCMS: m/z 420 (M+H).sup.+ (ES.sup.+); 418 (MH).sup. (ES.sup.).

Example 33: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-iso-propylpiperidine-1-carboxamide, Potassium Salt

[1426] ##STR00424##

[1427] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-isopropyl-3-sulfamoylpiperidine-1-carboxamide (Intermediate P26) to afford the title compound (55%) as a white solid.

[1428] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.35 (m, 1H), 4.0 (m, 1H), 3.85 (m, 1H), 3.42 (m, 1H), 2.82 (m, 9H), 2.68 (m, 2H), 2.28 (m, 1H), 2.02 (m, 4H), 1.79 (m, 2H), 1.45 (m, 1H) and 1.1 (d, 6H).

[1429] LCMS: m/z 449 (M+H).sup.+ (ES.sup.+); 447 (MH).sup. (ES.sup.).

Example 34: 1-(2-Fluoroethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-3-sulfonamide, Potassium Salt

[1430] ##STR00425##

[1431] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-fluoroethyl)piperidine-3-sulfonamide to afford the title compound (2%) as a white solid.

[1432] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.84 (m, 1H), 4.64 (m, 1H), 3.61 (m, 1H), 3.41 (m, 1H), 2.91 (m, 1H), 2.82 (m, 8H), 2.69 (m, 2H), 2.31 (m, 1H), 2.21 (m, 1H), 2.02 (m, 5H), 1.79 (m, 1H) and 1.61 (m, 2H).

[1433] LCMS: m/z 410 (M+H).sup.+ (ES.sup.+); 408 (MH).sup. (ES.sup.).

Example 35: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1,2,3,4-tetrahydroquinoline-3-sulfonamide, Potassium Salt

[1434] ##STR00426##

[1435] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1,2,3,4-tetrahydroquinoline-3-sulfonamide to afford the title compound (13%) as a white solid.

[1436] .sup.1H NMR (CD.sub.3OD) 6.92 (m, 3H), 6.58 (m, 2H), 3.92 (m, 2H), 3.73 (m, 2H), 3.11 (m, 2H), 2.82 (m, 8H) and 2.02 (m, 4H).

[1437] LCMS: m/z 412 (M+H).sup.+ (ES.sup.+).

Example 36: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methylpyrrolidine-3-sulfonamide, Potassium Salt

[1438] ##STR00427##

[1439] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-methyl-pyrrolidine-3-sulfonamide (Intermediate P27) to afford the title compound (19%) as a white solid.

[1440] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.21 (m, 1H), 3.1 (m, 1H), 2.9 (m, 1H), 2.82 (m, 9H), 2.62 (m, 1H), 2.42 (s, 3H), 2.33 (m, 1H), 2.19 (m, 1H) and 2.02 (m, 4H).

[1441] LCMS: m/z 364 (M+H).sup.+ (ES.sup.+); 362 (MH).sup. (ES.sup.).

Example 37: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) pyrrolidine-3-sulfonamide, Potassium Salt

[1442] ##STR00428##

[1443] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethyl-pyrrolidine-3-sulfonamide (Intermediate P28) to afford the title compound (30%) as a white solid.

[1444] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.21 (m, 1H), 3.0 (m, 2H), 2.82 (m, 10H), 2.7 (m, 2H), 2.38 (m, 1H), 2.22 (m, 1H), 2.02 (m, 4H) and 1.18 (t, 3H).

[1445] LCMS: m/z 378 (M+H).sup.+ (ES.sup.+); 376 (MH).sup. (ES.sup.).

Example 38: 1-Acetyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) pyrrolidine-3-sulfonamide, Potassium Salt

[1446] ##STR00429##

[1447] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-acetyl-pyrrolidine-3-sulfonamide (Intermediate P29) to afford the title compound (21%) as a white solid.

[1448] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.24 (m, 1H), 3.9 (m, 1H), 3.75 (m, 1H), 3.57 (m, 1H), 3.45 (m, 1H), 2.82 (m, 8H), 2.38 (m, 2H) and 2.02 (m, 7H).

[1449] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+); 390 (MH).sup. (ES.sup.).

Example 39: 1-Cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)pyrrolidine-3-sulfonamide, Potassium Salt

[1450] ##STR00430##

[1451] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclopropyl-pyrrolidine-3-sulfonamide (Intermediate P30) to afford the title compound (30%) as a white solid.

[1452] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.18 (m, 1H), 3.22 (m, 1H), 3.02 (m, 1H), 2.82 (m, 10H), 2.29 (m, 1H), 2.16 (m, 1H), 2.02 (m, 4H), 1.81 (m, 1H) and 1.45 (m, 4H).

[1453] LCMS: m/z 390 (M+H).sup.+ (ES.sup.+); 388 (MH).sup. (ES.sup.).

Example 40: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl) sulfamoyl)-N,N-dimethylpyrrolidine-1-carboxamide

[1454] ##STR00431##

[1455] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N,N-dimethyl-3-sulfamoylpyrrolidine-1-carboxamide (Intermediate P31) to afford the title compound as a white solid.

[1456] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.18 (m, 1H), 3.82 (m, 1H), 3.64 (m, 2H), 3.44 (m, 1H), 2.86 (s, 6H), 2.82 (m, 8H), 2.34 (m, 1H), 2.19 (m, 1H) and 2.02 (m, 4H).

[1457] LCMS: m/z 421 (M+H).sup.+ (ES.sup.+); 419 (MH).sup. (ES.sup.).

Example 41: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propylpyrrolidine-3-sulfonamide, Potassium Salt

[1458] ##STR00432##

[1459] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropylpyrrolidine-3-sulfonamide (Intermediate P32) to afford the title compound (36%) as a white solid.

[1460] .sup.1H NMR (CD.sub.30OD) 6.86 (s, 1H), 4.21 (m, 1H), 3.38 (m, 1H), 3.04 (m, 2H), 2.82 (m, 8H), 2.72 (m, 2H), 2.38 (m, 1H), 2.2 (m, 1H), 2.02 (m, 4H) and 1.19 (d, 6H).

[1461] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+); 390 (MH).sup. (ES.sup.).

Example 42: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) azetidine-3-sulfonamide

[1462] ##STR00433##

[1463] To a solution of benzyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)azetidine-1-carboxylate, potassium salt (Example 71) in methanol was added Pd/C and the reaction was heated to 65 C. under an atmosphere of hydrogen. Upon cooling, the mixture was filtered and purified by reversed phase chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (28%) as a white solid.

[1464] .sup.1H NMR (CD.sub.3OD) 6.84 (s, 1H), 4.8 (s, 1H), 4.58 (m, 1H), 4.04 (m, 1H), 3.7 (m, 1H), 3.3 (m, 1H), 2.8 (m, 8H) and 2.02 (m, 4H).

[1465] LCMS: m/z 337 (M+H).sup.+ (ES.sup.+).

Example 43: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) quinuclidine-3-sulfonamide, Potassium Salt

[1466] ##STR00434##

[1467] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and quinuclidine-3-sulfonamide (Intermediate P34) to afford the title compound (7%) as a white solid.

[1468] .sup.1H NMR (300 MHz, CD.sub.3OD) 6.86 (s, 1H), 4.18 (m, 1H), 3.97 (m, 1H), 3.82 (m, 1H), 3.62 (m, 1H), 3.58 (m, 2H), 3.08 (m, 1H), 2.82 (m, 8H), 2.41 (m, 2H), 2.02 (m, 4H), 1.77 (m, 2H) and 1.48 (m, 1H).

[1469] LCMS: m/z 390 (M+H).sup.+ (ES.sup.+); 388 (MH).sup. (ES.sup.).

Example 44: 1-(1-Ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyrrolidine-3-sulfonamide, Potassium Salt

[1470] ##STR00435##

[1471] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(1-ethylpiperidin-4-yl)pyrrolidine-3-sulfonamide (Intermediate P35) to afford the title compound (29%) as a white solid.

[1472] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.18 (m, 1H), 3.72 (m, 1H), 3.2 (m, 2H), 3.08 (m, 2H), 2.93 (m, 1H), 2.82 (m, 8H), 2.71 (m, 2H), 2.6 (m, 2H), 2.48 (m, 1H), 2.23 (m, 4H), 2.02 (m, 4H), 1.65 (m, 2H) and 1.18 (t, 3H).

[1473] LCMS: m/z 461 (M+H).sup.+ (ES.sup.+); 459 (MH).sup. (ES.sup.).

Example 45: (1R*,3R*,5S*)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-8-isopropyl-8-azabicyclo[3.2.1]octane-3-sulfonamide, Potassium Salt

[1474] ##STR00436##

[1475] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1R*,3R*,5S*)-8-isopropyl-8-azabicyclo[3.2.1]octane-3-sulfonamide (Intermediate P36) to afford the title compound (12%) as a white solid.

[1476] .sup.1H NMR (CD3OD) 6.86 (s, 1H), 4.02 (m, 1H), 2.82 (m, 8H), 2.68 (m, 1H), 2.22 (m, 10H), 2.02 (m, 4H) and 1.38 (d, 6H).

[1477] LCMS: m/z 432 (M+H).sup.+ (ES.sup.+); 430 (MH).sup. (ES.sup.).

Example 46: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propylazetidine-3-sulfonamide, Potassium Salt

[1478] ##STR00437##

[1479] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-iso-propylazetidine-3-sulfonamide (Intermediate P37) to afford the title compound (57%) as a white solid.

[1480] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.33 (m, 1H), 3.88 (m, 4H), 2.82 (m, 9H), 2.02 (m, 4H), and 1.03 (d, 6H).

[1481] LCMS: m/z 378 (M+H).sup.+ (ES.sup.+); 376 (MH).sup. (ES.sup.).

Example 47: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propylpiperidine-4-sulfonamide, Potassium Salt

[1482] ##STR00438##

[1483] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropylpiperidine-4-sulfonamide (Intermediate P138) to afford the title compound (59%) as a white solid.

[1484] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.03 (m, 2H), 2.82 (m, 8H), 2.72 (m, 1H), 2.18 (m, 5H), 2.02 (m, 4H), 1.88 (m, 2H) and 1.07 (d, 6H).

[1485] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+); 404 (MH).sup. (ES.sup.).

Example 48: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-[1,4-bipiperidine]-4-sulfonamide, Potassium Salt

[1486] ##STR00439##

[1487] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethyl-[1,4-bipiperidine]-4-sulfonamide (Intermediate P38) to afford the title compound (22%) as a white solid.

[1488] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.4 (m, 1H), 3.19 (m, 4H), 2.82 (m, 8H), 2.7 (m, 2H), 2.58 (m, 1H), 2.38 (m, 4H), 2.18 (m, 2H), 2.02 (m, 4H), 1.93 (m, 4H), 1.7 (m, 2H) and 1.18 (t, 3H).

[1489] LCMS: m/z 475 (M+H).sup.+ (ES.sup.+); 473 (MH).sup. (ES.sup.).

Example 49: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methylazetidine-3-sulfonamide, Potassium Salt

[1490] ##STR00440##

[1491] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-methylazetidine-3-sulfonamide (Intermediate P39) to afford the title compound (13%) as a white solid.

[1492] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.35 (m, 1H), 4.18 (m, 4H), 2.82 (m, 8H), 2.77 (s, 3H) and 2.02 (m, 4H).

[1493] LCMS: m/z 350 (M+H).sup.+ (ES.sup.+); 348 (MH).sup. (ES.sup.).

Example 50: 2-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-azaspiro[3.3]heptane-6-sulfonamide, Potassium Salt

[1494] ##STR00441##

[1495] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-ethyl-2-azaspiro[3.3]heptane-6-sulfonamide (Intermediate P40) to afford the title compound (35%) as a white solid.

[1496] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.05 (m, 1H), 3.61 (m, 4H), 2.82 (m, 8H), 2.73 (m, 2H), 2.64 (m, 2H), 2.53 (m, 2H), 2.02 (m, 4H) and 1.03 (t, 3H).

[1497] LCMS: m/z 404 (M+H).sup.+ (ES.sup.+); 402 (MH).sup. (ES.sup.).

Example 51: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-isopropylazetidin-3-yl)pyrrolidine-3-sulfonamide, Potassium Salt

[1498] ##STR00442##

[1499] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(1-isopropyl-azetidin-3-yl)pyrrolidine-3-sulfonamide (Intermediate P41) to afford the title compound (21%) as a white solid.

[1500] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.19 (m, 1H), 3.72 (m, 2H), 3.35 (m, 1H), 3.21 (m, 1H), 2.97 (m, 1H), 2.82 (m, 10H), 2.8 (m, 1H), 2.63 (m, 2H), 2.33 (m, 1H), 2.17 (m, 1H), 2.02 (m, 4H) and 1.03 (d, 6H).

[1501] LCMS: m/z 447 (M+H).sup.+ (ES.sup.+).

Example 52: (1R*,3R*,5S*)-8-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-8-azabicyclo[3.2.1]octane-3-sulfonamide, Potassium Salt

[1502] ##STR00443##

[1503] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1R*,3R*,5S*)-8-ethyl-8-azabicyclo[3.2.1]octane-3-sulfonamide (Intermediate P42) to afford the title compound (12%) as a white solid.

[1504] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.91 (m, 1H), 3.64 (m, 2H), 2.82 (m, 10H), 2.5 (m, 3H), 2.29 (m, 3H), 2.02 (m, 6H) and 1.12 (t, 3H).

[1505] LCMS: m/z 418 (M+H).sup.+ (ES.sup.+); 416 (MH).sup. (ES.sup.).

Example 53: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) azetidine-3-sulfonamide, Potassium Salt

[1506] ##STR00444##

[1507] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethylazetidine-3-sulfonamide (Intermediate P43) to afford the title compound (18%) as a white solid.

[1508] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.35 (m, 1H), 3.78 (m, 2H), 3.63 (m, 2H), 2.82 (m, 8H), 2.68 (m, 2H), 2.02 (m, 4H) and 1.01 (t, 3H).

[1509] LCMS: m/z 364 (M+H).sup.+ (ES.sup.+); 362 (MH).sup. (ES.sup.).

Example 54: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2,2,2-trifluoroacetyl)pyrrolidine-3-sulfonamide, Potassium Salt

[1510] ##STR00445##

[1511] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2,2,2-trifluoroacetyl)pyrrolidine-3-sulfonamide (Intermediate P44) to afford the title compound (15%) as a white solid.

[1512] .sup.1H NMR (CD.sub.3OD) 6.96 (s, 1H), 4.42 (m, 1H), 4.14 (m, 1H), 3.85 (m, 2H), 3.58 (m, 1H), 2.8 (m, 8H), 2.5 (m, 2H) and 2.04 (m, 4H).

[1513] LCMS: m/z 446 (M+H).sup.+ (ES.sup.+); 444 (MH).sup. (ES.sup.).

Example 55: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl pyrrolidine-3-sulfonamide, Potassium Salt

[1514] ##STR00446##

[1515] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2,2,2-trifluoroacetyl)pyrrolidine-3-sulfonamide (Intermediate P44) to afford the deprotected title compound (5%) as a white solid.

[1516] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 4.58 (m, 1H), 4.22 (m, 1H), 3.65 (m, 1H), 3.38 (m, 1H), 3.19 (m, 1H), 2.82 (m, 8H), 2.45 (m, 1H), 2.29 (m, 1H), and 2.02 (m, 4H).

[1517] LCMS: m/z 350 (M+H).sup.+ (ES.sup.+); 348 (MH).sup. (ES.sup.).

Example 56: 1-Acetyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) piperidine-3-sulfonamide, Potassium Salt

[1518] ##STR00447##

[1519] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-acetyl-piperidine-3-sulfonamide to afford the title compound (33%) as a white solid.

[1520] .sup.1H NMR (CD.sub.3OD) rotamer mixture 6 6.87 (s, 1H), 4.96 (m, 1H, rotamer), 4.32 (m, 1H, rotamer), 4.25 (m, 1H, rotamer), 3.85 (m, 1H, rotamer), 3.55 (m, 1H), 3.05 (m, 1H), 2.82 (m, 8H), 2.69 (m, 1H), 2.27 (m, 1H), 2.17 (s, 3H, rotamer), 2.09 (s, 3H, rotamer), 2.02 (m, 4H), 1.85 (m, 2H), 1.5 (m, 1H).

[1521] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+); 404 (MH).sup. (ES.sup.).

Example 57: 1-(Cyclopropylmethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-3-sulfonamide, Potassium Salt

[1522] ##STR00448##

[1523] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(cyclopropylmethyl)piperidine-3-sulfonamide (Intermediate P45) to afford the title compound (21%) as a white solid.

[1524] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.72 (m, 2H), 3.06 (m, 1H), 2.8 (m, 8H), 2.5 (m, 3H), 2.22 (m, 2H), 2.02 (m, 4H), 1.85 (m, 2H), 1.65 (m, 2H), 0.6 (m, 2H) and 0.21 (m, 2H).

[1525] LCMS: m/z 418 (M+H).sup.+ (ES.sup.+); 416 (MH).sup. (ES.sup.).

Example 58: 1-(Cyanomethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-3-sulfonamide, Potassium Salt

[1526] ##STR00449##

[1527] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(cyanomethyl) piperidine-3-sulfonamide to afford the title compound (41%) as a white solid.

[1528] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.67 (s, 2H), 3.6 (m, 1H), 3.29 (m, 2H), 2.82 (m, 8H), 2.47 (t, 1H), 2.21 (m, 2H), 2.02 (m, 4H), 1.84 (m, 1H) and 1.58 (m, 2H).

[1529] LCMS: m/z 403 (M+H).sup.+ (ES.sup.+); 401 (MH).sup. (ES.sup.).

Example 59: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-3-sulfonamide, Potassium Salt

[1530] ##STR00450##

[1531] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(prop-2-yn-1-yl)piperidine-3-sulfonamide to afford the title compound (44%) as a white solid.

[1532] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.57 (m, 1H), 3.33 (m, 4H), 2.82 (m, 8H), 2.65 (m, 1H), 2.42 (t, 1H), 2.2 (m, 2H), 2.02 (m, 4H), 1.82 (m, 1H) and 1.58 (m, 2H).

[1533] LCMS: m/z 402 (M+H).sup.+ (ES.sup.+); 400 (MH).sup. (ES.sup.).

Example 60: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methylpiperidine-3-sulfonamide, Potassium Salt

[1534] ##STR00451##

[1535] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-methylpiperidine-3-sulfonamide (Intermediate P46) to afford the title compound (11%) as a white solid.

[1536] .sup.1H NMR (CD.sub.3OD) 6.88 (s, 1H), 3.68 (m, 1H), 3.4 (m, 1H), 2.82 (m, 9H), 2.43 (m, 1H), 2.42 (s, 3H), 2.2 (m, 2H), 2.02 (m, 4H), 1.9 (m, 1H), and 1.64 (m, 2H).

[1537] LCMS: m/z 378 (M+H).sup.+ (ES.sup.+).

Example 61: 4-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N-dimethylpiperidine-1-carboxamide

[1538] ##STR00452##

[1539] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N,N-dimethyl-4-sulfamoylpiperidine-1-carboxamide (Intermediate P48) to afford the title compound (46%) as a white solid.

[1540] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.78 (m, 2H), 3.50 (m, 1H), 2.82 (m, 10H), 2.80 (s, 6H), 2.05 (m, 6H) and 1.8 (m, 2H).

[1541] LCMS: m/z 435 (M+H).sup.+ (ES.sup.+); 433 (MH).sup. (ES.sup.).

Example 62: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-isopropylazetidin-3-yl)piperidine-4-sulfonamide, Potassium Salt

[1542] ##STR00453##

[1543] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(1-isopropylazetidin-3-yl)piperidine-4-sulfonamide (Intermediate P49) to afford the title compound (37%) as a white solid.

[1544] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.59 (s, 1H), 3.75 (t, 2H), 3.02 (d, 2H), 2.99-2.69 (m, 12H), 2.13 (d, 2H), 2.02 (m, 4H), 1.95-1.76 (m, 4H), 1.05 (d, 6H).

[1545] LCMS: m/z 461 (M+H).sup.+ (ES.sup.+); 459 (MH).sup. (ES.sup.).

Example 63: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-isopropyl-2-azaspiro[3.3]heptane-6-sulfonamide, Potassium Salt

[1546] ##STR00454##

[1547] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-isopropyl-2-azaspiro[3.3]heptane-6-sulfonamide (Intermediate P50) to afford the title compound (41%) as a white solid.

[1548] .sup.1H NMR (CD.sub.3OD): =6.89 (s, 1H), 4.28-3.80 (m, 5H), 3.26-3.12 (m, 1H), 2.81 (dt, 8H), 2.73-2.55 (m, 4H), 2.04 (q, 4H), 1.14 (d, 6H).

[1549] LCMS: m/z 418 (M+H).sup.+ (ES.sup.+); 416 (MH).sup. (ES.sup.).

Example 64: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-methyl-2-azaspiro[3.3]heptane-6-sulfonamide, Potassium Salt

[1550] ##STR00455##

[1551] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-methyl-2-azaspiro[3.3] heptane-6-sulfonamide (Intermediate P51) to afford the title compound (14%) as a white solid.

[1552] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.04 (m, 5H), 2.96-2.72 (m, 11H), 2.72-2.55 (m, 4H), 2.02 (m, 4H).

[1553] LCMS: m/z 390 (M+H).sup.+ (ES.sup.+); 388 (MH).sup. (ES.sup.).

Example 65: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(pentan-3-yl)azetidine-3-sulfonamide, Potassium Salt

[1554] ##STR00456##

[1555] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(pentan-3-yl)azetidine-3-sulfonamide (Intermediate P52) to afford the title compound (31%) as a white solid.

[1556] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.31 (m, 1H), 4.16 (m, 4H), 2.82 (m, 9H), 2.04 (q, 4H), 1.78-1.41 (m, 4H), 0.92 (t, 6H).

[1557] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+); 404 (MH).sup. (ES.sup.).

Example 66: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1,2,3,4-tetrahydroquinoline-3-sulfonamide, Potassium Salt

[1558] ##STR00457##

[1559] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethyl-1,2,3,4-tetrahydroquinoline-3-sulfonamide (Intermediate P53) to afford the title compound (33%) as a white solid.

[1560] .sup.1H NMR (CD.sub.3OD): =6.95 (m, 3H), 6.81-6.51 (m, 2H), 3.76-3.41 (m, 2H), 3.21-3.01 (m, 2H), 2.83 (m, 10H), 2.29-1.91 (m, 5H), 1.15 (t, 3H).

[1561] LCMS: m/z 440 (M+H).sup.+ (ES.sup.+); 438 (MH).sup. (ES.sup.).

Example 67: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2,2,2-trifluoroethyl)piperidine-4-sulfonamide, Potassium Salt

[1562] ##STR00458##

[1563] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2,2,2-trifluoroethyl)piperidine-4-sulfonamide (Intermediate P54) to afford the title compound (49%) as a white solid.

[1564] .sup.1H NMR (CD.sub.3OD): =6.96 (s, 1H), 3.66-3.39 (m, 1H), 3.09 (dt, 5H), 2.82 (dt, 9H), 2.44 (t, 2H), 2.05 (m, 4H), 1.90 (dd, 2H).

[1565] LCMS: m/z 446 (M+H).sup.+ (ES.sup.+); 444 (MH).sup. (ES.sup.).

Example 68: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-2-oxopyrrolidine-3-sulfonamide, Potassium Salt

[1566] ##STR00459##

[1567] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropyl-2-oxopyrrolidine-3-sulfonamide (Intermediate P64) to afford the title compound (64%) as a white solid.

[1568] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.47-4.13 (m, 2H), 3.52 (dt, 1H) 3.32 (dt, 1H), 2.82 (q, 8H), 2.68-2.46 (m, 1H), 2.46-2.25 (m, 1H), 2.15-1.89 (m, 4H), 1.15 (d, 6H).

[1569] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+); 404 (MH).sup. (ES.sup.).

Example 69: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-8-isopropyl-8-azabicyclo[3.2.1]octane-3-sulfonamide Exo-Isomer, Potassium Salt

[1570] ##STR00460##

[1571] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1R*,3S*,5S*)-8-iso-propyl-8-azabicyclo[3.2.1]octane-3-sulfonamide (Intermediate P55) to afford the title compound (40%) as a white solid.

[1572] .sup.1H NMR (CD.sub.3OD): =6.95 (s, 1H), 4.57 (s, 1H), 4.34 (s, 1H), 4.12 (s, 1H), 2.85 (dt, 9H), 2.59 (s, 1H), 2.47-2.16 (m, 5H), 2.06 (m, 6H), 1.41 (d, 6H).

[1573] LCMS: m/z 432 (M+H).sup.+ (ES.sup.+); 430 (MH).sup. (ES.sup.).

Example 70: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-8-ethyl-8-azabicyclo[3.2.1]octane-3-sulfonamide Exo Isomers, Potassium Salt

[1574] ##STR00461##

[1575] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1R*,3S*,5S*)-8-ethyl-8-azabicyclo[3.2.1]octane-3-sulfonamide (Intermediate P56) to afford the title compound (23%) as a white solid.

[1576] .sup.1H NMR (CD.sub.3OD): =6.91 (s, 1H), 4.57 (s, 1H), 3.99 (d, 3H), 3.84-3.64 (m, 1H), 3.47 (dt, 2H), 3.04 (q, 2H), 2.85 (q, 9H), 2.65-2.40 (m, 1H), 2.40-1.65 (m, 9H).

[1577] LCMS: m/z 418 (M+H).sup.+ (ES.sup.+); 416 (MH).sup. (ES.sup.).

Example 71: Benzyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)azetidine-1-carboxylate, Potassium Salt

[1578] ##STR00462##

[1579] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and benzyl 3-sulfamoylazetidine-1-carboxylate (Intermediate P47) to afford the title compound (41%) as a white solid.

[1580] .sup.1H NMR (CD.sub.3OD): =7.51-7.15 (m, 5H), 6.93 (s, 1H), 5.09 (s, 2H), 4.31 (m, 4H), 2.80 (dt, 9H), 2.03 (m, 4H).

[1581] LCMS: m/z 470 (M+H).sup.+ (ES.sup.+); 468 (MH).sup. (ES.sup.).

Example 72: 1-Benzyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) azetidine-3-sulfonamide, Potassium Salt

[1582] ##STR00463##

[1583] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-benzylazetidine-3-sulfonamide (Intermediate P57) to afford the title compound (47%) as white solid.

[1584] .sup.1H NMR (CD.sub.3OD): =7.41-7.15 (m, 5H), 6.86 (s, 1H), 4.33 (t, 1H), 3.69 (s, 2H), 3.60 (d, 4H), 2.80 (dt, 8H), 2.02 (q, 4H).

[1585] LCMS: m/z 426 (M+H).sup.+ (ES.sup.+); 424 (MH).sup. (ES.sup.).

Example 73: 1-(1-Ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1586] ##STR00464##

[1587] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(1-ethylpiperidin-4-yl)azetidine-3-sulfonamide (Intermediate P58) to afford the title compound (59%) as a white solid.

[1588] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.31 (q, 1H), 3.65 (t, 2H), 3.54 (t, 2H), 3.00 (d, 2H), 2.83 (q, 9H), 2.51 (q, 2H), 2.25-1.93 (m, 6H), 1.81 (d, 2H), 1.34 (q, 2H), 1.12 (t, 3H).

[1589] LCMS: m/z 447 (M+H).sup.+ (ES.sup.+); 445 (MH).sup. (ES.sup.).

Example 74: 1-Acetyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) azetidine-3-sulfonamide, Potassium Salt

[1590] ##STR00465##

[1591] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-acetylazetidine-3-sulfonamide (Intermediate P59) to afford the title compound (5%) as a white solid.

[1592] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.54-4.32 (m, 2H), 4.32-4.07 (m, 2H), 3.55 (m, 1H), 2.82 (m, 8H), 2.02 (m, 4H), 1.87 (d, 3H).

[1593] LCMS: m/z 378 (M+H).sup.+ (ES.sup.+); 376 (MH).sup. (ES.sup.).

Example 75: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydro-2H-pyran-4-yl)azetidine-3-sulfonamide, Potassium Salt

[1594] ##STR00466##

[1595] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(tetrahydro-2H-pyran-4-yl)azetidine-3-sulfonamide (Intermediate P60) to afford the title compound (29%) as a white solid.

[1596] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.32 (m, 1H), 3.92 (ddd, 2H), 3.74-3.48 (m, 4H), 3.48-3.33 (m, 2H), 2.82 (m, 8H), 2.45 (dt, 1H), 2.02 (m, 4H), 1.70 (dt, 2H), 1.24 (dd, 2H).

[1597] LCMS: m/z 420 (M+H).sup.+ (ES.sup.+); 418 (MH).sup. (ES.sup.).

Example 76: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-propylazetidine-3-sulfonamide, Potassium Salt

[1598] ##STR00467##

[1599] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-propylazetidine-3-sulfonamide (Intermediate P61) to afford the title compound (30%) as a white solid.

[1600] .sup.1H NMR (CD.sub.3OD): =6.91 (s, 1H), 4.39 (m, 1H), 4.29 (d, 4H), 3.17-3.01 (m, 2H), 2.83 (m, 8H), 2.04 (m, 4H), 1.57 (m, 2H), 0.99 (t, 3H).

[1601] LCMS: m/z 378 (M+H).sup.+ (ES.sup.+); 376 (MH).sup. (ES.sup.).

Example 77: tert-Butyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)azetidine-1-carboxylate, Potassium Salt

[1602] ##STR00468##

[1603] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and tert-butyl 3-sulfamoylazetidine-1-carboxylate (Intermediate P62) to afford the title compound (9%) as a white solid.

[1604] .sup.1H NMR (CD.sub.3OD): =6.93 (s, 1H), 4.43 (d, 1H), 4.33-4.03 (m, 4H), 2.82 (m, 8H), 2.04 (m, 4H), 1.44 (s, 9H).

[1605] LCMS: m/z 434 (MH).sup. (ES.sup.).

Example 78: Methyl 2-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)azetidin-1-yl)acetate, Potassium Salt

[1606] ##STR00469##

[1607] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and methyl 2-(3-sulfamoylazetidin-1-yl)acetate (Intermediate P63) to afford the title compound (43%) as a white solid.

[1608] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.36 (m, 1H), 3.87-3.74 (m, 2H), 3.69 (s, 3H), 3.61 (dd, 2H), 3.39 (s, 2H), 2.81 (m, 8H), 2.03 (m, 4H).

[1609] LCMS: m/z 408 (M+H).sup.+ (ES.sup.+); 406 (MH).sup. (ES.sup.).

Example 79: 1-(1-Acetylazetidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[1610] ##STR00470##

[1611] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(1-acetylazetidin-3-yl)piperidine-4-sulfonamide (Intermediate P65) to afford the title compound (20%) as a white solid.

[1612] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.23 (m, 1H), 4.03 (m, 2H), 3.82 (dd, 1H), 3.45 (s, 1H), 3.20 (q, 1H), 2.99 (s, 2H), 2.84 (m, 10H), 2.17 (d, 2H), 2.04 (m, 5H), 1.97-1.78 (m, 4H).

[1613] LCMS: m/z 461 (M+H).sup.+ (ES.sup.+); 459 (MH).sup. (ES.sup.).

Example 80: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-methylazetidin-3-yl)piperidine-4-sulfonamide, Potassium Salt

[1614] ##STR00471##

[1615] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(1-methylazetidin-3-yl)piperidine-4-sulfonamide (Intermediate P66) to afford the title compound (29%) as a white solid.

[1616] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 3.59 (m, 2H), 3.40 (m, 2H), 3.00 (dq, 3H), 2.83 (m, 11H), 2.40 (s, 3H), 2.04 (m, 4H), 1.89 (q, 4H).

[1617] LCMS: m/z 433 (M+H).sup.+ (ES.sup.+); 431 (MH).sup. (ES.sup.).

Example 81: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(pentan-3-yl)pyrrolidine-3-sulfonamide, Potassium Salt

[1618] ##STR00472##

[1619] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(pentan-3-yl)pyrrolidine-3-sulfonamide (Intermediate P67) to afford the title compound (33%) as a white solid.

[1620] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.22 (S, 1H), 3.07 (m, 2H), 2.82 (m, 8H), 2.62-2.18 (m, 5H), 2.03 (m, 4H), 1.86-1.48 (m, 4H), 0.94 (td, 6H).

[1621] LCMS: m/z 420 (M+H).sup.+ (ES.sup.+); 418 (MH).sup. (ES.sup.).

Example 82: 1-(sec-Butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)pyrrolidine-3-sulfonamide, Potassium Salt

[1622] ##STR00473##

[1623] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(sec-butyl)pyrrolidine-3-sulfonamide (Intermediate P68) to afford the title compound (34%) as a white solid.

[1624] .sup.1H NMR (CD.sub.3OD): =6.90 (s, 1H), 4.21 (d, 1H), 3.62-3.40 (m, 1H), 3.23-3.07 (m, 1H), 2.98 (s, 1H), 2.84 (q, 10H), 2.35 (dd, 2H), 2.04 (m, 4H), 1.85 (d, 1H), 1.45 (s, 1H), 1.21 (s, 3H), 1.10-0.82 (m, 3H).

[1625] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+); 404 (MH).sup. (ES.sup.).

Example 83: 1-Butyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) azetidine-3-sulfonamide, Potassium Salt

[1626] ##STR00474##

[1627] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-butylazetidine-3-sulfonamide (Intermediate P69) to afford the title compound (43%) as a white solid.

[1628] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.36 (m, 1H), 3.93-3.59 (m, 4H), 2.81 (q, 8H), 2.66 (t, 2H), 2.02 (m, 4H), 1.48-1.16 (m, 4H), 0.93 (t, 3H).

[1629] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+); 390 (MH).sup. (ES.sup.).

Example 84: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxy-2-methylpropyl)azetidine-3-sulfonamide, Potassium Salt

[1630] ##STR00475##

[1631] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-hydroxy-2-methylpropyl)azetidine-3-sulfonamide (Intermediate P70) to afford the title compound (54%) as a white solid.

[1632] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.37 (m, 1H), 3.77 (m, 2H), 3.68 (m, 2H), 2.83 (m, 8H), 2.57 (s, 2H), 2.04 (m, 4H), 1.15 (s, 6H).

[1633] LCMS: m/z 408 (M+H).sup.+ (ES.sup.+); 406 (MH).sup. (ES.sup.).

Example 85: 1-Cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1634] ##STR00476##

[1635] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclopropylazetidine-3-sulfonamide (Intermediate P71) to afford the title compound (27%) as a white solid.

[1636] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.35 (m, 1H), 3.67 (m, 4H), 2.81 (m, 8H), 2.02 (m, 5H), 0.43 (m, 2H), 0.33 (m, 2H).

[1637] LCMS: m/z 376 (M+H).sup.+ (ES.sup.+); 374 (MH).sup. (ES.sup.).

Example 86: 1-(1,3-Difluoropropan-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1638] ##STR00477##

[1639] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(1,3-difluoropropan-2-yl)azetidine-3-sulfonamide (Intermediate P72) to afford the title compound (91%) as a white solid.

[1640] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.52 (m, 2H), 4.37 (m, 3H), 3.72 (d, 4H), 3.30 (m, 1H), 2.81 (m, 8H), 2.03 (m, 4H).

[1641] LCMS: m/z 414 (M+H).sup.+ (ES.sup.+); 412 (MH).sup. (ES.sup.).

Example 87: 1-(Cyanomethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1642] ##STR00478##

[1643] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(cyanomethyl)azetidine-3-sulfonamide (Intermediate P73) to afford the title compound (57%) as a white solid.

[1644] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.32 (m, 1H), 3.85-3.62 (m, 4H), 3.56 (s, 2H), 2.81 (m, 8H), 2.02 (m, 4H).

[1645] LCMS: m/z 375 (M+H).sup.+ (ES.sup.+); 373 (MH).sup. (ES.sup.).

Example 88: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-methoxyethyl)azetidine-3-sulfonamide, Potassium Salt

[1646] ##STR00479##

[1647] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-methoxyethyl)azetidine-3-sulfonamide (Intermediate P74) to afford the title compound (35%) as a white solid.

[1648] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.36 (m, 1H), 3.82-3.58 (m, 4H), 3.41 (t, 2H), 3.3 (s, 3H), 2.81 (m, 10H), 2.13-1.92 (m, 4H).

[1649] LCMS: m/z 394 (M+H).sup.+ (ES.sup.+).

Example 89: 1-(Cyclohexylmethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1650] ##STR00480##

[1651] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(cyclohexylmethyl)azetidine-3-sulfonamide (Intermediate P75) to afford the title compound (7%) as a white solid.

[1652] .sup.1H NMR (CD.sub.3OD): =6.89 (s, 1H), 4.37 (t, 1H), 3.93-3.67 (m, 4H), 2.83 (m, 9H), 2.61 (m, 1H), 2.12-1.95 (m, 4H), 1.73 (d, 5H), 1.27 (d, 4H), 0.95 (d, 2H).

[1653] LCMS: m/z 432 (M+H).sup.+ (ES.sup.+); 430 (MH).sup. (ES.sup.).

Example 90: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide, Potassium Salt

[1654] ##STR00481##

[1655] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (Intermediate P76) to afford the title compound (51%) as a white solid.

[1656] .sup.1H NMR (CD.sub.3OD): =8.57-8.37 (m, 2H), 7.82 (d, 1H), 7.41 (dd, 1H), 6.87 (s, 1H), 4.36 (q, 1H), 3.76 (s, 2H), 3.70-3.51 (m, 4H), 2.96-2.70 (m, 8H), 2.03 (m, 4H).

[1657] LCMS: m/z 427 (M+H).sup.+ (ES.sup.+); 425 (MH).sup. (ES.sup.).

Example 91: 2-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)azetidin-1-yl)-N,N-dimethylacetamide, potassium salt

[1658] ##STR00482##

[1659] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N,N-dimethyl-2-(3-sulfamoylazetidin-1-yl)acetamide (Intermediate P77) to afford the title compound (15%) as a white solid.

[1660] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.39 (m, 1H), 3.82 (t, 2H), 3.59 (t, 2H), 3.50 (s, 2H), 2.97 (s, 3H), 2.89 (s, 3H), 2.81 (m, 8H), 2.11-1.92 (m, 4H).

[1661] LCMS: m/z 421 (M+H).sup.+ (ES.sup.+); 419 (MH).sup. (ES.sup.).

Example 92: 1-(2-Chloroethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1662] ##STR00483##

[1663] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)piperidine-4-sulfonamide, potassium salt (Example 2) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-chloroethyl)azetidine-3-sulfonamide (Intermediate P78) to afford the title compound (55%) as a white solid.

[1664] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.35 (t, 1H), 3.72 (t, 2H), 3.61 (t, 2H), 3.52 (t, 2H), 2.98-2.69 (m, 10H), 2.02 (m, 4H).

[1665] LCMS: m/z 398 (M+H).sup.+ (ES.sup.+); 396 (MH).sup. (ES.sup.).

Example 93: 1-(tert-Butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1666] ##STR00484##

[1667] To a solution of 1-(tert-butyl)azetidine-3-sulfonamide (Intermediate P82; 10 mg, 0.052 mmol) in THF (3 mL) was added potassium tert-butoxide (6 mg, 0.052 mmol). The mixture was stirred at room temperature for 40 minutes. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1; 10 mg, 0.052 mmol) in THF (1 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and DMSO (0.5-1 mL) was added. The mixture (filtered over cotton wool when solids were present) was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (5 mg, 25%) as a white solid.

[1668] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.28 (m, 1H), 3.76 (t, 2H), 3.41 (t, 2H), 2.81 (m, 8H), 2.02 (m, 4H), 1.01 (s, 9H).

[1669] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+); 390 (MH).sup. (ES.sup.).

Example 94: 1-(Cyclopropylmethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1670] ##STR00485##

[1671] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(cyclopropylmethyl)azetidine-3-sulfonamide (Intermediate P83) to afford the title compound (34%) as a white solid.

[1672] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.38 (t, 1H), 4.09 (q, 4H), 2.83 (m, 10H), 2.02 (m, 4H), 0.89 (d, 1H), 0.58 (q, 2H), 0.28 (q, 2H).

[1673] LCMS: m/z 390 (M+H).sup.+ (ES.sup.+); 388 (MH).sup. (ES.sup.).

Example 95: 1-(2-Azidoethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1674] ##STR00486##

[1675] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-azidoethyl)azetidine-3-sulfonamide (Intermediate P85) to afford the title compound (33%) as a white solid.

[1676] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.36 (p, 1H), 3.71 (td, 2H), 3.58 (dd, 2H), 2.81 (m, 10H), 2.77-2.63 (m, 2H), 2.03 (m, 4H).

[1677] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (MH).sup. (ES.sup.).

Example 96: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2,2,2-trifluoroethyl)azetidine-3-sulfonamide, Potassium Salt

[1678] ##STR00487##

[1679] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2,2,2-trifluoroethyl)azetidine-3-sulfonamide (Intermediate P86) to afford the title compound (11%) as a white solid.

[1680] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.35 (t, 1H), 3.73 (dt, 4H), 3.16 (q, 2H), 2.81 (m, 8H), 2.02 (m, 4H).

[1681] LCMS: m/z 418 (M+H).sup.+ (ES.sup.+); 416 (MH).sup. (ES.sup.).

Example 97: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isobutylazetidine-3-sulfonamide, Potassium Salt

[1682] ##STR00488##

[1683] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isobutylazetidine-3-sulfonamide (Intermediate P84) to afford the title compound (19%) as a white solid.

[1684] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.36 (p, 1H), 3.92 (dt, 4H), 2.92-2.74 (m, 8H), 2.67 (d, 2H), 2.02 (m, 4H), 1.77 (dt, 1H), 0.92 (dd, 6H).

[1685] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+); 390 (MH).sup. (ES.sup.).

Example 98: 1-Cyclohexyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1686] ##STR00489##

[1687] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclohexylazetidine-3-sulfonamide (Intermediate P88) to afford the title compound (9%) as a white solid.

[1688] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.32 (p, 1H), 3.79 (dt, 4H), 2.82 (m, 8H), 2.44 (s, 1H), 2.02 (m, 4H), 1.94-1.54 (m, 5H), 1.41-0.84 (m, 5H).

[1689] LCMS: m/z 418 (M+H).sup.+ (ES.sup.+); 416 (MH).sup. (ES.sup.).

Example 99: 1-Cyclopentyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1690] ##STR00490##

[1691] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-cyclopentylazetidine-3-sulfonamide (Intermediate P89) to afford the title compound (10%) as a white solid.

[1692] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.32 (q, 1H), 3.78 (dt, 4H), 2.82 (m, 9H), 2.02 (m, 4H), 1.94-1.49 (m, 6H), 1.48-1.24 (m, 2H).

[1693] LCMS: m/z 404 (M+H).sup.+ (ES.sup.+); 402 (MH).sup. (ES.sup.).

Example 100: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-iminoethyl)azetidine-3-sulfonamide, Potassium Salt

[1694] ##STR00491##

[1695] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equiv.) and 1-(1-iminoethyl)azetidine-3-sulfonamide (Intermediate P90) to afford the title compound (8%) as a white solid.

[1696] .sup.1H NMR (CD.sub.3OD) (tautomeric mixture): =6.89 (s, 1H), 4.60 (q, 2H), 4.53-4.31 (m, 2H), 3.68-3.43 (m, 1H), 2.82 (m, 8H), 2.13 (s, 3H), 2.02 (m, 4H).

[1697] LCMS: m/z 377 (M+H).sup.+ (ES.sup.+); 375 (MH).sup. (ES.sup.).

Example 101: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(oxetan-3-ylmethyl)azetidine-3-sulfonamide, Potassium Salt

[1698] ##STR00492##

[1699] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(oxetan-3-ylmethyl)azetidine-3-sulfonamide (Intermediate P91) to afford the title compound (53%) as a white solid.

[1700] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.75 (dd, 2H), 4.39 (t, 2H), 4.31 (d, 1H), 3.73-3.59 (m, 2H), 3.52 (t, 2H), 3.05 (dt, 1H), 2.82 (m, 10H), 2.02 (m, 4H).

[1701] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+); 404 (MH).sup. (ES.sup.).

Example 102: 1-(2-(Dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1702] ##STR00493##

[1703] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-(dimethylamino)ethyl) azetidine-3-sulfonamide (Intermediate P92) to afford the title compound (20%) as a white solid.

[1704] .sup.1H NMR (D.sub.2O): =6.94 (s, 1H), 4.20 (t, 1H), 3.55 (t, 2H), 3.41 (t, 2H), 2.72 (m, 8H), 2.60 (t, 5H), 2.54 (s, 6H), 2.05-1.81 (m, 3H).

[1705] LCMS: m/z 407 (M+H).sup.+ (ES.sup.+); 405 (MH).sup. (ES.sup.).

Example 103: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyridin-4-ylmethyl)azetidine-3-sulfonamide, Potassium Salt

[1706] ##STR00494##

[1707] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(pyridin-4-ylmethyl) azetidine-3-sulfonamide (Intermediate P93) to afford the title compound (60%) as a white solid.

[1708] .sup.1H NMR (D.sub.2O): =8.38 (d, 2H), 7.24 (d, 2H), 6.96 (s, 1H), 4.25 (t, 1H), 3.69 (s, 2H), 3.61 (t, 2H), 3.50 (t, 2H), 2.75 (t, 4H), 2.63 (t, 4H), 1.91 (m, 4H).

[1709] LCMS: m/z 427 (M+H).sup.+ (ES.sup.+); 425 (MH).sup. (ES.sup.).

Example 104: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyridin-2-ylmethyl)azetidine-3-sulfonamide, Potassium Salt

[1710] ##STR00495##

[1711] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(pyridin-2-ylmethyl) azetidine-3-sulfonamide (Intermediate P94) to afford the title compound (47%) as a white solid.

[1712] .sup.1H NMR (D.sub.2O): =8.32 (d, 1H), 7.71 (t, 1H), 7.23 (d, 2H), 6.93 (s, 1H), 4.20 (t, 1H), 3.69 (s, 2H), 3.53 (dt, 4H), 2.71 (t, 4H), 2.59 (t, 4H), 1.87 (p, 4H).

[1713] LCMS: m/z 427 (M+H).sup.+ (ES.sup.+); 425 (MH).sup. (ES.sup.).

Example 105: 1-((2-Bromopyridin-3-yl)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1714] ##STR00496##

[1715] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-((2-bromopyridin-3-yl) methyl)azetidine-3-sulfonamide (Intermediate P95) to afford the title compound (46%) as a white solid.

[1716] .sup.1H NMR (D.sub.2O): =8.14 (dd, 1H), 7.64 (dd, 1H), 7.35 (dd, 1H), 6.96 (s, 1H), 4.25 (p, 1H), 3.76 (s, 2H), 3.62 (dt, 4H), 2.75 (t, 4H), 2.64 (t, 4H), 1.91 (m, 4H).

[1717] LCMS: m/z 505 (M+H).sup.+ (ES.sup.+); 503 (MH).sup. (ES.sup.).

Example 106: tert-Butyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-[1,3-biazetidine]-1-carboxylate, Potassium Salt

[1718] ##STR00497##

[1719] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and tert-butyl 3-sulfamoyl-[1,3-biazetidine]-1-carboxylate (Intermediate P96) to afford the title compound (33%) as a white solid.

[1720] .sup.1H NMR (D.sub.2O): =6.94 (s, 1H), 4.19 (t, 1H), 3.86 (d, 2H), 3.64-3.48 (m, 4H), 3.40 (m, 3H), 2.72 (t, 4H), 2.60 (t, 4H), 1.89 (m, 4H), 1.27 (d, 9H).

[1721] LCMS: m/z 491 (M+H).sup.+ (ES.sup.+); 489 (MH).sup. (ES.sup.).

Example 107: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-(methylthio)ethyl)azetidine-3-sulfonamide, Potassium Salt

[1722] ##STR00498##

[1723] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-(methylthio)ethyl) azetidine-3-sulfonamide (Intermediate P98) to afford the title compound (17%) as a white solid.

[1724] .sup.1H NMR (D.sub.2O): =6.99 (s, 1H), 4.26 (p, 1H), 3.80-3.64 (m, 2H), 3.54 (t, 2H), 2.78 (m, 6H), 2.66 (t, 4H), 2.46 (t, 2H), 2.02 (S, 3H), 1.94 (m, 4H).

[1725] LCMS: m/z 410 (M+H).sup.+ (ES.sup.+); 408 (MH).sup. (ES.sup.).

Example 108: 1-(2-Fluoroethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1726] ##STR00499##

[1727] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-fluoroethyl)azetidine-3-sulfonamide (Intermediate P99) to afford the title compound (61%) as a white solid.

[1728] .sup.1H NMR (D.sub.2O): =6.94 (s, 1H), 4.42 (t, 1H), 4.26 (t, 1H), 4.20 (d, 1H), 3.58 (t, 2H), 3.40 (t, 2H), 2.84-2.67 (m, 6H), 2.67-2.52 (m, 4H), 1.88 (m, 4H).

[1729] LCMS: m/z 382 (M+H).sup.+ (ES.sup.+); 380 (MH).sup. (ES.sup.).

Example 109: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(thietan-3-yl)azetidine-3-sulfonamide, Potassium Salt

[1730] ##STR00500##

[1731] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(thietan-3-yl)azetidine-3-sulfonamide (Intermediate P100) to afford the title compound (16%) as a white solid.

[1732] .sup.1H NMR (D.sub.2O): =6.94 (s, 1H), 4.17 (p, 1H), 3.89 (t, 1H), 3.44 (P, 4H), 3.09 (t, 2H), 2.97 (t, 2H), 2.72 (t, 4H), 2.60 (t, 4H), 1.89 (m, 4H).

[1733] LCMS: m/z 408 (M+H).sup.+ (ES.sup.+); 406 (MH).sup. (ES.sup.).

Example 110: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-[1,3-biazetidine]-3-sulfonamide, Potassium Salt

[1734] ##STR00501##

[1735] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-methyl-[1,3-biazetidine]-3-sulfonamide (Intermediate P97) to afford the title compound (13%) as a white solid.

[1736] .sup.1H NMR (D.sub.2O): =6.95 (s, 1H), 4.20 (p, 1H), 3.84-3.67 (m, 2H), 3.66-3.36 (m, 7H), 2.72 (t, 4H), 2.61 (t, 4H), 2.50 (s, 3H), 1.89 (m, 4H).

[1737] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (MH).sup. (ES.sup.).

Example 111: 1-(2-(3-(But-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1738] ##STR00502##

[1739] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl) azetidine-3-sulfonamide (Intermediate Plot) to afford the title compound (58%) as a white solid (light sensitive).

[1740] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.30 (t, 1H), 3.61 (t, 2H), 3.55-3.40 (m, 2H), 2.81 (m, 8H), 2.38 (t, 2H), 2.28 (t, 1H), 2.01 (m, 6H), 1.59 (t, 2H), 1.44 (t, 2H).

[1741] LCMS: m/z 456 (M+H).sup.+ (ES.sup.+); 454 (MH).sup. (ES.sup.).

Example 112: tert-Butyl-(((tert-butoxycarbonyl)imino)(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)azetidin-1-yl)methyl) Carbamate, Potassium Salt

[1742] ##STR00503##

[1743] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and tert-butyl (Z)-(((tert-butoxycarbonyl) amino)(3-sulfamoylazetidin-1-yl)methylene)carbamate (Intermediate P102) to afford the title compound (31%) as a white solid.

[1744] .sup.1H NMR (CDCl.sub.3): =6.85 (s, 1H), 6.68 (s, 1H), 4.62-4.08 (m, 5H), 2.90-2.56 (m, 8H), 1.96 (m, 4H), 1.41 (d, 18H).

[1745] LCMS: m/z 578 (M+H).sup.+ (ES.sup.+); 576 (MH).sup. (ES.sup.).

Example 113: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)azetidine-1-carboximidamide, TFA Salt

[1746] ##STR00504##

[1747] tert-Butyl-(((tert-butoxycarbonyl)imino) (3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)azetidin-1-yl)methyl)carbamate, potassium salt (Example 112; 100 mg, 0.17 mmol) in DCM (0.5 mL) was treated with trifluoroacetic acid (0.5 mL) and stirred for 2 hours. Then the reaction mixture was concentrated in vacuo and DMSO (0.5-1 mL) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (28%) as a white solid.

[1748] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.49-4.24 (m, 5H), 2.82 (m, 8H), 2.02 (m, 4H). .sup.19F-NMR indicated the presence of TFA.

[1749] LCMS: m/z 378 (M+H).sup.+ (ES.sup.+); 376 (MH).sup. (ES.sup.).

Example 114: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-[1,3-biazetidine]-3-sulfonamide, TFA Salt

[1750] ##STR00505##

[1751] Prepared as described for 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)azetidine-1-carboximidamide, TFA salt (Example 113) from tert-butyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-[1,3-biazetidine]-1-carboxylate, potassium salt (Example 106) to afford the title compound (24%) as a white solid.

[1752] .sup.1H NMR (D.sub.2O): =6.96 (s, 1H), 4.32-4.15 (m, 1H), 4.09-3.91 (m, 2H), 3.91-3.67 (m, 3H), 3.54 (m, 4H), 2.73 (t, 4H), 2.62 (t, 4H), 1.91 (m, 4H).

[1753] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+); 389 (MH).sup. (ES.sup.).

Example 115: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-(methylsulfonyl)ethyl)azetidine-3-sulfonamide, Potassium Salt and N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-(methylsulfinyl) ethyl)azetidine-3-sulfonamide, Potassium Salt

[1754] ##STR00506##

[1755] N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-(methylthio)ethyl) azetidine-3-sulfonamide, potassium salt (Example 107; 20 mg, 0.05 mmol) was dissolved in THF (2 mL) and cooled on ice. m-Chloroperbenzoic acid (75 wt %, 13 mg, 0.057 mmol) was added in one portion and the mixture was stirred for 2 hours at 0 C. Then the reaction mixture was concentrated in vacuo and DMSO (0.5-1 mL) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compounds (38%) as a white solid.

[1756] .sup.1H NMR (CD.sub.3OD) (mixture of sulfonyl/sulfinyl, ratio 2/1): =7.01 (sulfonyl) 6.95 (sulfinyl) (s, 1H), 4.36 (m, 1H), 3.94-3.58 (m, 4H), 3.19-2.97 (m, 4H), 2.97-2.73 (m, 8H), 2.73-2.59 (m, 3H), 2.23-1.97 (m, 4H).

[1757] LCMS: m/z 442 (M+H).sup.+ (ES.sup.+); 440 (MH).sup. (ES.sup.), sulfonyl.

[1758] LCMS: m/z 426 (M+H).sup.+ (ES.sup.+); 424 (MH).sup. (ES.sup.), sulfinyl.

Example 116: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(oxetan-3-yl)azetidine-3-sulfonamide, Potassium Salt

[1759] ##STR00507##

[1760] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(oxetan-3-yl)azetidine-3-sulfonamide (Intermediate P131) to afford the title compound (1%) as a white solid.

[1761] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+); 390 (MH).sup. (ES.sup.).

Example 117: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-oxidothietan-3-yl)azetidine-3-sulfonamide, Potassium Salt

[1762] ##STR00508##

[1763] N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(thietan-3-yl) azetidine-3-sulfonamide, potassium salt (Example 109; 25 mg, 0.06 mmol) was dissolved in THF (2 mL) and cooled on ice. m-Chloroperbenzoic acid (75 wt %, 17 mg, 0.74 mmol) was added in one portion and the mixture was stirred for 2 hours at 0 C. Then the reaction mixture was concentrated in vacuo and DMSO (0.5-1 mL) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compounds (15%) as a white solid.

[1764] .sup.1H NMR (CD.sub.3OD): =7.00 (s, 1H), 4.69 (s, 1H), 4.14 (t, 1H), 3.61 (t, 1H), 3.49 (d, 1H), 3.03 (dt, 3H), 2.95-2.78 (m, 8H), 2.78-2.66 (m, 3H), 2.06 (m, 4H).

[1765] LCMS: m/z 424 (M+H).sup.+ (ES.sup.+); 422 (MH).sup. (ES.sup.).

Example 118: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(3-methylcyclobutyl)azetidine-3-sulfonamide, Potassium Salt

[1766] ##STR00509##

[1767] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(3-methylcyclobutyl) azetidine-3-sulfonamide (Intermediate P103) to afford the title compound (22%) as a white solid.

[1768] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.31 (qd, 1H), 3.73-3.53 (m, 4H), 2.93-2.71 (m, 8H), 2.37 (d, 1H), 2.20 (td, 1H), 2.02 (m, 6H), 1.79-1.62 (m, 1H), 1.47 (dt, 1H), 1.08 (dd, 3H).

[1769] LCMS: m/z 404 (M+H).sup.+ (ES.sup.+); 402 (MH).sup. (ES.sup.).

Example 119: 1-(3,3-Dimethylcyclobutyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1770] ##STR00510##

[1771] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(3,3-dimethylcyclobutyl) azetidine-3-sulfonamide (Intermediate P104) to afford the title compound (9%) as a white solid.

[1772] .sup.1H NMR (CD.sub.3OD): =6.89 (s, 1H), 4.34 (t, 1H), 4.25-3.94 (m, 4H), 3.94-3.69 (m, 1H), 2.81 (m, 8H), 2.04 (m, 6H), 1.82 (t, 2H), 1.15 (d, 6H).

[1773] LCMS: m/z 418 (M+H).sup.+ (ES.sup.+); 416 (MH).sup. (ES.sup.).

Example 120: 1-(1,1-Dioxidothietan-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1774] ##STR00511##

[1775] N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(thietan-3-yl) azetidine-3-sulfonamide, potassium salt (Example 109; 18 mg, 0.044 mmol) was dissolved in THF (2 mL) and cooled on ice. m-Chloroperbenzoic acid (75 wt %, 18 mg, 0.078 mmol) was added in one portion and the mixture was stirred for 2 hours at 0 C. Then the reaction mixture was concentrated in vacuo and DMSO (0.5-1 mL) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compounds (47%) as a white solid.

[1776] .sup.1H NMR (CD.sub.3OD): =7.00 (s, 1H), 4.21 (m, 1H), 3.88 (s, 2H), 3.65 (m, 2H), 3.13 (dd, 1H), 2.83 (m, 12H), 2.07 (m, 4H).

[1777] LCMS: m/z 440 (M+H).sup.+ (ES.sup.+); 438 (MH).sup. (ES.sup.).

Example 121: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)azetidine-3-sulfonamide, Potassium Salt

[1778] ##STR00512##

[1779] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(tetrahydrofuran-3-yl) azetidine-3-sulfonamide (Intermediate P106) to afford the title compound (27%) as a white solid.

[1780] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.31 (p, 1H), 3.87 (q, 1H), 3.79-3.43 (m, 7H), 2.81 (m, 9H), 2.03 (m, 4H), 1.98-1.84 (m, 1H), 1.82-1.62 (m, 1H).

[1781] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (MH).sup. (ES.sup.).

Example 122: 1-(sec-Butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1782] ##STR00513##

[1783] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(sec-butyl)azetidine-3-sulfonamide (Intermediate P107) to afford the title compound (43%) as a white solid.

[1784] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.29 (p, 1H), 3.70 (t, 2H), 3.63-3.45 (m, 2H), 2.82 (m, 8H), 2.38 (m, 1H), 2.02 (m, 4H), 1.65-1.45 (m, 1H), 1.21-1.02 (m, 1H), 1.02-0.82 (m, 6H).

[1785] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+); 390 (MH).sup. (ES.sup.).

Example 123: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((1-methyl-1H-imidazol-2-yl)methyl)azetidine-3-sulfonamide, Potassium Salt

[1786] ##STR00514##

[1787] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-((1-methyl-1H-imidazol-2-yl)methyl)azetidine-3-sulfonamide (Intermediate P108) to afford the title compound (49%) as a white solid.

[1788] .sup.1H NMR (CD.sub.3OD): =7.00 (s, 1H), 6.84 (d, 2H), 4.34 (p, 1H), 3.74 (s, 2H), 3.70 (s, 3H), 3.68-3.52 (m, 4H), 2.80 (m, 8H), 2.01 (m, 4H).

[1789] LCMS: m/z 430 (M+H).sup.+ (ES.sup.+); 428 (MH).sup. (ES.sup.).

Example 124: 1-(2,2-Dimethylcyclobutyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1790] ##STR00515##

[1791] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2,2-dimethylcyclobutyl) azetidine-3-sulfonamide (Intermediate P109) to afford the title compound (16%) as a white solid.

[1792] .sup.1H NMR (CD.sub.3OD): =6.89 (s, 1H), 4.40 (t, 1H), 3.73 (dq, 4H), 3.02 (t, 1H), 2.83 (m, 8H), 2.04 (m, 4H), 1.79-1.63 (m, 2H), 1.63-1.46 (m, 2H), 1.10 (d, 6H).

[1793] LCMS: m/z 418 (M+H).sup.+ (ES.sup.+); 416 (MH).sup. (ES.sup.).

Example 125: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyrimidin-5-ylmethyl)azetidine-3-sulfonamide, Potassium Salt

[1794] ##STR00516##

[1795] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(pyrimidin-5-ylmethyl)azetidine-3-sulfonamide (Intermediate P105) to afford the title compound (8%) as a white solid.

[1796] .sup.1H NMR (CD.sub.3OD): =9.06 (s, 1H), 8.76 (s, 2H), 6.88 (s, 1H), 4.38 (t, 1H), 3.77 (s, 2H), 3.74-3.59 (m, 4H), 2.96-2.73 (m, 8H), 2.03 (m, 4H).

[1797] LCMS: m/z 428 (M+H).sup.+ (ES.sup.+); 426 (MH).sup. (ES.sup.).

Example 126: 1-(Cyclobutylmethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1798] ##STR00517##

[1799] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(cyclobutylmethyl) azetidine-3-sulfonamide (Intermediate Pill) to afford the title compound (14%) as a white solid.

[1800] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.34 (p, 1H), 3.72 (dd, 2H), 3.62 (dd, 2H), 2.81 (m, 8H), 2.65 (d, 2H), 2.40 (p, 1H), 2.02 (m, 6H), 1.95-1.64 (m, 4H).

[1801] LCMS: m/z 404 (M+H).sup.+ (ES.sup.+); 402 (MH).sup. (ES.sup.).

Example 127: tert-Butyl-(((tert-butoxycarbonyl)imino)(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)azetidin-1-yl) methyl) (methyl)carbamate, Potassium Salt

[1802] ##STR00518##

[1803] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and tert-butyl-(E)-(((tert-butoxycarbonyl)imino)(3-sulfamoylazetidin-1-yl)methyl) (methyl) carbamate (Intermediate P110) to afford the title compound (49%) as a white solid.

[1804] .sup.1H NMR (CDCl.sub.3): =6.83 (s, 1H), 6.81 (s, 1H), 4.51 (d, 1H), 4.24 (dd, 4H), 2.91 (s, 3H), 2.75 (m, 8H), 1.95 (m, 4H), 1.41 (d, 18H).

[1805] LCMS: m/z 592 (M+H).sup.+ (ES.sup.+); 590 (MH).sup. (ES.sup.).

Example 128: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-(hydroxyimino)propyl)azetidine-3-sulfonamide, Potassium Salt

[1806] ##STR00519##

[1807] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equiv.) and 1-(2-(hydroxyimino)propyl)azetidine-3-sulfonamide (Intermediate P112) to afford the title compound (6%) as a white solid.

[1808] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.47-4.26 (m, 1H), 3.59 (dt, 4H), 3.19 (s, 2H), 2.81 (m, 8H), 2.02 (m, 4H), 1.81 (s, 3H).

[1809] LCMS: m/z 407 (M+H).sup.+ (ES.sup.+); 405 (MH).sup. (ES.sup.).

Example 129: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-methylazetidine-1-carboximidamide, TFA Salt

[1810] ##STR00520##

[1811] Prepared as described for 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)azetidine-1-carboximidamide, TFA salt (Example 113) from tert-butyl-(((tert-butoxycarbonyl)imino)(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)azetidin-1-yl)methyl)(methyl)carbamate, potassium salt (Example 127) to afford the title compound (48%) as a white solid.

[1812] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.46-4.35 (m, 2H), 4.35-4.23 (m, 2H), 2.93-2.71 (m, 11H), 2.71-2.50 (m, 1H), 2.02 (m, 4H).

[1813] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+).

Example 130: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-hydroxypropan-2-yl)azetidine-3-sulfonamide, Potassium Salt

[1814] ##STR00521##

[1815] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equiv.) and 1-(1-hydroxypropan-2-yl)azetidine-3-sulfonamide (Intermediate P113) to afford the title compound (12%) as a white solid.

[1816] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.33 (p, 1H), 3.63 (tt, 4H), 3.43 (dd, 1H), 2.81 (m, 9H), 2.52 (q, 1H), 2.03 (m, 4H), 0.94 (d, 3H).

[1817] LCMS: m/z 394 (M+H).sup.+ (ES.sup.+); 392 (MH).sup. (ES.sup.).

Example 131: 1-(1,1-Difluoropropan-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1818] ##STR00522##

[1819] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(1,1-difluoropropan-2-yl)azetidine-3-sulfonamide (Intermediate P114) to afford the title compound (46%) as a white solid.

[1820] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 5.58 (td, 1H), 4.30 (p, 1H), 3.82-3.51 (m, 4H), 2.81 (m, 8H), 2.69 (ddd, 1H), 2.02 (m, 4H), 1.00 (d, 3H).

[1821] LCMS: m/z 414 (M+H).sup.+ (ES.sup.+); 412 (MH).sup. (ES.sup.).

Example 132: 1-Allyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) azetidine-3-sulfonamide, Potassium Salt

[1822] ##STR00523##

[1823] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-allylazetidine-3-sulfonamide (Intermediate P115) to afford the title compound (15%) as a white solid.

[1824] .sup.1H NMR (CD.sub.3OD): =6.89 (s, 1H), 5.77 (ddt, 1H), 5.54-5.30 (m, 2H), 4.36 (q, 1H), 4.20-3.97 (m, 4H), 3.55 (d, 2H), 2.81 (m, 8H), 2.17-1.93 (m, 4H).

[1825] LCMS: m/z 376 (M+H).sup.+ (ES.sup.+); 374 (MH).sup. (ES.sup.).

Example 133: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(prop-2-yn-1-yl)azetidine-3-sulfonamide, Potassium Salt

[1826] ##STR00524##

[1827] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(prop-2-yn-1-yl)azetidine-3-sulfonamide (Intermediate P116) to afford the title compound (14%) as a white solid.

[1828] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.31 (q, 1H), 3.66 (d, 4H), 3.31 (s, 2H), 2.81 (q, 8H), 2.71-2.57 (m, 1H), 2.02 (m, 4H).

[1829] LCMS: m/z 374 (M+H).sup.+ (ES.sup.+); 372 (MH).sup. (ES.sup.).

Example 134: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(3-hydroxypropyl)azetidine-3-sulfonamide, Potassium Salt

[1830] ##STR00525##

[1831] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equiv.) and 1-(3-hydroxypropyl)azetidine-3-sulfonamide (Intermediate P117) to afford the title compound (3%) as a white solid.

[1832] LCMS: m/z 394 (M+H).sup.+ (ES.sup.+); 392 (MH).sup. (ES.sup.).

Example 135: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-neopentylazetidine-3-sulfonamide, Potassium Salt

[1833] ##STR00526##

[1834] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-neopentylazetidine-3-sulfonamide (Intermediate P118) to afford the title compound (12%) as a white solid.

[1835] .sup.1H NMR (CD.sub.3OD): =6.92 (s, 1H), 4.54-4.29 (m, 5H), 3.06 (s, 2H), 2.79 (m, 8H), 2.16-1.93 (m, 4H), 1.00 (s, 9H).

[1836] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+); 404 (MH).sup. (ES.sup.).

Example 136: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((trimethylsilyl)methyl)azetidine-3-sulfonamide, Potassium Salt

[1837] ##STR00527##

[1838] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-((trimethylsilyl)methyl) azetidine-3-sulfonamide (Intermediate P119) to afford the title compound (32%) as a white solid.

[1839] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.32 (t, 1H), 3.89 (t, 2H), 3.70 (t, 2H), 2.81 (m, 8H), 2.33 (s, 2H), 2.02 (m, 4H), 0.08 (s, 9H).

[1840] LCMS: m/z 422 (M+H).sup.+ (ES.sup.+); 420 (MH).sup. (ES.sup.).

Example 137: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxypropyl)azetidine-3-sulfonamide, Potassium Salt

[1841] ##STR00528##

[1842] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equiv.) and 1-(2-hydroxypropyl)azetidine-3-sulfonamide (Intermediate P120) to afford the title compound (14%) as a white solid.

[1843] .sup.1H NMR (CD.sub.3OD): =6.86 (s, 1H), 4.37 (p, 1H), 3.84-3.47 (m, 4H), 2.81 (m, 9H), 2.50 (d, 2H), 2.13-1.93 (m, 4H), 1.10 (d, 3H).

[1844] LCMS: m/z 394 (M+H).sup.+ (ES.sup.+); 392 (MH).sup. (ES.sup.).

Example 118: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(4-hydroxybutyl)azetidine-3-sulfonamide, Potassium Salt

[1845] ##STR00529##

[1846] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), potassium tert-butoxide (2 equiv.) and 1-(4-hydroxybutyl)azetidine-3-sulfonamide (Intermediate P121) to afford the title compound (4%) as a white solid.

[1847] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.41-4.23 (m, 1H), 3.67 (t, 2H), 3.61-3.45 (m, 4H), 2.82 (m, 8H), 2.57 (t, 2H), 2.15-1.91 (m, 4H), 1.50 (m, 4H).

[1848] LCMS: m/z 408 (M+H).sup.+ (ES.sup.+); 406 (MH).sup. (ES.sup.).

Example 139: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-(3-methyl-3H-diazirin-3-yl)ethyl)azetidine-3-sulfonamide, Potassium Salt

[1849] ##STR00530##

[1850] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-(3-methyl-3H-diazirin-3-yl)ethyl)azetidine-3-sulfonamide (Intermediate P122) to afford the title compound (3%) as a white solid.

[1851] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.33 (p, 1H), 3.64 (t, 2H), 3.49 (q, 2H), 2.82 (m, 8H), 2.46 (t, 2H), 2.03 (m, 4H), 1.35 (t, 2H), 1.00 (s, 3H).

[1852] LCMS: m/z 418 (M+H).sup.+ (ES.sup.+); 416 (MH).sup. (ES.sup.).

Example 140: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((i-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl) azetidine-3-sulfonamide, Potassium Salt

[1853] ##STR00531##

[1854] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)azetidine-3-sulfonamide (Intermediate P123) to afford the title compound (16%) as a white solid.

[1855] .sup.1H NMR (CD.sub.3OD): =7.59 (d, 1H), 7.50 (dd, 1H), 6.87 (s, 1H), 6.51 (d, 1H), 4.32 (p, 1H), 3.71-3.57 (m, 3H), 3.53 (d, 4H), 3.47 (s, 2H), 2.80 (m, 8H), 2.01 (m, 4H).

[1856] LCMS: m/z 457 (M+H).sup.+ (ES.sup.+); 455 (MH).sup. (ES.sup.).

Example 141: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)--((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)azetidine-3-sulfonamide, Potassium Salt

[1857] ##STR00532##

[1858] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)azetidine-3-sulfonamide (Intermediate P124) to afford the title compound (13%) as a white solid.

[1859] .sup.1H NMR (CD.sub.3OD): =7.56 (d, 1H), 6.86 (s, 1H), 6.55-6.42 (m, 1H), 6.34 (dd, 1H), 4.37 (p, 1H), 3.68 (t, 2H), 3.59 (t, 4H), 3.52 (s, 3H), 2.93-2.73 (m, 8H), 2.01 (m, 4H).

[1860] LCMS: m/z 457 (M+H).sup.+ (ES.sup.+); 455 (MH).sup. (ES.sup.).

Example 142: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-(tetrahydrofuran-3-yl)ethyl)azetidine-3-sulfonamide, Potassium Salt

[1861] ##STR00533##

[1862] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-(tetrahydrofuran-3-yl)ethyl)azetidine-3-sulfonamide (Intermediate P125) to afford the title compound (26%) as a white solid.

[1863] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.43-4.24 (m, 1H), 3.97-3.77 (m, 2H), 3.77-3.63 (m, 4H), 3.55 (dd, 2H), 2.82 (m, 8H), 2.71-2.49 (m, 2H), 2.17 (td, 1H), 2.11-1.95 (m, 5H), 1.62-1.37 (m, 3H).

[1864] LCMS: m/z 434 (M+H).sup.+ (ES.sup.+); 432 (MH).sup. (ES.sup.).

Example 143: 1-(sec-Butyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl) azetidine-3-sulfonamide

[1865] ##STR00534##

[1866] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A3) and 1-(sec-butyl)azetidine-3-sulfonamide (Intermediate P107) to afford the title compound (26%) as white solid.

[1867] .sup.1H NMR (CD.sub.3OD): =6.82 (d, 2H), 4.27 (p, 1H), 3.89 (P, 4H), 3.22 (q, 2H), 2.70 (m, 1H), 1.61 (m, 1H), 1.18 (d, 14H), 1.03 (d, 3H), 0.92 (t, 3H).

Example 144: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((tetrahydrofuran-3-yl)methyl)azetidine-3-sulfonamide, Potassium Salt

[1868] ##STR00535##

[1869] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-((tetrahydrofuran-3-yl)methyl)azetidine-3-sulfonamide (Intermediate P126) to afford the title compound (51%) as a white solid.

[1870] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.34 (p, 1H), 3.82 (ddd, 2H), 3.77-3.61 (m, 2H), 3.51 (td, 2H), 3.39 (dd, 2H), 2.82 (m, 8H), 2.56 (dd, 2H), 2.39-2.18 (m, 1H), 2.02 (m, 5H), 1.57 (dq, 1H).

[1871] LCMS: m/z 420 (M+H).sup.+ (ES.sup.+); 418 (MH).sup. (ES.sup.).

Example 145: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((tetrahydrofuran-2-yl)methyl)azetidine-3-sulfonamide, Potassium Salt

[1872] ##STR00536##

[1873] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-((tetrahydrofuran-2-yl)methyl)azetidine-3-sulfonamide (Intermediate P127) to afford the title compound (22%) as a white solid.

[1874] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.34 (p, 1H), 3.98-3.78 (m, 2H), 3.68 (m, 5H), 2.81 (m, 8H), 2.73-2.56 (m, 2H), 2.02 (m, 5H), 1.87 (dt, 2H), 1.50 (dd, 1H).

[1875] LCMS: m/z 420 (M+H).sup.+ (ES.sup.+); 418 (MH).sup. (ES.sup.).

Example 146: (1R*,3R*,5S*)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl)-8-(1-methylazetidin-3-yl)-8-azabicyclo[3.2.1]octane-3-sulfonamide, Potassium Salt

[1876] ##STR00537##

[1877] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1R,3R,5S)-8-(1-methylazetidin-3-yl)-8-azabicyclo[3.2.1]octane-3-sulfonamide (Intermediate P128) to afford the title compound (8%) as a white solid.

[1878] .sup.1H NMR (CD.sub.3OD): =6.89 (s, 1H), 3.96 (m, 4H), 3.61 (m, 2H), 2.97-2.66 (m, 11H), 2.43 (m, 2H), 2.03 (m, 4H), 1.91 (m, 4H), 1.67 (m, 2H), 1.32 (m, 2H).

[1879] LCMS: m/z 459 (M+H).sup.+ (ES.sup.+); 457 (MH).sup. (ES.sup.).

Example 147: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-oxopyrrolidine-3-sulfonamide, Potassium Salt

[1880] ##STR00538##

[1881] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethyl-5-oxopyrrolidine-3-sulfonamide (Intermediate P81) to afford the title compound (62%) as a white solid.

[1882] .sup.1H NMR (CD.sub.3OD): =6.87 (s, 1H), 4.43-4.24 (m, 1H), 3.86 (dd, 1H), 3.74 (dd, 1H), 3.33 (m, 2H), 2.95-2.70 (m, 10H), 2.15-1.94 (m, 4H), 1.13 (t, 3H).

[1883] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+); 390 (MH).sup. (ES.sup.).

Example 148: 4-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-isopropyl-N,N-dimethylpyrrolidine-2-carboxamide, Potassium Salt

[1884] ##STR00539##

[1885] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-isopropyl-N,N-dimethyl-4-sulfamoylpyrrolidine-2-carboxamide (Intermediate P80) to afford the title compound (25%) as a white solid.

[1886] .sup.1H NMR (D.sub.2O): =6.96 (s, 1H), 4.07 (m, 2H), 3.36 (m, 1H), 3.18 (m, 1H), 3.02 (d, 6H), 2.68 (m, 8H), 2.46 (m, 1H), 1.90 (m, 4H), 1.75 (m, 2H), 1.01-0.83 (m, 6H).

[1887] LCMS: m/z 463 (M+H).sup.+ (ES.sup.+); 461 (MH).sup. (ES.sup.).

Example 149: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-4-methoxy-1-methylpyrrolidine-3-sulfonamide, Potassium Salt

[1888] ##STR00540##

[1889] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4-methoxy-1-methylpyrrolidine-3-sulfonamide (Intermediate P129) to afford the title compound (53%) as a white solid.

[1890] .sup.1H NMR (CD.sub.3OD) (mixture of isomers, ratio 2.5:1): =6.90 (s, 1H), 4.50 (minor), 4.57-4.19 (major) (m, 2H), 3.67 (dt, 1H), 3.45 (minor), 3.40 (major) (s, 3H), 3.14 (dd, 2H), 3.10-2.96 (m, 1H), 2.83 (m, 8H), 2.74 (minor), 2.70 (major) (s, 3H), 2.04 (m, 4H).

[1891] LCMS: m/z 394 (M+H).sup.+ (ES.sup.+); 392 (MH).sup. (ES.sup.).

Example 150: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methoxypyrrolidine-3-sulfonamide, Potassium Salt

[1892] ##STR00541##

[1893] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethyl-4-methoxypyrrolidine-3-sulfonamide (Intermediate P130) to afford the title compound (26%) as a white solid.

[1894] .sup.1H NMR (CD.sub.3OD) (mixture of isomers, ratio 6:1): =6.85 (s, 1H), 4.27 (m, 2H), 3.54 (m, 1H), 3.42 (minor), 3.39 (major) (s, 3H), 3.16-2.89 (m, 2H), 2.82 (m, 11H), 2.04 (m, 4H), 1.18 (t, 3H).

[1895] LCMS: m/z 408 (M+H).sup.+ (ES.sup.+); 406 (MH).sup. (ES.sup.).

Example 151: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1896] ##STR00542##

[1897] Prepared as described for 1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)azetidine-3-sulfonamide, potassium salt (Example 93) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-((tert-butyldimethylsilyl) oxy)ethyl)azetidine-3-sulfonamide (Intermediate P87) to afford the title compound (50%) as a white solid.

[1898] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.40 (m, 1H), 3.88 (t, 2H), 3.68 (m, 2H), 3.55 (m, 2H), 3.13 (m, 2H), 2.84 (m, 8H), 2.00 (m, 4H), 1.18 (s, 9H), o.1 (s, 6H).

[1899] LCMS: m/z 494 (M+H).sup.+ (ES.sup.+); 492 (MH).sup. (ES.sup.).

Example 152: 1-(2-Hydroxyethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfonamide, Potassium Salt

[1900] ##STR00543##

[1901] Upon reversed phase purification of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) azetidine-3-sulfonamide, potassium salt (Example 151), the deprotected product was also isolated (o1%) as a white solid.

[1902] .sup.1H NMR (CD.sub.3OD): =6.88 (s, 1H), 4.40 (s, 1H), 3.73 (t, 2H), 3.66 (t, 2H) (3.55 (t, 2H), 3.23 (m, 2H), 2.83 (m, 8H), 2.70 (t, 2H), 2.04 (m, 4H).

[1903] LCMS: m/z 380 (M+H).sup.+ (ES).

Example 153: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1904] ##STR00544##

[1905] 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A4) (0.30 g, 1.25 mmol) was dissolved in THF (10 mL). TEA (0.20 mL, 1.43 mmol) was added, followed by a solution of bis(trichloromethyl) carbonate (0.35 g, 1.18 mmol) in THF (2 mL). The mixture was stirred at room temperature for 1 hour, then concentrated in vacuo and dried for 30 minutes to afford the intermediate 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine as a pale yellow solid which was used without further purification.

[1906] 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P132) (45 mg, 0.21 mmol) was dissolved in dry THF (2 mL). NaO.sup.tBu (2 M in THF) (0.125 ml, 0.250 mmol) was added and the mixture was stirred at room temperature for 1 hour. A solution of 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (prepared above) (55 mg) in THF (2 mL) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in DMSO (2 mL) and purified by basic prep-HPLC to afford the title compound (41 mg, 40%) as a colourless powder.

[1907] .sup.1H NMR (DMSO-d6) 10.76 (s, 1H), 8.13 (d, J=2.6 Hz, 1H), 8.03 (dd, J=5.3, 0.7 Hz, 1H), 7.91 (s, 1H), 7.60 (dd, J=9.5, 2.6 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.83 (dd, J=5.3, 1.5 Hz, 1H), 6.65 (s, 1H), 6.47 (d, J=9.6 Hz, 1H), 4.99 (sept, J=6.8 Hz, 1H), 3.84 (s, 3H), 2.91 (t, J=7.5 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 1.98 (p, J=7.4 Hz, 2H), 1.29 (d, J=6.8 Hz, 6H).

[1908] LCMS: m/z 483.3 (M+H).sup.+ (ES.sup.+); 481.5 (MH).sup. (ES.sup.).

Example 154: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-H-inden-4-yl) carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide, Sodium Salt

Step A: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1909] ##STR00545##

[1910] Prepared according to the general procedure of 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 153) from 4-(4-amino-2,3-dihydro-1H-inden-5-yl)picolinonitrile (Intermediate A5) (0.03 g, 0.123 mmol) and 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P132) (0.027 g, 0.123 mmol) and purified by reversed phase flash C18 chromatography (12 g column, 0-60% MeCN/10 mM ammonium bicarbonate) to afford the title compound (35 mg, 30%) as a flocculent white solid.

[1911] .sup.1H NMR (DMSO-d6) 8.56 (d, J=5.1 Hz, 1H), 7.93 (d, J=2.6 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.75 (br s, 1H), 7.59 (dd, J=5.1, 1.8 Hz, 1H), 7.51 (dd, J=9.5, 2.5 Hz, 1H), 7.17-7.12 (m, 2H), 6.32 (d, J=9.4 Hz, 1H), 4.96 (sept, J=6.7 Hz, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.4 Hz, 2H), 1.98 (p, J=7.5 Hz, 2H), 1.25 (d, J=6.8 Hz, 6H). One exchangeable proton not observed.

[1912] LCMS: m/z 478.3 (M+H).sup.+ (ES.sup.+); 476.2 (MH).sup. (ES.sup.).

Step B: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide, Sodium Salt

[1913] ##STR00546##

[1914] N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.025 g, 0.052 mmol) was treated with 0.1 M NaOH solution (520 L) and the resultant solution was freeze-dried to afford the title compound (26 mg, 99%) as a white solid.

[1915] .sup.1H NMR (DMSO-d6) 8.54 (dd, J=5.1, 0.8 Hz, 1H), 7.91-7.89 (m, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.60 (dd, J=5.1, 1.8 Hz, 1H), 7.54-7.46 (m, 2H), 7.13-7.09 (m, 2H), 6.27 (d, J=9.4 Hz, 1H), 4.97 (sept, J=6.7 Hz, 1H), 2.89 (t, J=7.5 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 1.96 (p, J=7.5 Hz, 2H), 1.25 (d, J=6.8 Hz, 6H).

[1916] LCMS: m/z 478.3 (M+H).sup.+ (ES.sup.+); 476.2 (MH).sup. (ES.sup.).

Example 155: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide, Sodium Salt

Step A: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide

[1917] ##STR00547##

[1918] Prepared according to the general procedure of 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 153) from 4-(4-amino-2,3-dihydro-1H-inden-5-yl)picolinonitrile (Intermediate A5) (0.03 g, 0.123 mmol) and 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (Intermediate P133) (0.027 g, 0.123 mmol) and purified by reversed phase flash C18 chromatography (12 g column, 0-60% MeCN/10 mM ammonium bicarbonate) to afford the title compound (0.023 g, 19%) as a flocculent yellow solid.

[1919] .sup.1H NMR (DMSO-d6) 8.58 (d, J=5.1 Hz, 1H), 7.93 (s, 2H), 7.89 (d, J=1.7 Hz, 1H), 7.76 (br s, 1H), 7.59 (dd, J=5.2, 1.7 Hz, 1H), 7.19-7.12 (m, 2H), 4.84 (p, J=6.8 Hz, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 1.99 (p, J=7.5 Hz, 2H), 1.28 (d, J=6.8 Hz, 6H).

[1920] LCMS: m/z 479.3 (M+H).sup.+ (ES.sup.+); 477.2 (MH).sup. (ES.sup.).

Step B: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide, Sodium Salt

[1921] ##STR00548##

[1922] N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.015 g, 0.031 mmol) was treated with 0.1 M NaOH solution (310 L) and the resultant solution was freeze-dried to afford the title compound (16 mg, quant. yield) as a yellow solid.

[1923] .sup.1H NMR (DMSO-d6) 8.56 (d, J=5.1 Hz, 1H), 7.89 (t, J=1.6 Hz, 2H), 7.84 (d, J=1.1 Hz, 1H), 7.67-7.56 (m, 2H), 7.13-7.09 (m, 2H), 4.85 (sept, J=6.8 Hz, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.77 (t, J=7.3 Hz, 2H), 1.98 (p, J=7.5 Hz, 2H), 1.28 (d, J=6.8 Hz, 6H).

[1924] LCMS: m/z 479.3 (M+H).sup.+ (ES.sup.+); 477.1 (MH).sup. (ES.sup.).

Example 156: 4-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-5-oxo-4,5-dihydropyrazine-2-sulfonamide

[1925] ##STR00549##

[1926] Prepared according to the general procedure of 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 153) from 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (Intermediate P133) (26 mg, 0.12 mmol) and 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A4) (50 mg, 0.21 mmol) to afford the title compound (13.2 mg, 23%).

[1927] .sup.1H NMR (DMSO-d6) 8.09 (s, 1H), 8.05 (d, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.71 (s, 1H), 7.16 (d, J=7.7 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.86 (d, J=5.3 Hz, 1H), 6.65 (s, 1H), 4.86 (sept, J=7.2, 6.7 Hz, 1H), 3.86 (s, 3H), 2.90 (t, J=7.4 Hz, 2H), 2.69 (t, J=7.5 Hz, 2H), 1.98 (p, J=7.4 Hz, 2H), 1.30 (d, J=6.7 Hz, 6H). Partial ammonium salt.

[1928] LCMS: m/z 484.3 (M+H).sup.+ (ES.sup.+).

Example 157: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-isopropylazetidine-3-sulfonamide

[1929] ##STR00550##

[1930] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P134) (70 mg, 392.70 mol, 1 eq) in THF (2 mL) was added t-BuONa (37 mg, 392.70 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A6) (110 mg, 392.70 mol, 1 eq) was added. The reaction mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 12%-42%, 11.5 min) to give the title compound (80.02 mg, 43% yield, 96% purity on LCMS) as a white solid.

[1931] .sup.1H NMR (DMSO-d.sub.6) 8.75 (d, 1H), 8.06 (s, 1H), 7.77-7.66 (m, 2H), 7.21 (dd, 1H), 7.12 (dd, 1H), 3.78-3.49 (m, 4H), 3.26-3.22 (d, 2H), 2.83-2.79 (m, 1H), 1.15 (d, 6H) and 0.95 (d, 6H). One exchangeable proton not observed.

[1932] LCMS: m/z 460.2 (M+H).sup.+ (ES.sup.+).

Example 158: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-isopropylazetidine-3-sulfonamide

[1933] ##STR00551##

[1934] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P134) (70 mg, 392.70 mol, 1 eq) in THF (2 mL) was added t-BuONa (38 mg, 392.70 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A7) (112 mg, 392.70 mol, 1 eq) was added. The mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 12%-42%, 11.5 min) to give the title compound (87.88 mg, 48% yield, 99% purity on LCMS) as a white solid.

[1935] .sup.1H NMR (DMSO-d.sub.6) 8.11 (d, 1H), 7.17 (br s, 1H), 7.11 (d, 1H), 7.01 (s, 1H), 6.93 (d, 1H), 6.85 (s, 1H), 3.86 (s, 3H), 3.81-3.77 (m, 1H), 3.26-3.22 (m, 1H), 3.18-3.15 (m, 2H), 3.03-3.00 (m, 2H), 2.22-1.98 (m, 1H), 1.16-1.12 (m, 6H) and 0.80 (d, 6H). One exchangeable proton not observed.

[1936] LCMS: m/z 465.2 (M+H).sup.+ (ES.sup.+).

Example 159: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl) azetidine-3-sulfonamide

[1937] ##STR00552##

[1938] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P134) (70 mg, 392.70 mol, 1 eq) in THF (2 mL) was added t-BuONa (38 mg, 392.70 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A8) (104 mg, 392.70 mol, 1 eq) was added. The mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (56.2 mg, 32% yield, 100% purity on LCMS) as a white solid.

[1939] .sup.1H NMR (DMSO-d.sub.6) 8.13 (d, 1H), 7.49 (br s, 1H), 7.12 (d, 1H), 7.07 (d, 1H), 6.98 (d, 1H), 6.79 (s, 1H), 4.00-3.94 (m, 1H), 3.87 (s, 3H), 3.70-3.64 (m, 2H), 3.58-3.54 (m, 2H), 2.91 (t, 2H), 2.83 (t, 2H), 2.76-2.73 (m, 1H), 2.04-1-97 (m, 2H) and 0.94 (d, 6H).

[1940] One exchangeable proton not observed.

[1941] LCMS: m/z 445.2 (M+H).sup.+ (ES.sup.+).

Example 160: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropylazetidine-3-sulfonamide

[1942] ##STR00553##

[1943] A mixture of 1-isopropylazetidine-3-sulfonamide (Intermediate P134) (50 mg, 280.50 mol, 1 eq) and t-BuONa (27 mg, 280.50 mol, 1 eq) in THF (2 mL) was stirred at 25 C. for 10 minutes. 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A9) (71 mg, 280.50 mol, 1 eq) was added and the resulting mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 12%-42%, 10 min) to give the title compound (7.96 mg, 7% yield, 100% purity on LCMS) as a white solid.

[1944] .sup.1H NMR (DMSO-d.sub.6) 8.55 (d, 2H), 7.41-7.38 (m, 3H), 6.95 (d, 1H), 3.94-3.88 (m, 1H), 3.70-3.67 (m, 2H), 3.61-3.58 (m, 2H), 2.95 (t, 2H), 2.86 (t, 2H), 2.82-2.75 (m, 1H), 2.10-2.02 (m, 2H) and 0.96 (d, 6H). One exchangeable proton not observed.

[1945] LCMS: m/z 433.2 (M+H).sup.+ (ES.sup.+).

Example 161: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-cyclobutylazetidine-3-sulfonamide

[1946] ##STR00554##

[1947] A solution of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P135) (30 mg, 157.68 mol, 1 eq) and t-BuONa (15 mg, 157.68 mol, 1 eq) in THF (1 mL) was stirred at 25 C. for 10 minutes. 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A6) (44 mg, 157.68 mol, 1 eq) was added and the resulting mixture was stirred at 25 C. for 10 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (Column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (6.35 mg, 8% yield, 97% purity on LCMS) as a white solid.

[1948] .sup.1H NMR (DMSO-d.sub.6) 8.75 (d, 1H), 8.05 (s, 1H), 7.77-7.75 (m, 1H), 7.67-7.65 (m, 1H), 7.23-7.18 (m, 1H), 7.12 (d, 1H), 3.95-3.68 (m, 2H), 3.67-3.56 (m, 2H), 3.55-3.42 (m, 2H), 3.25-3.21 (m, 1H), 1.99-1.97 (m, 2H), 1.86-1.84 (m, 2H), 1.71-1.62 (m, 2H) and 1.16 (d, 6H). One exchangeable proton not observed.

[1949] LCMS: m/z 472.2 (M+H).sup.+ (ES.sup.+).

Example 162: 1-Cyclobutyl-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) phenyl) carbamoyl)azetidine-3-sulfonamide

[1950] ##STR00555##

[1951] To a solution of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P135) (25 mg, 131.40 mol, 1 eq) in THF (1 mL) was added t-BuONa (13 mg, 131.40 mol, 1 eq). The reaction mixture was stirred at 20 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A7) (38 mg, 131.40 mol, 1 eq) was added and the resulting mixture was stirred at 20 C. for 20 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 15%-45%,10 min) to give the title compound (41.16 mg, 66% yield, 100% purity on LCMS) as a white solid.

[1952] .sup.1H NMR (DMSO-d.sub.6) 8.16 (d, 1H), 7.61 (br s, 1H), 7.16 (d, 1H), 7.03-6.96 (m, 2H), 6.83 (s, 1H), 4.02-3.92 (m, 1H), 3.88 (s, 3H), 3.75-3.48 (m, 4H), 3.22-3.02 (m, 2H), 2.15-1.95 (m, 2H), 1.94-1.76 (m, 2H), 1.74-1.56 (m, 2H) and 1.14 (d, 6H). One exchangeable proton not observed.

[1953] LCMS: m/z 477.2 (M+H).sup.+ (ES.sup.+).

Example 163: 1-Cyclobutyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl) azetidine-3-sulfonamide

[1954] ##STR00556##

[1955] A mixture of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P135) (40 mg, 210.24 mol, 1 eq) and t-BuONa (20 mg, 210.24 mol, 1 eq) in THF (2 mL) was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A8) (56 mg, 210.24 mol, 1 eq) was added and the resulting mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 10%-40%, 10 min) to give the title compound (20.06 mg, 21% yield, 100% purity on LCMS) as a white solid.

[1956] .sup.1H NMR (DMSO-d.sub.6) 8.13 (d, 1H), 7.40 (br s, 1H), 7.12 (d, 1H), 7.06 (d, 1H), 6.96 (d, 1H), 6.77 (s, 1H), 4.06-3.98 (m, 1H), 3.87 (s, 3H), 3.49-3.44 (m, 3H), 3.38-3.35 (m, 2H), 2.91 (t, 2H), 2.82 (t, 2H), 2.03-1.99 (m, 2H), 1.98-1.94 (m, 2H), 1.85-1.81 (m, 2H) and 1.71-1.62 (m, 2H). One exchangeable proton not observed.

[1957] LCMS: m/z 457.3 (M+H).sup.+ (ES.sup.+).

Example 164: 1-Cyclobutyl-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3-sulfonamide

[1958] ##STR00557##

[1959] A mixture of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P135) (37 mg, 194.47 mol, 1 eq) and t-BuONa (19 mg, 194.47 mol, 1 eq) in THF (2 mL) was stirred at 25 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A9) (49 mg, 194.47 mol, 1 eq) was added and the resulting mixture was stirred at 25 C. for 10 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 0%-30%, 10 min) to give the title compound (18.09 mg, 20% yield, 97% purity on LCMS) as a yellow solid.

[1960] .sup.1H NMR (DMSO-d.sub.6) 8.57 (d, 2H), 7.57 (br s, 1H), 7.39 (d, 2H), 6.97 (d, 1H), 4.02-3.95 (m, 1H), 3.70-3.66 (m, 3H), 3.57-3.54 (m, 1H), 3.37-3.27 (m, 1H), 2.96 (t, 2H), 2.86 (t, 2H), 2.11-2.00 (m, 4H), 1.92-1.87 (m, 2H) and 1.72-1.65 (m, 2H). One exchangeable proton not observed.

[1961] LCMS: m/z 445.2 (M+H).sup.+ (ES.sup.+).

Example 165: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-ethylazetidine-3-sulfonamide

[1962] ##STR00558##

[1963] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P136) (40 mg, 243.57 mol, 1 eq) in THF (1 mL) was added t-BuONa (23 mg, 243.57 mol, 1 eq). The mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-picolinonitrile (Intermediate A6) (68 mg, 243.57 mol, 1 eq) was added and the mixture was stirred at 70 C. for 10 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (48.97 mg, 45% yield, 100% purity on LCMS) as a white solid.

[1964] .sup.1H NMR (DMSO-d.sub.6) 8.75 (d, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.22-7.18 (m, 1H), 7.12-7.09 (m, 1H), 3.83-3.76 (m, 5H), 3.24-3.20 (m, 1H), 2.93-2.88 (m, 2H), 1.16 (d, 6H) and 0.99 (t, 3H). One exchangeable proton not observed.

[1965] LCMS: m/z 446.2 (M+H).sup.+ (ES.sup.+).

Example 166: 1-Ethyl-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl) azetidine-3-sulfonamide

[1966] ##STR00559##

[1967] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P136) (40 mg, 243.57 mol, 1 eq) in THF (1 mL) was added t-BuONa (23 mg, 243.57 mol, 1 eq). The mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A7) (69 mg, 243.57 mol, 1 eq) was added and the mixture was stirred at 75 C. for another 10 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (46.05 mg, 42% yield, 100% purity on LCMS) as a white solid.

[1968] .sup.1H NMR (DMSO-d.sub.6) 8.15 (d, 1H), 7.48 (s, 1H), 7.17-7.12 (m, 1H), 7.03-6.94 (m, 2H), 6.84 (s, 1H), 3.99-3.77 (m, 8H), 3.24-3.20 (m, 1H), 2.95-2.92 (m, 2H), 1.15 (d, 6H) and 1.00 (t, 3H). One exchangeable proton not observed.

[1969] LCMS: m/z 451.2 (M+H).sup.+ (ES.sup.+).

Example 167: 1-Ethyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3-sulfonamide

[1970] ##STR00560##

[1971] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P136) (40 mg, 243.57 mol, 1 eq) in THF (1 mL) was added t-BuONa (23 mg, 243.57 mol, 1 eq). The mixture was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A8) (64 mg, 243.57 mol, 1 eq) was added and the mixture was stirred at 70 C. for 10 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (52.99 mg, 51% yield, 100% purity on LCMS) as a white solid.

[1972] .sup.1H NMR (DMSO-d.sub.6) 8.13 (d, 1H), 7.43 (br s, 1H), 7.12 (d, 1H), 7.06 (d, 1H), 6.97 (dd, 1H), 6.79 (s, 1H), 4.08-4.00 (m, 1H), 3.88 (s, 3H), 3.85-3.80 (m, 2H), 3.77-3.72 (m, 2H), 2.91 (t, 2H), 2.87-2.80 (m, 4H), 2.04-1.96 (m, 2H) and 0.98 (t, 3H). One exchangeable proton not observed.

[1973] LCMS: m/z 431.2 (M+H).sup.+ (ES.sup.+).

Example 168: 1-Ethyl-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl) azetidine-3-sulfonamide

[1974] ##STR00561##

[1975] A solution of 1-ethylazetidine-3-sulfonamide (Intermediate P136) (50 mg, 304.46 mol, 1 eq) and t-BuONa (29 mg, 304.46 mol, 1 eq) in THF (1 mL) was stirred at 25 C. for 10 minutes. Then a solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A9) (77 mg, 304.46 mol, 1 eq) in THF (2 mL) was added and the reaction mixture was stirred at 25 C. for 10 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B:MeCN]; B %: 5%-35%, 10 min) to give the title compound (9.59 mg, 8% yield, 100% purity on LCMS) as a white solid.

[1976] .sup.1H NMR (DMSO-d.sub.6) 8.57 (d, 2H), 7.43 (br s, 1H), 7.40 (d, 2H), 6.96 (d, 1H), 4.01-3.88 (m, 5H), 2.98-2.93 (m, 4H), 2.86 (t, 2H), 2.11-2.03 (m, 2H) and 1.01 (t, 3H).

[1977] One exchangeable proton not observed.

[1978] LCMS: m/z 419.2 (M+H).sup.+ (ES.sup.+).

Example 169: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-(pyridin-3-ylmethyl) azetidine-3-sulfonamide

[1979] ##STR00562##

[1980] A solution of 1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (Intermediate P137) (50 mg, 219.99 mol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A6) (68 mg, 241.99 mol, 1.1 eq) and t-BuONa (25 mg, 263.99 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %: 15%-45%, 12 min) to give the title compound (10 mg, 9%) as a white solid.

[1981] .sup.1H NMR (DMSO-d.sub.6) 8.74 (d, 1H), 8.50-8.47 (m, 2H), 8.05 (s, 1H), 8.00 (br s, 1H), 7.73 (d, 1H), 7.68 (d, 1H), 7.39-7.35 (m, 1H), 7.29-7.25 (m, 1H), 7.16 (d, 1H), 4.03-3.97 (m, 1H), 3.73-3.68 (m, 2H), 3.45-3.38 (m, 4H), 3.19-3.15 (m, 1H) and 1.14 (d, 6H). One exchangeable proton not observed.

[1982] LCMS: m/z 509.3 (M+H).sup.+ (ES.sup.+).

Example 170: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide

[1983] ##STR00563##

[1984] A solution of 1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (Intermediate P137) (50 mg, 219.99 mol, 1 eq), 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A8) (64 mg, 241.99 mol, 1.1 eq) and t-BuONa (25 mg, 263.99 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %: 15%-45%, 12 min) to give the title compound (37 mg, 34%) as a white solid.

[1985] .sup.1H NMR (DMSO-d.sub.6) 8.49-8.45 (m, 2H), 8.12 (d, 1H), 7.79 (br s, 1H), 7.67 (d, 1H), 7.38-7.33 (m, 1H), 7.18 (d, 1H), 7.09 (d, 1H), 6.92 (d, 1H), 6.73 (s, 1H), 4.19-4.15 (m, 1H), 3.80 (s, 3H), 3.66 (s, 2H), 3.50-3.43 (m, 2H), 3.38-3.34 (m, 2H), 2.91 (t, 2H), 2.78 (t, 2H) and 2.04-1.98 (m, 2H). One exchangeable proton not observed.

[1986] LCMS: m/z 494.2 (M+H).sup.+ (ES.sup.+).

Example 171: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-(pyridin-3-ylmethyl) azetidine-3-sulfonamide

[1987] ##STR00564##

[1988] To a solution of 1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (Intermediate P137) (54 mg, 235.98 mol, 1 eq) in THF (5 mL) was added t-BuONa (27 mg, 283.18 mol, 1.2 eq) and a solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A9) (60 mg, 235.98 mol, 1 eq) in THF (5 mL) and DCM (5 mL). The reaction mixture was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %: 5%-50%, 10 min) to give the title compound (35.53 mg, 31% yield, 99.4% purity on LCMS) as a white solid.

[1989] .sup.1H NMR (DMSO-d.sub.6) 8.56-8.54 (m, 2H), 8.49-8.47 (m, 2H), 7.76 (br s, 1H), 7.68 (d, 1H), 7.36 (dd, 3H), 7.00 (d, 1H), 4.17-4.12 (m, 1H), 3.68 (s, 2H), 3.47 (t, 2H), 3.40 (t, 2H), 2.96 (t, 2H), 2.84 (t, 2H) and 2.11-2.03 (m, 2H). One exchangeable proton not observed.

[1990] LCMS: m/z 482.2 (M+H).sup.+ (ES.sup.+).

Example 172: N-((2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1991] ##STR00565##

[1992] A solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P132) (60 mg, 225.09 mol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-picolinonitrile (Intermediate A6) (70 mg, 247.60 mol, 1.1 eq) and t-BuONa (26 mg, 270.11 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %: 15%-45%, 12 min) to give the title compound (30 mg, 26%) as a white solid.

[1993] .sup.1H NMR (DMSO-d.sub.6) 8.57 (d, 1H), 7.99-7.92 (m, 3H), 7.64-7.62 (m, 1H), 7.47-7.45 (m, 1H), 7.25-7.22 (m, 1H), 7.14-7.11 (m, 1H), 6.36 (d, 1H), 4.99-4.91 (m, 1H), 3.10-3.05 (m, 1H), 1.25 (d, 6H) and 1.09 (d, 6H). One exchangeable proton not observed.

[1994] LCMS: m/z 498.3 (M+H).sup.+ (ES.sup.+).

Example 173: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1995] ##STR00566##

[1996] A solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P132) (60 mg, 225.09 mol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A7) (71 mg, 247.60 mol, 1.1 eq) and t-BuONa (26 mg, 270.11 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 2%-32%, 10 min) to give the title compound (61 mg, 54%) as a white solid.

[1997] .sup.1H NMR (DMSO-d.sub.6) 7.97 (d, 2H), 7.51 (d, 2H), 7.13 (dd, 1H), 6.96-6.89 (m, 2H), 6.73 (s, 1H), 6.35 (d, 1H), 5.00-4.95 (m, 1H), 3.83 (s, 3H), 3.09-3.04 (m, 1H), 1.25 (d, 6H) and 1.05 (d, 6H). One exchangeable proton not observed.

[1998] LCMS: m/z 503.2 (M+H).sup.+ (ES.sup.+).

Example 174: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1999] ##STR00567##

[2000] A solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P132) (50 mg, 187-58 mol, 1 eq), 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A9) (52 mg, 206.34 mol, 1.1 eq) and t-BuONa (22 mg, 225.10 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %:12%-42%, 12 min) to give the title compound (6 mg, 7% yield, 99.17% purity on LCMS) as a white solid.

[2001] .sup.1H NMR (DMSO-d.sub.6) 8.46 (d, 2H), 8.08 (s, 1H), 7.83 (br s, 1H), 7.58 (dd, 1H), 7.26 (d, 2H), 6.99 (d, 1H), 6.45 (d, 1H), 5.02-4.94 (m, 1H), 2.94 (t, 2H), 2.71 (t, 2H), 2.07-2.01 (m, 2H) and 1.28 (d, 6H). One exchangeable proton not observed.

[2002] LCMS: m/z 471.2 (M+H).sup.+ (ES.sup.+).

Example 175: N-((4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-isopropylazetidine-3-sulfonamide

[2003] ##STR00568##

[2004] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P134) (200 mg, 1.12 mmol, 1 eq) in THF (5 mL) was added MeONa (60 mg, 1.12 mmol, 1 eq). The reaction mixture was stirred at 25 C. for 30 minutes. Then 3-(5-fluoro-2-isocyanato-3-isopropylphenyl)pyridine (Intermediate A10) (431 mg, 1.68 mmol, 1.5 eq) was added and the resulting mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (column: Welch Ultimate XB_C18, 35 mm*235 mm*20/35 m, mobile phase: [A: water (0.05% ammonia hydroxide); B: MeCN]; B %: 0%-40%, 10 min) to give the title compound (33 mg, 7% yield, 100% purity on LCMS) as a white solid.

[2005] .sup.1H NMR (DMSO-d.sub.6) 8.60-8.51 (m, 2H), 7.92-7.77 (m, 1H), 7.57 (s, 1H), 7.44-7.40 (m, 1H), 7.14 (d, 1H), 7.00 (d, 1H), 3.92-3.74 (m, 3H), 3.29-2.95 (m, 4H), 1.26-1.10 (m, 6H) and 1.02 (d, 6H). One exchangeable proton not observed.

[2006] LCMS: m/z 435.2 (M+H).sup.+ (ES.sup.+).

Example 176: N-((4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-isopropylpiperidine-4-sulfonamide

[2007] ##STR00569##

[2008] To a solution of 1-isopropylpiperidine-4-sulfonamide (Intermediate P138) (720 mg, 3.49 mmol, 1 eq) in THF (10 mL) was added NaOMe (226 mg, 4.19 mmol, 1.2 eq) and 3-(5-fluoro-2-isocyanato-3-isopropylphenyl)pyridine (Intermediate A10) (805 mg, 3.14 mmol, 0.9 eq). Then the reaction mixture was stirred at 70 C. for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 250 mm*50 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 15%-45%, 10 min) to give the title compound (69.36 mg, 4% yield, 100% purity on LCMS) as a white solid.

[2009] .sup.1H NMR (DMSO-d.sub.6) 8.57 (s, 1H), 8.48 (d, 1H), 7.87-7.80 (m, 1H), 7.36-7.32 (m, 1H), 7.25 (s, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 6.09 (s, 1H), 2.95-2.85 (m, 1H), 2.79-2.76 (m, 2H), 2.70-2.63 (m, 2H), 1.98-1.85 (m, 2H), 1.65-1.61 (m, 2H), 1.42-1.38 (m, 2H), 1.14 (d, 6H) and 0.94 (d, 6H). One exchangeable proton not observed.

[2010] LCMS: m/z 463.4 (M+H).sup.+ (ES.sup.+).

Example 177: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-(pyridin-3-ylmethyl) azetidine-3-sulfonamide

[2011] ##STR00570##

[2012] A solution of 1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (Intermediate P137) (50 mg, 219.99 mol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A7) (69 mg, 241.99 mol, 1.1 eq) and t-BuONa (25 mg, 263.99 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m, mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (44 mg, 38%) as a white solid.

[2013] .sup.1H NMR (DMSO-d.sub.6) 8.47 (s, 2H), 8.12 (d, 1H), 7.67 (d, 2H), 7.35 (dd, 1H), 7.19 (d, 1H), 7.01-6.95 (m, 2H), 6.80 (s, 1H), 4.04-3.98 (m, 1H), 3.78 (s, 3H), 3.64 (s, 2H), 3.43-3.36 (m, 4H), 3.16-3.12 (m, 1H) and 1.12 (d, 6H). One exchangeable proton not observed.

[2014] LCMS: m/z 514.3 (M+H).sup.+ (ES.sup.+).

Example 178: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-2-oxo-1,2-dihydropyrimidine-5-sulfonamide, Sodium Salt

[2015] ##STR00571##

[2016] A suspension of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (0.033 g, 0.137 mmol) (Intermediate A4) and (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-2-oxo-1,2-dihydropyrimidin-5-yl)sulfonyl) amide (Intermediate P139) (0.069 g, 0.123 mmol) in dry MeCN (2 mL) was stirred at 50 C. for 2 hours. Then the reaction mixture was concentrated in vacuo and the crude product was purified by prep-HPLC (column: Waters Xbridge C18, 19 mm*15 mm*5m; mobile phase: [A: water (0.1% NH.sub.4HCO.sub.3); B: MeCN]; B %: 10%-40%) to afford 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-oxo-1,2-dihydropyrimidine-5-sulfonamide (0.031 g, 52%) as a flocculent white solid.

[2017] The free acid (0.024 g, 0.050 mmol) was treated with 0.1 M NaOH (aq) (0.500 ml, 0.05 mmol) and the resultant solution was freeze-dried to afford the title compound (0.025 g, 99%) as a white solid.

[2018] .sup.1H NMR (DMSO-d6) 8.65 (d, J=3.0 Hz, 1H), 8.35 (d, J=3.1 Hz, 1H), 7.98 (d, J=5.2 Hz, 1H), 7.24 (br s, 1H), 7.08 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.88 (dd, J=5.3, 1.4 Hz, 1H), 6.70 (t, J=1.0 Hz, 1H), 4.76 (sept, J=6.7 Hz, 1H), 3.82 (s, 3H), 2.88 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.4 Hz, 2H), 1.94 (P, J=7.5 Hz, 2H), 1.30 (d, J=6.8 Hz, 6H).

[2019] LCMS: m/z 484.1 (M+H).sup.+ (ES.sup.+); 482.1 (MH).sup. (ES.sup.).

Example 179: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-oxo-1,2-dihydropyridine-4-sulfonamide, Sodium Salt

[2020] ##STR00572##

[2021] To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A4) (0.156 g, 0.65 mmol) in DCM (5 mL) and saturated aqueous NaHCO.sub.3 (5 mL) was added a solution of bis(trichloromethyl) carbonate (0.079 g, 0.264 mmol) in toluene (1 mL) to the DCM layer without stirring. The reaction mixture was stirred for 1 hour, passed through a phase separator, dried (MgSO.sub.4), filtered and concentrated in vacuo to afford crude isocyanate intermediate as an orange oil which was used without further purification. The crude isocyanate intermediate was dissolved in dry THF (11 mL).

[2022] A solution of 1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (Intermediate P140) (0.050 g, 0.224 mmol) in dry THF (3 mL) was treated with sodium tert-butoxide (2 M in THF) (0.120 ml, 0.24 mmol). The reaction mixture was stirred at room temperature for 1 hour, treated with a solution of the crude isocyanate intermediate in dry THF (4 mL) and then stirred at room temperature for 22 hours. The reaction mixture was concentrated in vacuo and the residue purified by reversed phase flash C18 chromatography (liquid load) (12 g cartridge, 5-50% MeCN/10 mM ammonium bicarbonate) to afford 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-oxo-1,2-dihydropyridine-4-sulfonamide (0.079 g, 70%) as a flocculent white solid. The free acid (0.071 g, 0.141 mmol) was treated with 0.1 M NaOH (aq) (1.410 ml, 0.141 mmol) and the mixture was freeze-dried to afford the title compound (0.073 g, 102%) as a white solid.

[2023] .sup.1H NMR (DMSO-d6) 8.06 (dd, J=5.3, 0.7 Hz, 1H), 7.87 (dd, J=6.9, 2.1 Hz, 1H), 7.76 (dd, J=7.0, 2.1 Hz, 1H), 7.30 (br s, 1H), 7.06 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 6.94 (dd, J=5.3, 1.5 Hz, 1H), 6.76 (t, J=1.00 Hz, 1H), 6.30 (t, J=6.9 Hz, 1H), 5.14 (sept, J=6.8 Hz, 1H), 3.85 (s, 3H), 2.85 (t, J=7.4 Hz, 2H), 2.67 (t, J=7.4 Hz, 2H), 1.90 (p, J=7.5 Hz, 2H), 1.30 (d, J=6.8 Hz, 6H).

[2024] LCMS: m/z 483.1 (M+H).sup.+ (ES.sup.+); 481.0 (MH).sup. (ES.sup.).

Example 180: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide, Sodium Salt

[2025] ##STR00573##

[2026] A solution of 1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (Intermediate P140) (0.05 g, 0.224 mmol) in dry THF (4 mL) was treated with 2 M sodium tert-butoxide in THF (0.12 ml, 0.240 mmol) under nitrogen. The resultant suspension was stirred at room temperature for 1 hour, then treated with a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.049 g, 0.247 mmol) in dry THF (1 mL) and stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reversed phase flash C18 chromatography (liquid load) (12 g cartridge, 0-75% MeCN/10 mM ammonium bicarbonate) to afford N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (0.059 g, 63%) as a flocculent white solid. The free acid (0.05 g, 0.119 mmol) was treated with 0.1 M NaOH (1.191 ml, 0.119 mmol) and the resultant solution was freeze-dried to afford the title compound (0.052 g, 99%) as a white solid.

[2027] .sup.1H NMR (DMSO-d6) 7.88-7.84 (m, 2H), 7.47 (s, 1H), 6.75 (s, 1H), 6.33 (t, J=6.9 Hz, 1H), 5.11 (sept, J=6.8 Hz, 1H), 2.73 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.87 (p, J=7.4 Hz, 4H), 1.29 (d, J=6.9 Hz, 6H).

[2028] LCMS: m/z 438.3 (M+Na).sup.+ (ES.sup.+); 414.2 (MH).sup. (ES.sup.).

Example 181: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide, Sodium Salt

[2029] ##STR00574##

[2030] A solution of 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (Intermediate P133) (0.06 g, 0.273 mmol) in dry THF (4 mL) was treated with 2M sodium tert-butoxide in THF (0.15 ml, 0.300 mmol) under nitrogen. The resultant suspension was stirred at room temperature for 45 minutes, and then treated with a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.061 g, 0.306 mmol) in dry THF (1 mL) and stirred for 21 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (22 mL). The aqueous layer was collected and retained. The organic layer was concentrated in vacuo and the residue was dissolved in MeCN (2 mL) and combined with the aqueous layer. The resultant suspension was filtered through cotton wool and then purified by reversed phase flash C18 chromatography (12 g cartridge, 5-75% MeCN/10 mM ammonium bicarbonate) to afford N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.075 g, 66%) as a flocculent white solid. The free acid (0.05 g, 0.120 mmol) was treated with 0.1 M NaOH (1.200 ml, 0.120 mmol) and the resultant solution was freeze-dried to afford the title compound (00.0053 g, 101%) as a white solid.

[2031] .sup.1H NMR (DMSO-d6) 7.96 (d, J=1.1 Hz, 1H), 7.90 (d, J=1.0 Hz, 1H), 7.46 (s, 1H), 6.76 (s, 1H), 4.88 (sept, J=6.8 Hz, 1H), 2.74 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.3 Hz, 4H), 1.88 (p, J=7.4 Hz, 4H), 1.31 (d, J=6.8 Hz, 6H).

[2032] LCMS: m/z 417.3 (M+H).sup.+ (ES.sup.+); 415.2 (MH).sup. (ES.sup.).

Example 182: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-sulfonamide

[2033] ##STR00575##

[2034] 2 M Sodium tert-butoxide in THF (0.138 ml, 0.277 mmol) was added to a solution of 1-isopropyl-2-oxo-1,2-dihydropyridine-3-sulfonamide (Intermediate P141) (0.06 g, 0.264 mmol) in anhydrous THF (4 mL) at room temperature. The mixture was stirred for 1 hour before 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.058 g, 0.290 mmol) was added in a single portion. The reaction mixture was stirred for 21 hours at room temperature, concentrated in vacuo, then redissolved in DMSO (1.5 mL) and purified by reversed phase flash C18 chromatography (12 g cartridge, 5-100% MeCN/10 mM ammonium bicarbonate) to afford the title compound (0.023 g, 21%) as a white solid.

[2035] .sup.1H NMR (DMSO-d6) 8.19-8.00 (m, 3H), 6.89 (s, 1H), 6.46 (t, J=7.0 Hz, 1H), 5.11 (sept, J=6.8 Hz, 1H), 2.76 (t, J=7.4 Hz, 4H), 2.56 (t, J=7.2 Hz, 4H), 1.91 (p, J=7.4 Hz, 4H), 1.32 (d, J=6.8 Hz, 6H). One exchangeable proton not observed.

[2036] LCMS: m/z 416.2 (M+H).sup.+ (ES.sup.+), 438.3 (M+Na).sup.+ (ES.sup.+).

Example 183: (R.SUP..)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[2037] ##STR00576##

[2038] A solution of (R)-1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P142) (0.047 g, 0.196 mmol) in dry THF (4 mL) was treated with 2M sodium tert-butoxide in THF (0.103 ml, 0.206 mmol) under nitrogen. The resultant suspension was stirred at room temperature for 1 hour, and then treated with a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.043 g, 0.216 mmol) in dry THF (1 mL) and stirred for 20 hours. The reaction mixture was concentrated in vacuo to afford crude product as a green solid which was purified by prep-HPLC (column: Waters Xbridge C18, 19 mm*15 mm*5 m; mobile phase: [A: water (0.1% NH.sub.4HCO.sub.3); B: MeCN]; B %: 10%-40%) to afford the title compound (0.016 g, 19%) as a flocculent white solid.

[2039] .sup.1H NMR (DMSO-d6) 8.17 (d, J=2.6 Hz, 1H), 7.85 (br s, 1H), 7.75 (dd, J=9.6, 2.7 Hz, 1H), 6.88 (s, 1H), 6.44 (d, J=9.6 Hz, 1H), 4.92 (d, J=5.5 Hz, 1H), 4.04 (dd, J=12.9, 3.7 Hz, 1H), 3.85 (ddd, J=9.4, 7.0, 4.7 Hz, 1H), 3.64 (dd, J=12.9, 8.o Hz, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.92 (p, J=7.5 Hz, 4H), 1.06 (d, J=6.3 Hz, 3H). One exchangeable proton not observed.

[2040] LCMS: m/z 432.3 (M+H).sup.+ (ES.sup.+); 430.1 (MH).sup. (ES.sup.).

Example 184: 1-(2-(Dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[2041] ##STR00577##

[2042] A solution of 1-(2-(dimethylamino)ethyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P143) (0.034 g, 0.100 mmol) in dry THF (3 mL) was treated with 2M sodium tert-butoxide in THF (0.07 ml, 0.140 mmol) under nitrogen. The resultant suspension was stirred at room temperature for 1 hour, and then treated with a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.035 g, 0.176 mmol) in dry THF (1 mL) and stirred for 20 hours. The reaction mixture was concentrated in vacuo to afford crude product as an off white solid which was purified by reversed phase flash C18 chromatography (liquid load in water) (12 g cartridge, 5-75% MeCN/10 mM ammonium bicarbonate) to afford the title compound (0.017 g, 38%) as a flocculent white solid.

[2043] .sup.1H NMR (DMSO-d6) 8.28 (d, J=2.6 Hz, 1H), 7.85 (s, 1H), 7.75 (dd, J=9.6, 2.7 Hz, 1H), 6.88 (s, 1H), 6.46 (d, J=9.6 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 2.80-2.70 (m, 6H), 2.60 (t, J=7.4 Hz, 4H), 2.34 (s, 6H), 1.92 (p, J=7.4 Hz, 4H). One exchangeable proton not observed.

[2044] LCMS: m/z 445.3 (M+H).sup.+ (ES.sup.+); 443.3 (MH).sup. (ES.sup.).

Example 185: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide, Sodium Salt

[2045] ##STR00578##

[2046] Sodium tert-butoxide (2 M in THF) (0.048 mL, 0.096 mmol) was added to a solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P132) (19.7 mg, 0.091 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (20 mg, 0.100 mmol) was added and the reaction mixture was stirred at room temperature overnight. The resultant white precipitate was collected by filtration, washing with THF. The solid was dissolved in MeCN, filtered and dried in vacuo to afford the title compound (5 mg, 12%) as a white solid.

[2047] .sup.1H NMR (DMSO-d6) 8.00 (d, J=2.5 Hz, 1H), 7.66 (dd, J=9.4, 2.5 Hz, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 6.32 (d, J=9.3 Hz, 1H), 5.01 (sept, J=6.8 Hz, 1H), 2.75 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.3 Hz, 4H), 1.88 (p, J=7.4 Hz, 4H), 1.28 (d, J=6.8 Hz, 6H).

[2048] LCMS: m/z 416.3 (M+H).sup.+ (ES.sup.+).

Example 186: 1-Ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[2049] ##STR00579##

[2050] To a solution of 1-ethylpiperidine-4-sulfonamide (Intermediate P6; 90 mg, 0.37 mmol) in THF (5 mL) was added potassium tert-butoxide (49 mg, 0.44 mmol). The mixture was stirred at room temperature for 45 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A11; 90 mg, 0.32 mmol) was added and the mixture was stirred for 2 hours room temperature. The reaction mixture was concentrated in vacuo and DMSO (0.5-1 mL) was added. The mixture (filtered over cotton wool when solids were present) was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (18 mg, to %) as a white solid.

[2051] .sup.1H NMR (methanol-d.sub.4) 8.10 (d, 1H), 7.03 (d, 1H), 6.87 (s, 1H), 6.84 (s, 1H), 3.92 (s, 3H), 3.23 (m, 2H), 3.07 (m, 1H), 3.00 (m, 4H), 2.68 (m, 2H), 2.32-2.08 (m, 4H), 2.03 (m, 2H), 1.86 (m, 2H), 1.18 (t, 3H).

[2052] LCMS: m/z 477 (M+H).sup.+ (ES.sup.+); 475 (MH).sup. (ES.sup.).

Example 187: 1-(sec-Butyl)-N-((4-chloro-2,6-diisopropylphenyl)carbamoyl) azetidine-3-sulfonamide, Potassium Salt

[2053] ##STR00580##

[2054] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 186) using 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A15) and 1-(sec-butyl)azetidine-3-sulfonamide (Intermediate P107) to afford the title compound (25%) as a white solid.

[2055] .sup.1H NMR (CD.sub.3OD) 7.08 (m, 2H), 4.28 (t, 1H), 3.70 (t, 2H), 3.58 (t, 2H), 3.24 (m, 2H), 2.42 (d, 1H), 1.55 (s, 1H), 1.18 (d, 13H), 0.95 (d, 3H), 0.89 (t, 3H).

[2056] LCMS: m/z 431 (M+H).sup.+ (ES.sup.+); 429 (MH).sup. (ES.sup.).

Example 188: 1-Ethyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1I-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[2057] ##STR00581##

[2058] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 186) using 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A8) and 1-ethylpiperidine-4-sulfonamide (Intermediate P6) to afford the title compound (54 mg, 30%) as a white solid.

[2059] .sup.1H NMR (methanol-d.sub.4) 8.08 (d, 1H), 7.25-7.08 (m, 2H), 7.03 (dd, 1H), 6.86 (s, 1H), 3.92 (s, 3H), 3.39-3.17 (m, 3H), 2.95 (m, 4H), 2.71 (q, 2H), 2.33 (t, 2H), 2.22-1.97 (m, 4H), 1.97-1.72 (m, 2H), 1.18 (t, 3H).

[2060] LCMS: m/z 459 (M+H).sup.+ (ES.sup.+); 457 (MH).sup. (ES.sup.).

Example 189: 1-Ethyl-N-((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl) piperidine-4-sulfonamide, Potassium Salt

[2061] ##STR00582##

[2062] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 186) using 8-isocyanato-1,2,3,5-tetrahydro-s-indacene (Intermediate A14) and 1-ethylpiperidine-4-sulfonamide (Intermediate P6) to afford the title compound (77 mg, 34%) as a white solid.

[2063] .sup.1H NMR (methanol-d.sub.4) (mixture of isomers) 7.14, 7.06 (s, 1H), 6.91, 6.77 (m, 1H), 6.46, 6.41 (m, 1H), 3.64-3.44 (m, 2H), 3.31 (m, 2H), 3.23 (m, 1H), 2.89 (m, 4H), 2.74-2.54 (m, 2H), 2.31 (d, 2H), 2.25-1.85 (m, 6H), 1.16 (t, 3H).

[2064] LCMS: m/z 390 (M+H).sup.+ (ES.sup.+); 388 (MH).sup. (ES.sup.).

Example 190: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-ethylpiperidine-4-sulfonamide, Potassium Salt

[2065] ##STR00583##

[2066] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 186) using 4-(54-isocyanato-2,3-dihydro-H-inden-5-yl)picolinonithoxypyridine (Intermediate A12) and 1-ethylpiperidine-4-sulfonamide (Intermediate P6) to afford the title compound (18 mg, 18%) as a white solid.

[2067] .sup.1H NMR (methanol-d.sub.4) 8.66 (dd, 1H), 7.95 (d, 1H), 76.8873 (dd, 1H), 7.20 (q, 2H), 3.55 (m, 1H), 3.09 (q, 2H), 2.98 (m, 4H), 2.85 (, 4H), 2.13 (m, 2H), 2.1-1.97 (d, 6H)), 1.31 (t, 3H).

[2068] LCMS: m/z 454 (M+H).sup.+ (ES.sup.+); 452 (MH).sup. (ES.sup.).

Example 191: 1-Ethyl-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) phenyl)carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[2069] ##STR00584##

[2070] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 186) using 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A7) and 1-ethylpiperidine-4-sulfonamide (Intermediate P6) to afford the title compound (23 mg, 14%) as a white solid.

[2071] .sup.1H NMR (methanol-d.sub.4) 8.09 (d, 1H), 7.06 (dd, 2H), 6.88 (m, 2H), 3.92 (s, 3H), 3.72 (m, 1H), 3.19 (m, 1H), 3.08 (m, 2H), 2.49 (d, 2H), 1.87 (m, 6H), 1.23 (d, 6H), 1.12 (t, 3H).

[2072] LCMS: m/z 479 (M+H).sup.+ (ES.sup.+); 477 (MH).sup. (ES.sup.).

Example 192: 1-Ethyl-N-((5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[2073] ##STR00585##

[2074] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 186) using 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A13) and 1-ethylpiperidine-4-sulfonamide (Intermediate P6) to afford the title compound (11 mg, 13%) as a white solid.

[2075] .sup.1H NMR (methanol-d.sub.4) 8.55-8.42 (m, 2H), 7.58-7.44 (m, 2H), 7.24-7.05 (m, 2H), 3.22 (d, 2H), 3.07 (m, 1H), 2.97 (m, 4H), 2.65 (t, 2H), 2.23 (t, 2H), 2.10 (m, 2H), 2.04-1.67 (m, 4H), 1.18 (t, 3H).

[2076] LCMS: m/z 429 (M+H).sup.+ (ES.sup.+); 427 (MH).sup. (ES.sup.).

Example 193: 1-(Ethyl-d5)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)piperidine-4-sulfonamide, Potassium Salt

[2077] ##STR00586##

[2078] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 186) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(ethyl-d5)piperidine-4-sulfonamide (Intermediate P145) to afford the title compound (75 mg, 38%) as a white solid.

[2079] .sup.1H NMR (methanol-d.sub.4) 6.87 (s, 1H), 3.44 (m, 1H), 3.16 (d, 2H), 2.82 (m, 8H), 2.15 (m, 4H), 2.10-1.84 (m, 6H).

[2080] LCMS: m/z 397 (M+H).sup.+ (ES.sup.+); 395 (MH).sup. (ES.sup.).

Example 194: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) azepane-4-sulfonamide, Potassium Salt

[2081] ##STR00587##

[2082] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 186) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-ethylazepane-4-sulfonamide (Intermediate P144) to afford the title compound (17 mg, 27%) as a white solid.

[2083] .sup.1H NMR (methanol-d.sub.4) 6.89 (s, 1H), 3.72 (dp, 1H), 3.37-3.18 (m, 2H), 3.13-2.91 (m, 3H), 2.85 (dq, 8H), 2.41 (ddt, 1H), 2.24 (ddd, 2H), 2.03 (m, 6H), 1.92-1.70 (m, 2H), 1.21 (t, 3H).

[2084] LCMS: m/z 406 (M+H).sup.+ (ES.sup.+); 404 (MH).sup. (ES.sup.).

Example 195: N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methylazepane-4-sulfonamide, Potassium Salt

[2085] ##STR00588##

[2086] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 186) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-methylazepane-4-sulfonamide (prepared like Intermediate P144) to afford the title compound (11 mg, 9%) as a white solid.

[2087] .sup.1H NMR (methanol-d.sub.4) 6.89 (s, 1H), 3.83-3.66 (m, 1H), 3.14-2.95 (m, 4H), 2.83 (m, 8H), 2.66 (s, 3H), 2.47-2.19 (m, 2H), 2.18-1.93 (m, 6H), 1.83 (dd, 2H).

[2088] LCMS: m/z 392 (M+H).sup.+ (ES.sup.+).

ExamplesBiological Studies

NLRP3 and Pyroptosis

[2089] It is well established that the activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-113) from the cell.

THP-1 Cells: Culture and Preparation

[2090] THP-1 cells (ATCC # TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma # S8636) and penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma # P4333) in 10% Fetal Bovine Serum (FBS) (Sigma # F0804). The cells were routinely passaged and grown to confluency (10.sup.6cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma # T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma # L4524) to give a 1 g/ml Final Assay Concentration (FAC). 40 l of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

THP-1 Cells Pyroptosis Assay

[2091] The following method step-by-step assay was followed for compound screening. [2092] 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 g/ml LPS in 40 l of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) [2093] 2. Add 51 compound (8 points half-log dilution, with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [2094] 3. Incubate for 3 hrs at 37 C. and 5% CO.sub.2 [2095] 4. Add 5 l nigericin (Sigma # N7143) (FAC 5 M) to all wells [2096] 5. Incubate for 1 hr at 37 C. and 5% CO.sub.2 [2097] 6. At the end of the incubation period, spin plates at 300g for 3 mins and remove supernatant [2098] 7. Then add 50 l of resazurin (Sigma # R7017) (FAC 100 M resazurin in RPMI medium without FBS) and incubate plates for a further 1-2 hrs at 37 C. and 5% CO.sub.2 [2099] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [2100] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

96-Well Plate Map

[2101]

TABLE-US-00006 1 2 3 4 5 6 7 8 9 10 11 12 A High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low B High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low C High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low D High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low E High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low F High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low G High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low H High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low High MCC950 (10 uM) Compound 8-point half-log dilution Low Drug free control

[2102] The results of the pyroptosis assay performed are summarised in Table 1 below as THP IC.sub.50.

Human Whole Blood IL1 Release Assay

[2103] For systemic delivery, the ability to inhibit NLRP3 when the compounds are present within the bloodstream is of great importance. For this reason, the NLRP3 inhibitory activity of a number of compounds in human whole blood was investigated in accordance with the following protocol.

[2104] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [2105] 1. Plate out 80 l of whole blood containing 1 g/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [2106] 2. Add 10 l compound (8 points half-log dilution with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [2107] 3. Incubate for 3 hrs at 37 C., 5% CO.sub.2 [2108] 4. Add lop nigericin (Sigma # N7143) (10 M FAC) to all wells [2109] 5. Incubate for 1 hr at 37 C., 5% CO.sub.2 [2110] 6. At the end of the incubation period, spin plates at 300g for 5 mins to pellet cells and remove 20 l of supernatant and add to 96-well v-bottom plates for IL-1 analysis (note: these plates containing the supernatants can be stored at 80 C. to be analysed at a later date) [2111] 7. IL-1 was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [2112] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[2113] The results of the human whole blood assay are summarised in Table 1 below as HWB IC.sub.50.

TABLE-US-00007 TABLE 1 NLRP3 inhibitory activity (1 M = +++, 10 M = ++, >10 M = +, not determined = ND). Example No THP IC.sub.50 HWB IC.sub.50 1 ++ ++ 2 ++ ++ 3 ++ ++ 4 ++ ++ 5 +++ ++ 6 +++ +++ 7 +++ ++ 8 ++ +++ 9 +++ +++ 10 ++ ND 11 ++ ND 12 ++ ND 13 +++ + 14 ++ ND 15 ++ ND 16 ++ ++ 17 ++ ND 18 +++ +++ 19 ++ ND 20 ++ ND 21 ++ ND 22 ++ ND 23 ++ ND 24 +++ +++ 25 ++ ND 26 ++ ND 27 ++ ND 28 ++ ND 29 ++ ND 30 ++ ND 31 +++ +++ 32 ++ ++ 33 ++ ND 34 +++ ++ 35 +++ + 36 ++ ND 37 +++ +++ 38 ++ ND 39 +++ ++ 40 ++ ND 41 +++ +++ 42 ++ ND 43 ++ ND 44 ++ ND 45 +++ +++ 46 +++ +++ 47 ++ ND 48 ++ ND 49 +++ +++ 50 ++ ND 51 ++ ND 52 ++ ND 53 +++ +++ 54 ++ ND 55 ++ ND 56 ++ ND 57 ++ ND 58 ++ ND 59 ++ ND 60 ++ ND 61 ++ ND 62 ++ ND 63 ++ ND 64 ++ ND 65 +++ +++ 66 +++ ND 67 ++ ND 68 +++ ND 69 +++ ND 70 +++ +++ 71 +++ + 72 +++ ++ 73 ++ ND 74 ++ ND 75 +++ +++ 76 +++ +++ 77 ++ ND 78 ++ ND 79 ++ ND 80 ++ ND 81 ++ ND 82 ++ ND 83 ++ ND 84 +++ ND 85 +++ ND 86 ++ ND 87 ++ ND 88 +++ ND 89 ++ ND 90 +++ +++ 91 ++ ND 92 +++ ++ 93 +++ +++ 94 +++ +++ 95 +++ ++ 96 +++ ++ 97 +++ +++ 98 +++ +++ 99 +++ +++ 100 ++ ND 101 +++ +++ 102 ++ ND 103 +++ ++ 104 +++ ND 105 +++ + 106 ++ ND 107 +++ ND 108 +++ +++ 109 +++ +++ 110 ++ ND 111 ++ ND 112 ++ ND 113 +++ +++ 114 ++ ND 115 ++ ND 116 ++ ND 117 +++ ND 118 +++ ND 119 ++ ND 120 ++ ND 121 +++ +++ 122 +++ +++ 123 ++ ND 124 +++ ++ 125 +++ ++ 126 ++ ++ 127 ++ ND 128 ++ ND 129 ++ ND 130 +++ +++ 131 +++ ++ 132 +++ +++ 133 +++ +++ 134 +++ ++ 135 +++ ++ 136 ++ ND 137 +++ ++ 138 +++ +++ 139 ++ ND 140 +++ ND 141 +++ ++ 142 +++ ND 143 ++ ND 144 +++ ++ 145 +++ ++ 146 ++ ND 147 ++ ND 148 ++ ND 149 ++ ND 150 +++ ND 151 +++ ND 152 +++ +++ 153 +++ +++ 154 +++ +++ 155 +++ +++ 156 +++ +++ 157 ++ ND 158 +++ +++ 159 +++ +++ 160 +++ +++ 161 ++ ND 162 +++ +++ 163 +++ +++ 164 +++ +++ 165 ++ ND 166 ++ ND 167 +++ +++ 168 +++ ND 169 ++ ND 170 ++ ++ 171 +++ ND 172 +++ +++ 173 +++ +++ 174 +++ +++ 175 +++ ND 176 ++ ND 177 ++ ND 178 +++ +++ 179 +++ ND 180 ++ ND 181 +++ +++ 182 ++ ND 183 +++ ND 184 ++ ND 185 +++ ++ 186 ++ ND 187 ++ ND 188 ++ ND 189 +++ ++ 190 ++ ND 191 ++ ++ 192 ++ ++ 193 +++ +++ 194 +++ +++ 195 +++ ND

PK Protocol

[2114] Pharmacokinetic parameters were determined in male Sprague Dawley rats (Charles River, UK, 250-300 g; or Vital River Laboratory Animal Technology Co Ltd, Beijing, China, 7-9 weeks old). Animals were individually housed during the study and maintained under a 12 h light/dark cycle. Animals had free access to food and water except that orally dosed animals were food deprived overnight prior to the study.

[2115] For intravenous administration, compounds were formulated as a solution in water or DMSO:PBS [10:90] in 2 mL/kg dosing volume and administered via tail vein. For oral administration, compounds were formulated as a solution in water or DMSO:water [10:90] in 5 mL/kg dosing volume and administered orally.

[2116] Serial blood samples (about 120-300 L) were taken from each animal at each of 8 time-points post dose (0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h). Samples were held on ice for no longer than 30 minutes before centrifugation (10,000 rpm (8,385 g) for 3 minutes; or 5,696 rpm (3,000 g) for 15 minutes) for plasma generation. Plasma was frozen on dry ice prior to bioanalysis. PK parameters were generated from LC-MS/MS data using Dotmatics or Phoenix WinNonlin 6.3 software.

TABLE-US-00008 TABLE 2 PK data (intravenous administration) Example Dose AUC T.sub.1/2 V.sub.dss Cl No (mg/kg) (ng .Math. hr/mL) (hr) (L/kg) (mL/min .Math. kg) 1 1 1949.4 1.2 0.58 8.5 6 1 2344.0 2.7 0.61 7.2 9 1 2669.0 3.9 0.63 6.5 18 1 1531.6 0.9 0.42 10.9 31 1 2753.6 4.5 0.47 6.1 37 1.46 2247.9 2.1 0.59 10.8 41 1 1853.9 2.9 0.78 9.1 45 0.66 703.1 3.3 2.06 15.6 46 1 2077.2 1.2 0.45 8.2 70 1.86 2552.9 1.7 0.53 12.1 76 1 2647.5 1.0 0.25 6.3 94 2.09 1407.8 1.1 1.62 25.2 99 1 1670.9 0.6 0.42 10.0 109 1 1732.0 1.3 0.64 9.6 153 1 510.7 1.1 1.21 32.6 156 1 1518.0 1.0 0.31 11.0

TABLE-US-00009 TABLE 3 PK data (oral administration) Example Dose C.sub.max AUC T.sub.max T.sub.1/2 Cl No (mg/kg) (ng/mL) (ng .Math. hr/mL) (hr) (hr) (mL/min .Math. kg) Bioavailability 6 3 1768.6 5395.0 0.5 2.7 9.3 76.7 46 3 1330.0 3513.7 0.67 1.4 14.6 56.4

[2117] As is evident from the results presented in Table 1, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and in particular in the human whole blood assay.

[2118] As is evident from the results presented in Tables 2 and 3, the compounds of the invention show advantageous pharmacokinetic properties, for example half-life T.sub.1/2, area under the curve AUC, clearance Cl and/or bioavailability, compared to the prior art compounds.

[2119] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.