NOVEL SULFONAMIDE CARBOXAMIDE COMPOUNDS

Abstract

The present invention relates to compounds of formula (I): Formula (I) wherein Q is selected from O or S; L is a saturated or unsaturated, optionally substituted C.sub.1-C.sub.12 hydrocarbylene group optionally including one or more heteroatoms N, O or S; R.sup.1 is NR.sup.3R.sup.4, OR.sup.5, (CNR.sup.6)R.sup.7, (CO)R.sup.8, CN, N.sub.3, a quaternary ammonium group or an optionally substituted heterocycle; R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently hydrogen or a saturated or unsaturated, optionally substituted C.sub.1-C.sub.10 hydrocarbyl group optionally including one or more heteroatoms N, O or S; wherein optionally L and R.sup.3, or L and R.sup.4, or R.sup.3 and R.sup.4, or L and R.sup.5, or L and R.sup.6, or L and R.sup.7, or R.sup.6 and R.sup.7, or L and R.sup.8 together with the atom(s) to which they are attached may form a 3- to 12-membered, saturated or unsaturated, optionally substituted cyclic group; and R.sup.2 is a cyclic group substituted at the a-position, wherein R.sup.2 may optionally be further substituted; provided that the atom of L which is attached to the sulfur atom of the sulfonylurea group is a carbon atom and is not a ring atom of a heterocyclic or aromatic group. 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 NLRP.sub.3.

##STR00001##

Claims

1. A compound of formula (I): ##STR00383## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is selected from 0 or S; L is a saturated or unsaturated C.sub.1-C.sub.12 hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbylene group may optionally be substituted, and wherein the hydrocarbylene group may optionally include one or more heteroatoms N, O or S in its carbon skeleton; R.sup.1 is NR.sup.3R.sup.4, OR.sup.5, (CNR.sup.6)R.sup.7, (CO)R.sup.8, CN, N.sub.3, a quaternary ammonium group or an optionally substituted heterocycle; R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently hydrogen or a saturated or unsaturated C.sub.1-C.sub.10 hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton; wherein optionally L and R.sup.3, or L and R.sup.4, or R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached may form a 3- to 12-membered saturated or unsaturated cyclic group, wherein the cyclic group may optionally be substituted; wherein optionally L and R.sup.5 together with the oxygen atom to which they are attached may form a 3- to 12-membered saturated or unsaturated cyclic group, wherein the cyclic group may optionally be substituted; wherein optionally L and R.sup.6, or L and R.sup.7, or R.sup.6 and R.sup.7 together with the (CN) group to which they are attached may form a 3- to 12-membered saturated or unsaturated cyclic group, wherein the cyclic group may optionally be substituted; wherein optionally L and R.sup.8 together with the (CO) group to which they are attached may form a 3- to 12-membered saturated or unsaturated cyclic group, wherein the cyclic group may optionally be substituted; R.sup.2 is a cyclic group substituted at the -position, wherein R.sup.2 may optionally be further substituted; provided that the atom of L which is attached to the sulfur atom of the sulfonylurea group is a carbon atom and is not a ring atom of a heterocyclic or aromatic group.

2. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein L is a saturated or unsaturated C.sub.1-C.sub.8 hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include cyclic groups, and wherein the hydrocarbylene group may optionally be substituted with one or more substituents independently selected from halo, CN, N(R.sup.9).sub.2, OR.sup.9 or oxo (O) groups, wherein R.sup.9 is independently selected from a hydrogen atom or a C.sub.1-C.sub.3 alkyl group.

3. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the atom of L which is attached to the sulfur atom of the sulfonylurea group is a carbon atom and is not a ring atom of any cyclic group.

4. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is NR.sup.3R.sup.4, and R.sup.3 and R.sup.4 are each independently hydrogen or a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 cycloalkyl, phenyl or benzyl group, each of which may optionally be substituted with one or more substituents independently selected from halo, CN, N(R.sup.9).sub.2, OR.sup.9 or oxo (O) groups, wherein R.sup.9 is independently selected from a hydrogen atom or a C.sub.1-C.sub.3 alkyl group.

5. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is OR.sup.5, and R.sup.5 is hydrogen or a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 cycloalkyl, phenyl or benzyl group, each of which may optionally be substituted with one or more substituents independently selected from halo, CN, N(R.sup.9).sub.2, OR.sup.9 or oxo (O) groups, wherein R.sup.9 is independently selected from a hydrogen atom or a C.sub.1-C.sub.3 alkyl group.

6. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is (CNR.sup.6)R.sup.7, and R.sup.6 and R.sup.7 are each independently hydrogen or a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 cycloalkyl, phenyl or benzyl group, each of which may optionally be substituted with one or more substituents independently selected from halo, CN, N(R.sup.9).sub.2, OR.sup.9 or oxo (O) groups, wherein R.sup.9 is independently selected from a hydrogen atom or a C.sub.1-C.sub.3 alkyl group.

7. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is (CO)R.sup.8, and R.sup.8 is hydrogen or a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 cycloalkyl, phenyl or benzyl group, each of which may optionally be substituted with one or more substituents independently selected from halo, CN, N(R.sup.9).sub.2, OR.sup.9 or oxo (O) groups, wherein R.sup.9 is independently selected from a hydrogen atom or a C.sub.1-C.sub.3 alkyl group.

8. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is (CO)R.sup.8 and, L and R.sup.8 together with the (CO) group to which they are attached form a 4-, 5- or 6-membered saturated cyclic group, wherein the cyclic group may optionally include one further heteroatom N, O or S in its carbon skeleton, and wherein the cyclic group may optionally be substituted with one or more substituents independently selected from halo, CN, N(R.sup.9).sub.2, OR.sup.9, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkylene or oxo (O) groups, wherein R.sup.9 is independently selected from a hydrogen atom or a C.sub.1-C.sub.3 alkyl group.

9. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof 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.

10. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 9, 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.

11. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 10, 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.

12. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.2 is a cyclic group substituted at the -position with a monovalent heterocyclic group or a monovalent aromatic group, wherein a ring atom of the heterocyclic or aromatic group is directly attached to the -ring atom of the cyclic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the cyclic group may optionally be further substituted.

13. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof 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.

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

15. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the compound is selected from the group consisting of: ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398##

16. (canceled)

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

18. (canceled)

19. A method of treating or preventing a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1 to the subject, thereby treating or preventing the disease, disorder or condition, optionally wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

20. The method as claimed in 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; and (xvi) allodynia; and (xvii) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

21. The method as claimed in 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).

22. (canceled)

23. The method as claimed in claim 19, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

24. A method of inhibiting NLRP3 in a subject, comprising administering the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1 to the subject thereby inhibiting NLRP3.

25. A method of analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 by a compound, comprising contacting a cell or non-human animal with the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, and analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 in the cell or non-human animal by the compound.

Description

EXAMPLESCOMPOUND SYNTHESIS

[0427] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0428] 2-MeTHF 2-methyltetrahydrofuran [0429] Ac.sub.2O acetic anhydride [0430] AcOH acetic acid [0431] aq aqueous [0432] Boc tert-butyloxycarbonyl [0433] br broad [0434] Cbz carboxybenzyl [0435] CDI 1,1-carbonyl-diimidazole [0436] conc concentrated [0437] d doublet [0438] DABCO 1,4-diazabicyclo[2.2.2]octane [0439] DCE 1,2-dichloroethane, also called ethylene dichloride [0440] DCM dichloromethane [0441] DIPEA N,N-diisopropylethylamine, also called Hnig's base [0442] DMA dimethylacetamide [0443] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0444] DME dimethoxyethane [0445] DMF N,N-dimethylformamide [0446] DMSO dimethyl sulfoxide [0447] eq or equiv equivalent [0448] (ES+) electrospray ionization, positive mode [0449] Et ethyl [0450] EtOAc ethyl acetate [0451] EtOH ethanol [0452] h hour(s) [0453] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0454] HPLC high performance liquid chromatography [0455] LC liquid chromatography [0456] m multiplet [0457] m-CPBA 3-chloroperoxybenzoic acid [0458] Me methyl [0459] MeCN acetonitrile [0460] MeOH methanol [0461] (M+H)+ protonated molecular ion [0462] MHz megahertz [0463] min minute(s) [0464] MS mass spectrometry [0465] Ms mesyl, also called methanesulfonyl [0466] MsCl mesyl chloride, also called methanesulfonyl chloride [0467] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0468] m/z mass-to-charge ratio [0469] NaO.sup.tBu sodium tert-butoxide [0470] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0471] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0472] NMP N-methylpyrrolidine [0473] NMR nuclear magnetic resonance (spectroscopy) [0474] Pd(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o) [0475] Pd(dppf)C.sub.2 [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [0476] PE petroleum ether [0477] Ph phenyl [0478] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0479] prep-HPLC preparative high performance liquid chromatography [0480] prep-TLC preparative thin layer chromatography [0481] PTSA p-toluenesulfonic acid [0482] q quartet [0483] RP reversed phase [0484] RT room temperature [0485] s singlet [0486] Sept septuplet [0487] sat saturated [0488] SCX solid supported cation exchange (resin) [0489] t triplet [0490] T3P propylphosphonic anhydride [0491] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0492] TEA triethylamine [0493] TFA 2,2,2-trifluoroacetic acid [0494] THF tetrahydrofuran [0495] TLC thin layer chromatography [0496] wt % weight percent or percent by weight

EXPERIMENTAL METHODS

Analytical Methods

[0497] NMR spectra were recorded at 300, 400 or 500 MHz (unless stated otherwise) with chemical shifts reported in parts per million. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. Spectra were recorded using one of the following machines: [0498] 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. [0499] An Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console. [0500] A Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control. [0501] A Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe. [0502] A Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe.

[0503] LC-MS Methods: 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.

Reversed Phase HPLC Conditions for the LCMS Analytical Methods:

Methods 1a and 1b:

[0504] Waters Xselect CSH C18 XP column, 2.5 m (4.630 mm) at 40 C.; flow rate 2.5-4.5 mL min.sup.1 eluted with a water-acetonitrile gradient containing either 0.1% v/v formic acid (Method 1a) or 10 mM ammonium bicarbonate in water (Method 1b) over 4 minutes employing UV detection at 254 nm. Gradient information: 0-3.00 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 3.00-3.01 min, held at 5% water-95% acetonitrile, flow rate increased to 4.5 mL min.sup.1; 3.01-3.50 min, held at 5% water-95% acetonitrile; 3.50-3.60 min, returned to 95% water-5% acetonitrile, flow rate reduced to 3.50 mL min.sup.1; 3.60-3.90 min, held at 95% water-5% acetonitrile; 3.90-4.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 2.5 mL min.sup.1.

[0505] 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). [0506] Pump flow: 0.6 mL/min UV detection: 215, 238 nm [0507] Injection volume: 0.2 L Run time: 4.0 min [0508] Column temperature: 35 C. Mass detection: API-ES +ve and ve [0509] Pump Program:

TABLE-US-00001 Gradient Time (min) % A % B 0.0 80 20 0.5 80 20 2.0 0 100

Reversed Phase HPLC Conditions for the UPLC Analytical Methods:

Methods 2a and 2b:

[0510] Waters BEH C18 (2.130 mm, 1.7 m) at 40 C.; flow rate 0.77 mL min.sup.1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 2a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 2b) over 3 min employing UV detection at 254 nm. Gradient information: 0-0.11 min, held at 95% water-5% acetonitrile, flow rate 0.77 mL min.sup.1; 0.11-2.15 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 2.15-2.49 min, held at 5% water-95% acetonitrile, flow rate 0.77 mL min.sup.1; 2.49-2.56 min, returned to 95% water-5% acetonitrile; 2.56-3.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 0.77 mL min.sup.1.

Purification Methods

Method 1 (Acidic Preparation):

[0511] Waters X-Select CSH column C18, 5 m (1950 mm), flow rate 28 mL/min eluting with a water-acetonitrile gradient containing 0.1% v/v formic acid over 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 minutes, 20% acetonitrile; 0.2-5.5 minutes, ramped from 20% acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, ramped from 40% acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, held at 95% acetonitrile.

Method 2 (Basic Preparation):

[0512] Waters X-Bridge Prep column C18.5 m (1950 mm), flow rate 28 mL/min eluting with a 10 mM ammonium bicarbonate-acetonitrile gradient over 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 minutes, 10% acetonitrile; 0.2-5.5 minutes, ramped from 10% acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, ramped from 40% acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, held at 95% acetonitrile.

Method 3:

[0513] Phenomenex Gemini column, 10 m (15025 mm), flow rate=25 mL/min eluting with a water-acetonitrile gradient containing 0.04% NH.sub.3 at pH 10 over 9 minutes using UV detection at 220 and 254 nm. Gradient information: 0-9 minutes, ramped from 8% to 35% acetonitrile; 9-9.2 minutes, ramped from 35% to 100% acetonitrile; 9.2-15.2 minutes, held at 100% acetonitrile.

Method 4:

[0514] 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.

[0515] Revelis C18 reversed-phase 12 g cartridge

TABLE-US-00002 Carbon loading 18% Surface area 568 m.sup.2/g Pore diameter 65 Angstrom pH (5% slurry) 5.1 Average particle size 40 m

[0516] 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:

[0517]

TABLE-US-00003 Time (min) A: water (%) B: MeOH (%) 0 100 0 5 100 0 30 30 70 30.1 0 100 35 0 100

[0518] Detection wavelength: 215, 235, 254 and 280 nm. Before each new run, the cartridge was cleaned using the conditioning method.

SYNTHESIS OF INTERMEDIATES

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

[0519] ##STR00135##

[0520] To a solution of phosgene (4.45 mL, 20% weight in toluene, 8.4 mmol) in ethyl acetate (90 mL) was added dropwise a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in ethyl acetate (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.

[0521] .sup.1H NMR (CDC.sub.3) 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m, 4H).

Intermediate A2: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-H-inden-5-yl)pyridine

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

[0522] ##STR00136##

[0523] To a mixture of 7-fluoro-2,3-dihydro-1H-inden-1-one 9.5 g, 3.27 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.

[0524] .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-H-inden-1-ol

[0525] ##STR00137##

[0526] 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 (500 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.

[0527] .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

[0528] ##STR00138##

[0529] 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.

[0530] .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

[0531] ##STR00139##

[0532] 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.

[0533] .sup.1H NMR (CDCl.sub.3) 6.69 (t, 1H), 6.44 (dd, 1H), 0.47 (br s, 2H), 2.95 (t, 2H), 2.75 (t, 2H), 2.75 (t, 2 H) and 2.19-2.11 (m, 2H).

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

[0534] ##STR00140##

[0535] 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, 1:0 to 20:1) to give the title compound (8.51 g, 67%) as a brown solid.

[0536] .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

[0537] ##STR00141##

[0538] 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)Cl.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, 4% yield, 90.98% purity on HPLC) as a brown solid.

[0539] .sup.1H NMR (CDC.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

[0540] ##STR00142##

[0541] 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 A3: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile

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

[0542] ##STR00143##

[0543] 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)Cl.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.

[0544] .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).

[0545] LCMS: m/z 152.2 (M+H).sup.+(ES.sup.+).

Step B: 4-Fluoro-2-isopropylaniline

[0546] ##STR00144##

[0547] 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.

[0548] .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).

[0549] LCMS: m/z 154.2 (M+H).sup.+(ES.sup.+).

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

[0550] ##STR00145##

[0551] 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.

[0552] .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).

[0553] LCMS: m/z 232.1 (M+H).sup.+(ES.sup.+).

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

[0554] ##STR00146##

[0555] 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)Cl.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.

[0556] .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).

[0557] LCMS: m/z 256.2 (M+H).sup.+(ES.sup.+).

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

[0558] ##STR00147##

[0559] 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 5C. 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 A4: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine

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

[0560] ##STR00148##

[0561] 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)Cl.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).

[0562] .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).

[0563] LCMS: m/z 261.1 (M+H).sup.+(ES.sup.+).

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

[0564] ##STR00149##

[0565] 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 5C. 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 A5: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

Step A: 4-Nitro-2,3-dihydro-1H-indene

[0566] ##STR00150##

[0567] To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol, 62.50 mL, 1 eq) in concentrated H.sub.2SO.sub.4 (30 mL) was added a mixture of HNO.sub.3 (50 mL, 69 wt % in water) and concentrated H.sub.2SO.sub.4 (50 mL) dropwise at 0 C. over a period of 3.5 hours. The reaction mixture was stirred at 0 C. for 0.5 hour. Then the reaction mixture was poured into ice water (600 mL) and extracted with ethyl acetate (2400 mL). The combined organic layers were washed with water (500 mL), saturated aqueous NaHCO.sub.3 solution (500 mL) and brine (2500 mL). The organic layer was 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, 1:0 to 100:1) to give the title compound (55 g, 66%) as a colourless oil.

[0568] .sup.1H NMR (CDCl.sub.3): 7.98 (d, 1H), 7.51 (d, 1H), 7.30 (t, 1H), 3.41 (t, 2H), 302 (t, 2H) and 2.22-2.20 (m, 2H).

Step B: 2,3-Dihydro-H-inden-4-amine

[0569] ##STR00151##

[0570] To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g, contained another regio-isomer) in MeOH (500 mL) was added Pd/C (5 g, 10 wt % loading on activated carbon) under N.sub.2 atmosphere. The suspension was degassed under vacuum and purged with H.sub.2 several times. The reaction mixture was stirred under H.sub.2 (50 psi) at 20 C. for 12 hours. The reaction 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, 1:0 to 100:4) to give the title compound (19.82 g, 43% yield, 96.39% purity on LCMS) as a brown oil.

[0571] .sup.1H NMR (CDCl.sub.3): 7.01 (t, 1H), 6.71 (d, 1H), 6.51 (d, 1H), 3.57 (br s, 2H), 2.93 (t, 2H), 2.75 (t, 2H) and 2.16-2.08 (m, 2H).

[0572] LCMS: m/z 134.2 (M+H).sup.+(ES.sup.+).

Step C: N-(2,3-Dihydro-H-inden-4-yl)acetamide

[0573] ##STR00152##

[0574] To a solution of 2,3-dihydro-1H-inden-4-amine (19.8 g, 148.66 mmol, 1 eq) and TEA (19.56 g, 193.26 mmol, 1.3 eq) in DCM (300 mL) was added dropwise Ac.sub.2O (17.45 g, 170.96 mmol, 1.15 eq) over 6 minutes at 0 C. Then the reaction mixture was warmed to 16 C. and stirred for 1.4 hours. The mixture was poured into water (500 mL) and extracted with DCM (2300 mL). The combined organic phases were washed with brine (2500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (25.74 g, 96% yield, 96.69% purity on LCMS) as a white solid.

[0575] .sup.1H NMR (CDCl.sub.3): 7.70 (d, 1H), 7.15 (t, 1H), 7.02 (d, 1H), 2.95 (t, 2H), 2.81 (t, 2H), 2.18 (s, 3H) and 2.15-2.08 (m, 2H).

[0576] LCMS: m/z 176.2 (M+H).sup.+(ES.sup.+)

Step D: N-(5-Bromo-2,3-dihydro-H-inden-4-yl)acetamide

[0577] ##STR00153##

[0578] N-(2,3-dihydro-1H-inden-4-yl)acetamide (34.6 g, 197.46 mmol, 1 eq), p-toluenesulfonic acid (18.70 g, 108.60 mmol, 0.55 eq) and Pd(OAc).sub.2 (2.22 g, 9.87 mmol, 0.05 eq) were suspended in toluene (400 mL) and stirred at 20 C. for 0.5 hour under air atmosphere. NBS (38.66 g, 217.20 mmol, 1.1 eq) was added. Then the reaction mixture was stirred at 20 C. for 2 hours. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (2500 mL). The combined organic phases were washed with brine (2500 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 (13.9 g, 27% yield, 98.1% purity on LCMS) as a white solid.

[0579] .sup.1H NMR (CDCl.sub.3): 7.33 (d, 1H), 7.16 (s, 1H), 6.98 (d, 1H), 2.92-2.83 (m, 4H), 2.21 (s, 3H) and 2.10-2.02 (m, 2H).

[0580] LCMS: m/z 254.1 (M+H).sup.+(ES.sup.+).

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

[0581] ##STR00154##

[0582] A mixture of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide (45.68 g, 179.76 mmol, 1 eq) in EtOH (200 mL) and concentrated HCl (300 mL, 36 wt % in water) was stirred at 80 C. for 36 hours. The reaction mixture was cooled to 0 C. in an ice bath and some solid precipitated. The suspension was filtered. The filter cake was washed with ice water (50 mL) and dried in vacuo to give the title compound (34.1 g, 72% yield, 94.08% purity on LCMS, HCl salt) as a grey solid.

[0583] .sup.1H NMR (DMSO-d.sub.6): 7.67 (br s, 2H), 7.24 (d, 1H), 6.69 (d, 1H), 2.85 (t, 2H), 2.79 (t, 2H) and 2.04-1.96 (m, 2H).

[0584] LCMS: m/z 212.0 (M+H).sup.+(ES.sup.+).

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

[0585] ##STR00155##

[0586] A solution of (2-methoxypyridin-4-yl)boronic acid (25.11 g, 164.15 mmol, 1.2 eq), 5-bromo-2,3-dihydro-1H-inden-4-amine (34 g, 136.80 mmol, 1 eq, HCl salt) and K.sub.2CO.sub.3 (60.50 g, 437.74 mmol, 3.2 eq) in dioxane (500 mL) and H.sub.2O (100 mL) was degassed with nitrogen for 15 minutes before Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (6 g, 7.35 mmol, 0.053 eq) was added. The reaction mixture was heated to 80 C. for 12 hours. The mixture was poured into water (500 mL) and extracted with ethyl acetate (2500 mL). The combined organic phases were washed with brine (2700 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, 1:0 to 10:1) to give the title compound (27.4 g, 79% yield, 95% purity on LCMS) as a white solid.

[0587] .sup.1H NMR (CDCl.sub.3): 8.22 (d, 1H), 7.03-7.00 (m, 1H), 6.99 (d, 1H), 6.87 (s, 1H), 6.77 (d, 1H), 3.99 (s, 3H), 3.77 (br s, 2H), 2.97 (t, 2H), 2.77 (t, 2H) and 2.21-2.13 (m, 2H).

[0588] LCMS: m/z 241.2 (M+H).sup.+(ES.sup.+).

Step G: 4-(4-Isocyanato-2,3-dihydro-H-inden-5-yl)-2-methoxypyridine

[0589] ##STR00156##

[0590] To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50-35 mmol, 1.1 eq) in THF (275 mL) was added bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) in portions 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.

[0591] .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 A6: 3-(5-Fluoro-2-isocyanato-3-isopropylphenyl)pyridine

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

[0592] ##STR00157##

[0593] 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 N.sub.2 three times. Then Pd(dppf)Cl.sub.2 (5.10 g, 6.97 mmol, 0.077 eq) was added under N.sub.2 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.

[0594] .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). LCMS: m/z 231.2 (M+H).sup.+(ES.sup.+).

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

[0595] ##STR00158##

[0596] 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 A7: 4-(4-Isocyanato-2,3-dihydro-H-inden-5-yl)-2-methoxypyridine

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

[0597] ##STR00159##

[0598] 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 under air for 16 hours. The dark green mixture was diluted with EtOAc (20 mL), and then washed with saturated aq. 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, 0-30% 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.

[0599] LCMS m/z 296.3/298.3 (M+H).sup.+(ES.sup.+).

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

[0600] ##STR00160##

[0601] 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% aq.) (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 2M aq. NaOH. The mixture was extracted with dichloromethane (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 (0.138 g, 29%).

[0602] .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

[0603] ##STR00161##

[0604] 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)Cl.sub.2. CH.sub.2C12 (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80 C. (bath temperature) for 2 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (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 (0.289 g, 87%) as a pale yellow crystalline solid.

[0605] .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), NH.sub.2 not observed.

[0606] LCMS m/z 241.3 (M+H).sup.+(ES.sup.+).

Step D: 4-(4-Isocyanato-2,3-dihydro-H-inden-5-yl)-2-methoxypyridine

[0607] ##STR00162##

[0608] 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (500 mg, 2.081 mmol) was dissolved in DCM (10 mL) and sat aq NaHCO.sub.3 (5 mL) was added. A solution of triphosgene (250 mg, 0.842 mmol) in DCM (5 mL) was added and the mixture stirred at room temperature for 1 hour. The organic phase was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to afford the title compound (523 mg, 94%) as a pale yellow oil that was used without further purification.

[0609] .sup.1H NMR (CDCl.sub.3) 8.25 (d, J=5.2 Hz, 1H), 7.18-7.13 (m, 2H), 7.01 (dd, J=5.3, 1.5 Hz, 1H), 6.86 (s, 1H), 4.03 (s, 3H), 3.04 (t, J=7.5 Hz, 4H), 2.21 (p, J=7.5 Hz, 2H).

Intermediate A8: 4-(4-Isocyanato-2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine

Step A: N-(5-Bromo-2,3-dihydrobenzofuran-4-yl)acetamide

[0610] ##STR00163##

[0611] N-(2,3-dihydrobenzofuran-4-yl)acetamide (13.1 g, 73.9 mmol), 4-methylbenzenesulfonic acid hydrate (7.73 g, 40.7 mmol) and diacetoxypalladium (0.830 g, 3.70 mmol) were suspended in toluene (250 mL) and stirred for 20 minutes. NBS (14.47 g, 81 mmol) was added and the mixture was stirred for 30 minutes, diluted with EtOAc (150 mL), and washed with aq NaHCO.sub.3 (100 mL) and aq Na.sub.2S203 (10 wt %, 100 mL). The aqueous phases were further extracted with DCM (150 mL). The organic phases were combined, dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the title compound (22.27 g, quant., purity 85% by LCMS) which was used crude in the next step.

[0612] LCMS; m/z 255.9, 257.9 (M+H).sup.+(ES.sup.+).

Step B: 5-Bromo-2,3-dihydrobenzofuran-4-amine

[0613] ##STR00164##

[0614] A solution of N-(5-bromo-2,3-dihydrobenzofuran-4-yl)acetamide (22.27 g, 73.9 mmol) in MeOH (400 mL) and conc H.sub.2SO.sub.4 (40 mL) was stirred at reflux for 18 hours. The volatiles were removed under reduced pressure, the residue taken up in DCM (300 mL) and basified with aq NaOH 1 M (100 mL). The organic phase was separated, dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (220 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (9.17 g, 57%) as an off white solid.

[0615] .sup.1H NMR (CDCl.sub.3) 7.16 (dt, J=8.4, 0.9 Hz, 1H), 6.17 (d, J=8.4 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.99 (br. s, 2H), 3.05 (t, J=8.7 Hz, 2H).

Step C: 5-(2-Methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-amine

[0616] ##STR00165##

[0617] Prepared according to the general procedure of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A7, Step C) from 5-bromo-2,3-dihydrobenzofuran-4-amine and (2-methoxypyridin-4-yl)boronic acid to afford the title compound (2.25 g, 79%) as an off white solid.

[0618] .sup.1H NMR (DMSO-d.sub.6) 8.15 (d, J=5.2 Hz, 1H), 6.99 (dd, J=5.3, 1.5 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.78 (s, 1H), 6.14 (d, J=8.1 Hz, 1H), 4.91 (s, 2H), 4.54 (t, J=8.7 Hz, 2H), 3.87 (s, 3H), 3.01 (t, J=8.7 Hz, 2H).

[0619] LCMS; m/z 243.1 (M+H).sup.+(ES.sup.+).

Step D: 4-(4-Isocyanato-2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine

[0620] ##STR00166##

[0621] Prepared according to the general procedure of 4-(4-isocyanato-2,3-dihydro-H-inden-5-yl)-2-methoxypyridine (Intermediate A7, Step D) from 5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-amine to afford the title compound (926 mg, 79%) as a pale yellow solid.

[0622] .sup.1H NMR (CDCl.sub.3) 8.23 (d, J=5.3 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.98 (dd, J=5.3, 1.4 Hz, 1H), 6.83 (s, 1H), 6.74 (d, J=8.3 Hz, 1H), 4.72 (t, J=8.7 Hz, 2H), 4.02 (s, 3H), 3.33 (t, J=8.7 Hz, 2H).

Intermediate A9: 5-Chloro-2-isocyanato-1,3-diisopropylbenzene

[0623] ##STR00167##

[0624] 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%).

[0625] .sup.1H NMR (CDCl.sub.3) 7.07 (d, 2H), 3.17 (h, 2H), 1.24 (d, 12H).

Intermediate A10: 5-Fluoro-2-isocyanato-1,3-diisopropylbenzene

[0626] ##STR00168##

[0627] 4-Fluoro-2,6-diisopropylaniline (1 g, 5.12 mmol) and triethylamine (0.785 mL, 5.63 mmol) were dissolved in THF (10 mL) and cooled to 0 C. Triphosgene (0.760 g, 2.56 mmol) was added to the mixture portionwise and the reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated in vacuo. Isohexane (50 mL) was added and the suspension filtered through silica (3 g). The filtrate was dried under reduced pressure to afford the title compound (900 mg, 75%) as a colourless oil.

[0628] .sup.1H NMR (DMSO-d6) 6.80 (d, J=9.4 Hz, 2H), 3.27-3.12 (m, 2H), 1.23 (d, J=6.8 Hz, 12H).

Intermediate P1: (1-Ethylpiperidin-4-yl)methanesulfonamide

[0629] ##STR00169##

[0630] To a suspension of piperidin-4-yl-methanesulfonamide hydrochloric acid (200 mg, 0.93 mmol) and potassium carbonate (514 mg, 3.7 mmol, 4.0 equiv.) in acetonitrile (10 mL) was added iodoethane (74 L, 0.93 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature overnight and then filtered. The residue was washed with methanol and the filtrates were combined and concentrated in vacuo. The crude was dissolved in methanol, coated on hydromatrix and then submitted for normal phase flash chromatography on silica gel using dichloromethane and a mixture of 3.5 M ammonia in methanol to afford the title compound (176 mg, 91%).

[0631] .sup.1H NMR (CD.sub.3OD) 3.34 (m, 2H), 3.09 (d, 2H), 2.93 (q, 2H), 2.64 (t, 2H), 2.19 (m, 3H), 1.58 (q, 2H) and 1.23 (t, 3H).

Intermediate P2: 3-(4-(Dimethylamino)piperidin-1-yl)propane-1-sulfonamide

[0632] ##STR00170##

[0633] To a solution of 3-chloropropane-1-sulfonamide (213 mg, 1.35 mmol) in acetonitrile (10 mL) was added triethylamine (225 L, 1.62 mmol, 1.2 equiv.), N,N-dimethylpiperidin-4-amine (208 mg, 1.62 mmol, 1.2 equiv.) and potassium iodide (45 mg, 0.27 mmol). The reaction mixture was irradiated in the microwave at 100 C. for 90 minutes and heated for another 2 hours conventionally at 100 C. The mixture was allowed to cool to room temperature and concentrated in vacuo to afford the crude title compound (>100% yield); the material still contained salts and impurities but was used without further purification.

[0634] .sup.1H NMR (CD.sub.3OD) 3-3 (m, 2H), 3.21 (m, 2H), 3.03 (m, 2H), 2.75 (m, 2H), 2.5 (m, 1H), 2.33 (s, 6H), 1.95 (m, 2H) and 1.72-1.42 (m, 4H).

Intermediate P3: 3-(Diethylamino)propane-1-sulfonamide

[0635] ##STR00171##

[0636] To a solution of 3-chloropropane-1-sulfonamide (203 mg, 1.29 mmol) in acetonitrile (10 mL) was added triethylamine (214 L, 1.55 mmol, 1.2 equiv.), N,N-diethylamine (159 L, 1.55 mmol, 1.2 equiv.) and potassium iodide (43 mg, 0.26 mmol) and the reaction mixture was irradiated in the microwave at 100 C. for 90 minutes. Additional potassium iodide (150 mg) was added and the resulting mixture was heated conventionally for another 2 hours at 100 C. Upon cooling to room temperature the mixture was concentrated in vacuo to afford the crude title compound (>100% yield); the material still contained salts and impurities but was used without further purification.

[0637] .sup.1H NMR (CD.sub.3OD) 2.86 (m, 6H), 2.47 (m, 2H), 2.23 (m, 2H) and 1.18 (t, 6H).

[0638] LCMS: m/z 195.1 (M+H).sup.+(ES.sup.+).

Intermediate P4: 3-(Dimethylamino)propane-1-sulfonamide

[0639] ##STR00172##

[0640] To a solution of 3-chloropropane-1-sulfonamide (203 mg, 1.29 mmol) in 2M dimethylamine in THF (7 mL) was added triethylamine (0.18 mL, 1.29 mmol) and potassium iodide (214 mg, 1.29 mmol). The mixture was heated in the microwave at 80 C. for 90 minutes. The solvents were evaporated and the residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent to afford the title compound (51 mg, 24%), as a white solid.

[0641] .sup.1H NMR (CD.sub.3OD) 3.20 (t, 2H), 2.44 (t, 2H), 2.24 (s, 6H), 2.04 (m, 2H).

Intermediate P5: 4-Morpholinobutane-1-sulfonamide

[0642] ##STR00173##

[0643] To a solution of 4-chlorobutane-1-sulfonamide (250 mg, 1.46 mmol) in acetonitrile (5 mL) was added potassium carbonate (200 mg, 1.46 mmol), potassium iodide (40 mg, 0.24 mmol) and morpholine (140 mg, 1.6 mmol). The mixture was refluxed under nitrogen for 18 hours. The solvents were evaporated and the residue was purified by chromatography on silicagel using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent to afford the title compound (56 mg, 17%) as a white solid.

[0644] .sup.1H NMR (Chloroform-d) 4.70 (s, 2H), 3.82-3.58 (m, 4H), 3.34-3.04 (m, 2H), 2.64-2.24 (m, 6H), 1.93 (m, 2H), 1.79-1.52 (m, 2H).

Intermediate P6: 4-(Diethylamino)butane-1-sulfonamide

[0645] ##STR00174##

[0646] To a solution of 4-chlorobutane-1-sulfonamide (250 mg, 1.46 mmol) in acetonitrile (5 mL) was added potassium carbonate (200 mg, 1.46 mmol), potassium iodide (60 mg, 0.36 mmol) and diethylamine (0.3 mL, 2.9 mmol). The mixture was refluxed under nitrogen for 18 hours. The solvents were evaporated and the residue was purified by chromatography on silicagel using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent to afford the title compound (60 mg, 20%) as a colourless oil.

[0647] .sup.1H NMR (Chloroform-d) 3.35-2.86 (m, 2H), 2.72-2.33 (m, 6H), 1.91 (m, 2H), 1.78-1.48 (m, 2H), 1.03 (t, 6H).

Intermediate P7: 2-(Benzyl(ethyl)amino)ethane-1-sulfonamide

[0648] ##STR00175##

[0649] Ethene sulfonamide (250 mg, 2.33 mmol) was dissolved in THF (12.5 mL) and N-ethylbenzylamine (0.36 mL, 331 mg, 2.45 mmol) was added and the solution stirred for 15 minutes at ambient temperature. Triethylamine (0.98 mL, 0.71 g, 7.0 mmol) was added and the mixture stirred for 24 hours at room temperature. The now slightly turbid mixture was evaporated in vacuo. The residue was dissolved in a few mL of DCM/MeOH (1/1) and applied to automated column chromatography (40 g SiO.sub.2, 5-30% MeOH/3.5N ammonia in DCM). This afforded the title compound (420 mg, 1.73 mmol, 74%) in 99.3% purity (ELSD-HPLC) after evaporation of the selected fractions.

[0650] .sup.1H NMR (CDC.sub.3) 7.30 (m, 5H), 3.64 (s, 2H), 3.17 (dd, 2H), 3.04 (dd, 2H), 2.59 (q, 2H), 1.10 (t, 3H).

Intermediate P8: 2-Morpholinoethane-1-sulfonamide

[0651] ##STR00176##

[0652] Prepared according to 2-(benzyl(ethyl)amino)ethane-1-sulfonamide (Intermediate P7) using ethene sulfonamide (375 mg, 3.5 mmol) and morpholine (0.35 mL, 351 mg, 4.03 mmol) to yield the title compound (520 mg, 61%) after column chromatography. HPLC-MS: 100% (ELSD), M 194+1 (ACPI pos.)

[0653] .sup.1H NMR (DMSO-d6) 6.75 (s, 2H), 3.56 (dd, J=4.8, 4.4 Hz, 4H), 3.32 (s, 2H), 3.15 (dd, J=8.7, 6.4 Hz, 2H), 2.69 (dd, J=9.7, 8.0 Hz, 2H), 2.39 (dd, J=5.3, 4.4 Hz, 2H).

Intermediate P9: 4-(Benzyl(ethyl)amino)butane-1-sulfonamide

[0654] ##STR00177##

[0655] To a solution of 4-chlorobutane-1-sulfonamide (200 mg, 1.17 mmol) in acetonitrile (5 mL) was added and ethylbenzylamine (2 mL, 13.5 mmol). The mixture was refluxed under nitrogen for 18 hours. The solvents were evaporated and the residue was triturated with heptane. The resulting solids were filtered and dried to afford the title compound as a white solid (300 mg, 95%).

[0656] .sup.1H NMR (Chloroform-d) 7.80-6.71 (m, 5H), 4.58 (s, 2H), 3.56 (s, 2H), 3.12 (t, 2H), 2.47 (m, 4H), 1.97 (m, 2H), 1.60 (m, 2H), 1.11 (t, 3H).

Intermediate P10: 3-Morpholinopropane-1-sulfonamide

[0657] ##STR00178##

[0658] To a solution of 3-chloropropane-1-sulfonamide (200 mg, 1.17 mmol) in acetonitrile (5 mL) was added morpholine (0.44 g, 5 mmol). The mixture was refluxed under nitrogen for 18 hours. The solvents were evaporated and the residue was triturated with t-butylmethyl ether. The resulting oil was decanted and triturated with heptane. The heptane was decanted to afford the title compound as a colourless oil (90 mg, 34%).

[0659] .sup.1H NMR (Chloroform-d) 3.71 (m, 4H), 3.24 (t, 2H), 2.62-2.40 (m, 6H), 2.08 (m, 2H).

Intermediate P11: 3-(Piperidin-1-yl)propane-1-sulfonamide

[0660] ##STR00179##

[0661] To a solution of 3-chloropropane-1-sulfonamide (200 mg, 1.27 mmol) in acetonitrile (5 mL) was added piperidine (0.44 g, 5 mmol). The mixture was refluxed under nitrogen for 18 hours. The solvents were evaporated and the residue was triturated with t-butylmethyl ether. The solids were filtered and triturated in THF. The solids were filtered and the mother liquor was evaporated to afford the title compound as an oil that solidified upon standing (100 mg, 38%).

[0662] .sup.1H NMR (Chloroform-d) 3.23 (t, J=6.6 Hz, 2H), 2.64-2.33 (m, 6H), 2.09 (m, 2H), 1.60 (m, 4H), 1.47 (dd, 2H).

Intermediate P12: 2-(Diethylamino)ethane-1-sulfonamide

[0663] ##STR00180##

[0664] Prepared according to 2-(benzyl(ethyl)amino)ethane-1-sulfonamide (Intermediate P7) using ethene sulfonamide (ca. 60% content, 500 mg, 2.8 mmol) and diethylamine (0.43 mL, 307 mg, 4.2 mmol) to yield the title compound (186 mg, 36%) after column chromatography.

[0665] HPLC-MS: 84% purity by ELSD, M 180+1 (ACPI pos.)

[0666] .sup.1H NMR (DMSO-d6) 6.74 (s, 2H), 3.13-3.01 (m, 2H), 2.88-2.76 (m, 2H), 2.52-2.38 (m, 4H overlapping with d-DMSO), 0.96 (t, J=7.1 Hz, 6H).

Intermediate P13: 2-(Ethylamino)ethane-1-sulfonamide

[0667] ##STR00181##

[0668] Prepared according to 2-(benzyl(ethyl)amino)ethane-1-sulfonamide (Intermediate P7) using ethene sulfonamide (ca. 60% content, 500 mg, 2.8 mmol) and ethylamine (2M in THF, 2.1 mL, 4.2 mmol) to yield the title compound (131 mg, 30%) after column chromatography.

[0669] HPLC-MS: 98% (ELSD), M 152+1 (ACPI pos.)

[0670] .sup.1H NMR (DMSO-d6) 6.74 (s, 2H), 3.09 (t, J=7.0 Hz, 2H), 2.87 (t, J=7.0 Hz, 2H), 2.54 (m, 2H, overlapping with d-DMSO), 0.96 (t, J=7.2 Hz, 3H).

Intermediate P14: (1-Ethylazetidin-3-yl)methanesulfonamide

[0671] ##STR00182##

[0672] To a solution of 7 M ammonia in methanol (2 mL, 14 mmol) was added (azetidin-3-yl)methanesulfonyl fluoride hydrochloride (250 mg, 1.3 mmol). The reaction mixture was stirred for one hour and then concentrated in vacuo. The solid material was suspended in acetonitrile (10 mL) and then acetaldehyde (109 L, 1.95 mmol) was added followed by sodium triacetoxyborohydride (413 mg, 1.95 mmol). The reaction mixture was stirred overnight at room temperature. The solution was concentrated in vacuo. The crude material 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 ammonia (3.5 M) in methanol to afford the title compound (17 mg, 7%), which was used without further purification.

[0673] .sup.1H NMR (CD.sub.3OD) 3.90 (m, 2H), 3.55 (m, 2H), 3.38 (m, 2H), 3.20 (m, 1H), 2.88 (q, 2H), 1.08 (t, 3H).

Intermediate P15: (1-Methylpiperidin-4-yl)methanesulfonamide

[0674] ##STR00183##

[0675] To a suspension of piperidin-4-yl-methanesulfonamide hydrochloric acid (200 mg, 0.93 mmol, 1.0 equiv.), triethylamine (0.16 mL, 1.16 mmol, 1.2 equiv.), formaldehyde (37% in water, stabilized with methanol; 80 L, 0.98 mmol, 1.05 equiv.) in acetonitrile (10 mL) and sodium triacetoxyborohydride (246 mg, 1.16 mmol, 1.25 equiv.) was added. The reaction mixture was stirred overnight and then concentrated in vacuo. The crude material 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 ammonia (3.5 M) in methanol to afford the title compound (82 mg, 43%), which was used without further purification.

[0676] .sup.1H NMR (DMSO-d6) 6.76 (s, 2H), 2.88 (d, 2H), 2.69 (m, 2H), 2.10 (s, 3H), 1.78 (m, 5H), 1.25 (m, 2H).

Intermediate P16: (1-Methylpyrrolidin-3-yl)methanesulfonamide

[0677] ##STR00184##

[0678] Prepared as described for (1-methylpiperidin-4-yl)methanesulfonamide (Intermediate P15) from (pyrrolidin-3-yl)methanesulfonamide hydrochloride and formaldehyde. The title compound (95 mg, 53%) was used without further purification.

[0679] .sup.1H NMR (DMSO-d6) 6.75 (s, 2H), 3.00 (dd, 2H), 2.67 (m, 1H), 2.37 (m, 2H), 2.24 (m, 5H), 2.00 (m, 1H), 1.49 (m, 1H).

Intermediate P17: (1-Ethylpyrrolidin-3-yl)methanesulfonamide

[0680] ##STR00185##

[0681] Prepared as described for (1-methylpiperidin-4-yl)methanesulfonamide (Intermediate P15) from (pyrrolidin-3-yl)methanesulfonamide hydrochloride and acetaldehyde. The title compound (86 mg, 44%) was used without further purification.

[0682] .sup.1H NMR (DMSO-d6) 6.76 (s, 2H), 3.01 (m, 2H), 2.71 (m, 1H), 2.37 (m, 4H), 2.23 (m, 2H), 1.99 (m, 1H), 1.48 (m, 1H), 0.98 (t, 3H).

Intermediate P18: (1-Isopropylpyrrolidin-3-yl)methanesulfonamide

[0683] ##STR00186##

[0684] Prepared as described for (1-methylpiperidin-4-yl)methanesulfonamide (Intermediate P15) from (pyrrolidin-3-yl)methanesulfonamide hydrochloride and acetone. The title compound (167 mg, 81%) was used without further purification.

[0685] .sup.1H NMR (DMSO-d6) 6.75 (s, 2H), 3.01 (m, 2H), 2.79 (dd, 1H), 2.55 (m, 1H), 2.41 (m, 1H), 2.27 (m, 3H), 1.97 (m, 1H), 1.47 (m, 1H), 0.98 (dd, 6H).

Intermediate P19: 1-(Dimethylamino)propane-2-sulfonamide

[0686] ##STR00187##

[0687] Prepared as described for (1-methylpiperidin-4-yl)methanesulfonamide (Intermediate P15) from 1-aminopropane-2-sulfonamide hydrochloride, except that 2 equivalents of formaldehyde and sodium triacetoxyborohydride were used instead of one. The title compound (16 mg, 13%) was used without further purification.

[0688] .sup.1H NMR (CD3OD) 3.50 (m, 1H), 3.21 (m, 1H), 3.01 (dd, 1H), 2.71 (s, 6H), 1.40 (d, 3H).

Intermediate P20: 2-(Piperidin-1-yl)ethane-1-sulfonamide

[0689] ##STR00188##

[0690] Prepared according to 2-(benzyl(ethyl)amino)ethane-1-sulfonamide (Intermediate P7) using ethene sulfonamide (375 mg, 3.15 mmol) and piperidine (0.36 mL, 308 mg, 3.62 mmol) to yield the title compound (206 mg, 34%) after column chromatography.

[0691] HPLC-MS: 100% (ELSD), M 192+1 (ACPI pos.)

[0692] .sup.1H NMR (Chloroform-d) 3.20 (dd, J=7.4, 6.5 Hz, 2H), 2.87 (dd, J=5.5, 4.6 Hz, 2H), 2.48 (t, J=5.2 Hz, 3H), 1.63-149 (m, 5H), 1.49-1.42 (m, 2H).

Intermediate P21: 2-(Azetidin-1-yl)ethane-1-sulfonamide

[0693] ##STR00189##

[0694] Prepared according to 2-(benzyl(ethyl)amino)ethane-1-sulfonamide (Intermediate P7) using ethene sulfonamide (375 mg, 3.15 mmol) and azetidine hydrochloride (339 mg, 3.62 mmol) to yield the title compound (396 mg, 76%) after column chromatography.

[0695] HPLC-MS: 68% (ELSD), M 164+1 (ACPI pos.)

[0696] .sup.1H NMR (Chloroform-d) 3.96-3.76 (m, 2H), 3.37-3.16 (m, 2H), 2.43 (m, 4H), 1.18 (dq, J=9.4, 5.7, 4.5 Hz, 2H).

Intermediate P22: 3-(Ethyl(methyl)amino)propane-1-sulfonamide

[0697] ##STR00190##

[0698] To a solution of 3-chloropropane-1-sulfonamide (200 mg, 1.27 mmol) in acetonitrile (4 mL) was added N-methylethanamine (300 mg, 5.08 mmol). The mixture was heated in the microwave at 80 C. for 30 minutes. The solvents were evaporated and the residue was triturated with TBME. The resulting solids were isolated by decantation of the solution and THF (5 mL) was added to the remaining solids followed by 200 mg triethylamine. After 3 hours the mixture was filtered and the filtrate concentrated to afford the title compound as a white solid (70 mg, 31%).

[0699] .sup.1H NMR (Chloroform-d) 3.18-3.04 (m, 2H), 2.64-2.41 (m, 4H), 2.29 (s, 3H), 2.12-1.92 (m, 2H), 1.11 (t, 3H).

Intermediate P23: (4-Cyanophenyl)methanesulfonamide

[0700] ##STR00191##

[0701] To a solution of saturated ammonia in THF (3 mL) was added dropwise a solution of (4-cyanophenyl)methanesulfonyl chloride (100 mg, 646 mol, 1 eq) in THF (1 mL). The mixture was stirred at 20 C. for 1 hour and then concentrated under reduced pressure. The residue was diluted with water (3 mL) and then the mixture was extracted into ethyl acetate (23 mL). The combined organic layers were washed with brine (3 mL), dried (anhydrous Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the title compound (110 mg, >100%) as a white solid.

[0702] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.85 (d, 2H), 7.56 (d, 2H), 6.93 (br s, 2H) and 4.40 (s, 2H).

Intermediate P24: 2-Ethyl-2-azaspiro[3.3]heptane-6-sulfonamide

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

[0703] ##STR00192##

[0704] 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.

[0705] .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

[0706] ##STR00193##

[0707] 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.

[0708] .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

[0709] ##STR00194##

[0710] 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 (1 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%).

[0711] .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, trifluoroacetic acid salt

[0712] ##STR00195##

[0713] 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.

[0714] .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

[0715] ##STR00196##

[0716] To a mixture of 2-azaspiro[3.3]heptane-6-sulfonamide trifluoroacetic acid salt (75 mg, 0.43 mmol), triethylamine (160 mg, 1.6 mmol) and acetonitrile (5 mL) was added ethyliodide (66 mg, 0.43 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo. 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%).

[0717] .sup.1H NMR (CD.sub.3OD): =3.67 (m, 1H), 3.24 (d, 4H), 2.50 (d, 4H), 2.43 (q, 2H) and 0.95 (t, 3H).

Intermediate P25: 2-Isopropyl-2-azaspiro[3.3]heptane-6-sulfonamide

[0718] ##STR00197##

[0719] 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.

[0720] .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 P26: 2-Methyl-2-azaspiro[3.3]heptane-6-sulfonamide

[0721] ##STR00198##

[0722] 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.

[0723] .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 P27: 3-(Benzyl(ethyl)amino)propane-1-sulfonamide

Step A: 3-(Benzyl(ethyl)amino)propane-1-sulfonic acid

[0724] ##STR00199##

[0725] To a solution of 1,2-oxathiolane 2,2-dioxide (1 g, 8.19 mmol, 719.42 L, 1 eq) in DCM (5 mL) was added N-benzylethanamine (3.94 g, 29.15 mmol, 3.56 eq) at 0 C. Then the resulting mixture was stirred at 25 C. for 2.5 hours. The mixture was concentrated in vacuo. The residue was triturated with EtOAc (40 mL) to give the title compound (2.4 g, crude) as a white solid.

[0726] .sup.1H NMR (DMSO-d.sub.6): 7.37-7.23 (m, 5H), 4.08 (s, 2H), 2.91 (q, 2H), 2.50-2.40 (m, 4H), 1.81-173 (m, 2H) and 0.98 (t, 3H).

[0727] LCMS: m/z 258.1 (M+H).sup.+(ES.sup.+).

Step B: 3-(Benzyl(ethyl)amino)propane-1-sulfonyl chloride

[0728] ##STR00200##

[0729] A solution of 3-(benzyl(ethyl)amino)propane-1-sulfonic acid (2.1 g, 8.16 mmol, 1 eq) in SOCl.sub.2 (17.22 g, 144.74 mmol, 17.74 eq) was stirred at 80 C. for 6 hours. The mixture was concentrated in vacuo to give the title compound (2 g, crude) as a yellow oil, which was used directly in the next step.

Step C: 3-(Benzyl(ethyl)amino)propane-1-sulfonamide

[0730] ##STR00201##

[0731] To a solution of 3-(benzyl(ethyl)amino)propane-1-sulfonyl chloride (2 g, crude) in THF (3 mL) was added to a saturated solution of NH.sub.3 in THF (100 mL) at 0 C. Then the mixture was stirred at 20 C. for 14 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (1.15 g, 62% yield, 100% purity on LCMS) as a white solid.

[0732] .sup.1H NMR (CDCl.sub.3): 7.37-7.28 (m, 5H), 4.98 (br s, 2H), 3.57 (s, 2H), 3.15 (t, 2H), 2.61-2.52 (m, 4H), 2.06-2.00 (m, 2H) and 1.07 (t, 3H).

Intermediate P28: 3-Methoxypropane-1-sulfonamide

Step A: Sodium 3-methoxypropane-1-sulfonate

[0733] ##STR00202##

[0734] A mixture of 1-bromo-3-methoxypropane (2 g, 13.07 mmol, 1 eq) and Na.sub.2SO.sub.3 (1.65 g, 13.07 mmol, 1 eq) in H.sub.2O (20 mL) was heated to 100 C. and stirred for 16 hours. Then the reaction mixture was cooled and lyophilized to give the title compound (2.25 g, 97%, Na salt) as a white solid.

[0735] .sup.1H NMR (D.sub.2O): 3.56 (t, 2H), 3.34 (s, 3H), 2.95-2.92 (m, 2H) and 2.02-1.94 (m, 2H).

[0736] LCMS: m/z 155.1 (MNa+H).sup.+(ES.sup.+).

Step B: 3-Methoxypropane-1-sulfonyl chloride

[0737] ##STR00203##

[0738] A solution of sodium 3-methoxypropane-1-sylfonate (0.7 g, 4.54 mmol, 1 eq) in POCl.sub.3 (8.25 g, 53.80 mmol, 11.85 eq) was stirred at 80 C. for 5 hours. Then the mixture was stirred at 100 C. for 2 hours. The mixture was diluted with DCM (80 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (600 mg, crude) as a yellow oil, which was used directly in the next step.

Step C: 3-Methoxypropane-1-sulfonamide

[0739] ##STR00204##

[0740] NH.sub.3 (15 psi) was bubbled into THF (20 mL) at 0 C. for 5 minutes. A solution of 3-methoxypropane-1-sulfonyl chloride (600 mg, crude) in THF (2 mL) was added to the NH.sub.3/THF solution (20 mL). Then the mixture was stirred at 20 C. for 14 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude compound (300 mg, crude) as a yellow oil.

[0741] .sup.1H NMR (CDCl.sub.3): 4.94 (br s, 2H), 3.53 (t, 2H), 3.35 (s, 3H), 3.25 (t, 2H) and 2.17-2.10 (m, 2H).

Intermediate P20: 3-(Dimethylamino)-2-methylpropane-1-sulfonamide

[0742] ##STR00205##

[0743] 3-Chloro-2-methylpropane-1-sulfonamide (50 mg, 0.3 mmol) was dissolved in dimethylamine (5 mL, 2M in THF). The mixture was heated for 30 minutes at 180 C. in a microwave. The solvents were evaporated. The residue was triturated in THF (20 mL) and triethylamine (100 mg, 1 mmol). The solids were filtered off and the solvent was evaporated to afford the title compound (14 mg, 11%) as a white solid.

[0744] .sup.1H NMR (Methanol-d.sub.4) 3.30 (m, 2H), 2.93 (m, 2H), 2.38 (s, 6H), 1.40 (m, 1H), 1.16 (d, 3H).

Intermediate P30: 3-Azidopropane-1-sulfonamide

[0745] ##STR00206##

[0746] To a solution of 3-chloropropane-1-sulfonamide (200 mg, 1.3 mmol) in acetone (10 mL) was added sodium azide (200 mg, 3 mmol) in water (1 mL). The mixture was refluxed for 36 hours. The solvents were evaporated. The residue was triturated with THF. The THF layer was filtered and evaporated to afford the title compound as a yellow oil (200 mg, 9 6%).

[0747] .sup.1H NMR (CD.sub.3OD) 3.51 (t, 2H), 3.17 (t, 2H), 2.07 (m, 2H).

Intermediate P31: (1-(Oxetan-3-yl)pyrrolidin-3-yl)methanesulfonamide

[0748] ##STR00207##

[0749] To a suspension of (pyrrolidin-3-yl)methanesulfonamide hydrochloride (100 mg, 0.50 mmol, 0.5 equiv.), triethylamine (83 L, 0.6 mmol, 1.2 equiv.) and 3-oxetanone (35 L, 0.55 mmol, 1.1 equiv.) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (132 mg, 0.625 mmol, 1.25 equiv.). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The crude material 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 ammonia in methanol (3.5 M) to afford the title compound (37 mg, 33%), which was used without further purification.

[0750] .sup.1H NMR (DMSO-d.sub.6) 6.77 (s, 2H), 4.53 (td, 2H), 4.40 (td, 2H), 3.60-3.45 (m, 1H), 3.03 (d, 2H), 2.72 (dd, 1H), 2.57-2.52 (m, 1H), 2.44-2.32 (m, 2H), 2.20 (dd, 1H), 2.08-1.93 (m, 1H), 1.58-1.43 (m, 1H).

Intermediate P32: N,N,N-Trimethyl-3-sulfamoylpropan-1-aminium

[0751] ##STR00208##

[0752] To trimethylamine (4.2 M in ethanol, 4 mL, 16.8 mmol) was added 3-chloropropane-1-sulfonamide (159 mg, 1 mol). The mixture was heated for 30 minutes at 100 C. in a microwave. The solids were collected by filtration to afford the title compound (100 mg, 55%).

[0753] .sup.1H NMR (dmso-D.sub.6) 3.45 (m, 2H), 3.10 (s, 9H), 3.07 (m, 2H), 2.17 (m, 2H).

Intermediate P33: 3-(Benzyl(methyl)amino)propane-1-sulfonamide

[0754] ##STR00209##

[0755] To 3-chloropropane sulfonamide (200 mg, 1.3 mmol) in acetonitrile (5 mL) was added N-methylbenzylamine (1 g, 5.1 mmol). The reaction was refluxed for 18 hours. The solvents were evaporated and the residue was triturated in TBME. The solids were filtered off and the solvent was evaporated. The residue was triturated in heptane. The solids were collected by filtration to afford the title compound (214 mg, 70%) as a white solid.

[0756] .sup.1H NMR (CDC.sub.3) 7.30 (m, 5H), 3.54 (s, 2H), 3.22 (t, 2H), 2.53 (m, 2H), 2.25 (s, 3H), 2.09 (t, 2H).

Intermediate P34: 2-(3-Methyl-3H-diazirin-3-yl)ethane-1-sulfonamide

[0757] ##STR00210##

A solution of NH.sub.3 in water (25%, 5 mL) was cooled to 4 C. 2-(3-Methyl-3H-diazirin-3-yl)ethane-1-sulfonyl chloride (150 mg, 0.82 mmol) in THF (3 mL) was added. The mixture was stirred for 18 hours at room temperature. The organic layer was separated, dried (on sodium sulphate), filtered and evaporated to afford the title compound (75 mg, 50%) as a colourless oil, which solidified upon standing.

[0758] .sup.1H NMR (CD.sub.3OD) 3.15 (t, 2H), 1.78 (t, 2H), 1.05 (s, 3H).

Intermediate P35: 3-(Methoxy(methyl)amino)propane-1-sulfonamide

[0759] ##STR00211##

[0760] To 3-chloropropane sulfonamide (200 mg, 1.3 mmol) in acetonitrile (5 mL) was added N,O-dimethylhydroxylamine (310 mg, 5 mmol) and triethylamine (1.4 g, 14 mmol). The mixture was refluxed for 18 hours. The solvents were evaporated and the residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as a colourless oil (100 mg, 43%).

[0761] .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).

Intermediate P36: ((1S,E)-2-(Hydroxyimino)-7,7-dimethylbicyclo[2.2.1]heptan-1-yl)methanesulfonamide

[0762] ##STR00212##

[0763] To a suspension of (1S)-10-camphorsulfonamide (505 mg, 2.18 mmol) in ethanol (7 mL) and demineralized water (3.5 mL) was added sodium acetate (360 mg, 4.37 mmol), followed by hydroxylamine hydrochloride (303 mg, 4.37 mmol). The mixture was stirred at reflux overnight and then concentrated in vacuo to remove the ethanol. The residual water phase was extracted with dichloromethane and the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (448 mg, 83%) as a white solid.

[0764] .sup.1H NMR (Chloroform-d) 6.95 (d, J=25.2 Hz, 1H), 5.62 (s, 2H), 3.51 (d, J=15.0 Hz, 1H), 3.23 (d, J=15.0 Hz, 1H), 2.62 (dt, J=18.2, 4.0 Hz, 1H), 2.25-1.83 (m, 5H), 1.36 (ddd, J=12.8, 8.6, 4.7 Hz, 1H), 0.96 (s, 3H), 0.86 (s, 3H).

Intermediate P37: 3-(Azetidin-1-yl)propane-1-sulfonamide

[0765] ##STR00213##

[0766] To a solution of azetidine HCl (267 mg, 2.8 mmol) in methanol (4 mL) was added a solution of sodium hydroxide (114 mg, 2.8 mmol) in water (1 mL) and 3-chloropropane-1-sulfonamide (200 mg, 1.3 mmol). The mixture was heated for 30 minutes at 100 C. in a microwave. The solvents were evaporated and the residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as a colourless oil (10 mg, 4%).

[0767] .sup.1H NMR (CD.sub.3OD) 4.19 (m, 4H), 3.37 (m, 2H), 3.19 (t, 2H), 2.52 (m, 2H), 2.17 (m, 2H).

Intermediate P38: 3-(Methyl(prop-2-yn-1-yl)amino)propane-1-sulfonamide

[0768] ##STR00214##

[0769] To 3-chloropropane sulfonamide (200 mg, 1.3 mmol) in acetonitrile (20 mL) was added 3-methylamino-1-propyne (340 mg, 5.1 mmol) and potassium iodide (60 mg, 0.36 mmol). The reaction was refluxed for 18 hours. The solvents were evaporated and the residue was triturated in THF. The THF layer was decanted and evaporated to afford the title compound (175 mg, 73%) as a white solid.

[0770] .sup.1H NMR (CDCl.sub.3) 3.37 (s, 2H), 3.23 (t, 2H), 2.63 (t, 2H), 2.33 (s, 3H), 2.26 (s, 1H), 2.05 (m, 2H).

Intermediate P39: (4-Methylmorpholin-2-yl)methanesulfonamide

[0771] ##STR00215##

[0772] To a suspension of morpholin-2-ylmethanesulfonamide hydrochloride (40 mg, 0.18 mmol), triethylamine (19 mg, 0.18 mmol, 1.0 equiv.) and formaldehyde (37% in water stabilized with methanol; 18 mg, 0.22 mmol, 1.2 equiv.) in acetonitrile (5 mL) was added sodium triacetoxyborohydride (47 mg, 0.22 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature overnight. Methanol was added and the mixture was concentrated to afford the crude title compound (0.1 g), which was used without further purification.

Intermediate P40: (4-Ethylmorpholin-2-yl)methanesulfonamide

[0773] ##STR00216##

[0774] To a suspension of morpholin-2-ylmethanesulfonamide hydrochloride (32 mg, 0.15 mmol), triethylamine (15 mg, 0.15 mmol, 1.0 equiv.) and acetaldehyde (8 mg, 0.18 mmol, 1.2 equiv.) in acetonitrile (5 mL) was added sodium triacetoxyborohydride (38 mg, 0.18 mmol, 1.2 equiv.). The reaction mixture was stirred overnight. Methanol was added and the mixture was concentrated to afford the crude title compound (90 mg), which was used without further purification.

Intermediate P41: (4-Isopropylmorpholin-2-yl)methanesulfonamide

[0775] ##STR00217##

[0776] To a suspension of morpholin-2-ylmethanesulfonamide hydrochloride (31 mg, 0.14 mmol), triethylamine (14 mg, 0.14 mmol, 1.0 equiv.) and acetone (10 mg, 0.17 mmol, 1.2 equiv.) in acetonitrile (5 mL) was added sodium triacetoxyborohydride (36 mg, 0.17 mmol, 1.2 equiv.). The reaction mixture was stirred overnight. Methanol was added and the mixture was concentrated to afford the crude title compound (90 mg), which was used without further purification.

Intermediate P42: (2-Isopropyl-6-oxa-2-azaspiro[3.4]octan-7-yl) methanesulfonamide

[0777] ##STR00218##

[0778] Prepared as described for (2-methyl-6-oxa-2-azaspiro[34]octan-7-yl)methane-sulfonamide (Intermediate P45) from (6-oxa-2-azaspiro[3.4]octan-7-yl) methanesulfonamide TFA salt and acetone to afford the title compound as an oil (10 mg, 33%).

[0779] .sup.1H NMR (CD.sub.3OD) 4.31 (m, 1H), 3.99 (d, 1H), 3.86 (d, 1H), 3.28 (m, 6H), 2.54 (m, 1H), 2.44 (m, 1H), 1.96 (m, 1H), 0.97 (d, 6H).

Intermediate P43: 3-(Dimethylamino)butane-1-sulfonamide

Step A: 3-Azidobutane-1-sulfonamide

[0780] ##STR00219##

[0781] To 3-chlorobutane-1-sulfonamide chloride (50 mg, 0.3 mmol) in DMF (3 mL) was added NaN.sub.3 (25 mg, 0.4 mmol). The reaction was heated for 18 hours at 100 C. The solvents were evaporated and the residue was triturated in chloroform. The chloroform layer was filtered and evaporated to afford the title compound as a brown oil (25 mg, 47%).

[0782] .sup.1H NMR (CDCl.sub.3) 3.15 (m, 2H), 2.96 (d, 3H), 2.01 (m, 2H), 1.36 (d, 3H).

Step B: 3-Aminobutane-1-sulfonamide

[0783] ##STR00220##

[0784] To 3-azidobutane-1-sulfonamide (130 mg, 0.73 mmol) in THF (5 mL) was added PdC (20 mg, 10% Pd). The mixture was stirred for 18 hours under hydrogen atmosphere. The mixture was filtered over Celite and evaporated to afford the title compound as a brown oil (120 mg, 100%).

[0785] .sup.1H NMR (CDCl.sub.3) 3.17 (m, 2H), 3.12 (m, 2H), 2.01 (m, 2H), 1.36 (d, 3H).

Step C: 3-(Dimethylamino)butane-1-sulfonamide

[0786] ##STR00221##

[0787] To 3-aminobutane-1-sulfonamide (110 mg, 0.72 mmol) in acetonitrile (5 mL) was added paraformaldehyde (86 mg, 3 mmol). Then sodium triacetoxyborohydride (612 mg, 3 mmol) was added and the mixture was stirred for 18 hours at room temperature. Methanol (10 mL) was added and the solvents were evaporated (2). The residue was triturated in THF (20 mL) containing triethylamine (0.7 g, 7 mmol). The solids were filtered and the solvent was evaporated. The residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as a colourless oil (14 mg, 11%).

[0788] .sup.1H NMR (CD.sub.3OD) 3.18 (t, 2H), 2.63 (m, 1H), 2.60 (s, 6H), 2.2 (m, 2H), 1.24 (d, 3H).

Intermediate P44: (2-Ethyl-6-oxa-2-azaspiro[3.4]octan-7-yl) methanesulfonamide

[0789] ##STR00222##

[0790] Prepared as described for (2-methyl-6-oxa-2-azaspiro[3.4]octan-7-yl)methane-sulfonamide (Intermediate P45) from (6-oxa-2-azaspiro[3.4]octan-7-yl) methanesulfonamide TFA salt and ethanal to afford the title compound as an oil (15 mg, 13%).

[0791] .sup.1H NMR (CD.sub.3OD) 4.33 (m, 1H), 4.02 (d, 1H), 3.88 (d, 1H), 3.35 (m, 6H), 2.62 (q, 2H), 2.45 (m, 1H) 2.03 (m, 1H), 1.00 (t, 3H).

Intermediate P45: (2-Methyl-6-oxa-2-azaspiro[3.4]octan-7-yl) methanesulfonamide

Step A: (6-Oxa-2-azaspiro[3.4]octan-7-yl)methanesulfonamide, TFA Salt

[0792] ##STR00223##

[0793] To a solution of N-Boc-(6-oxa-2-azaspiro[3.4]octan-7-yl)methanesulfonamide (330 mg, 1 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (2 mL). After stirring for 18 hours at room temperature under nitrogen, the solvents were evaporated to afford the title compound as a pale yellow oil (330 mg, 100%).

[0794] .sup.1H NMR (CD.sub.3OD) 4.30 (m, 1H), 4.10 (m, 5H), 3.91 (m, 1H), 3.35 (m, 2H), 2.59 (m, 1H), 2.16 (m, 1H).

Step B: (2-Methyl-6-oxa-2-azaspiro[3.4]octan-7-yl)methanesulfonamide

[0795] ##STR00224##

[0796] To the TFA salt of (6-oxa-2-azaspiro[3.4]octan-7-yl)methanesulfonamide (150 mg, 0.48 mmol) in acetonitrile (10 mL), was added triethylamine (100 mg, 0.99 mmol), paraformaldehyde (30 mg, 0.97 mmol), followed by sodium triacetoxyborohydride (205 mg, 0.97 mmol). After 18 hours stirring at room temperature under nitrogen, methanol (10 mL) was added and the mixture was evaporated (2). The residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as an oil (17 mg, 17%).

[0797] .sup.1H NMR (CD.sub.3OD) 4.33 (m, 1H), 4.02 (d, 1H), 3.88 (d, 1H), 3.60 (m, 4H), 3.32 (m, 2H), 2.53 (s, 3H), 2.45 (m, 1H) 2.03 (m, 1H).

Intermediate P46: 3-(Dimethylamino)-2,2-dimethylpropane-1-sulfonamide

Step A: 3-Azido-2,2-dimethylpropane-1-sulfonamide

[0798] ##STR00225##

[0799] To 3-Chloro-2,2-dimethylpropane-1-sulfonamide (130 mg, 0.7 mmol) in DMF (3 mL) was added NaN.sub.3 (91 mg, 1.4 mmol). The reaction was heated for 48 hours at 120 C. The solvents were evaporated and the residue was triturated in THF. The solids were filtered and the THF was evaporated to afford the crude title compound (220 mg, 61%) as a brown oil.

[0800] .sup.1H NMR (CDCl.sub.3) 2.95 (s, 2H), 2.87 (s, 2H), 1.27 (s, 6H).

Step B: 3-Amino-2,2-dimethylpropane-1-sulfonamide

[0801] ##STR00226##

[0802] To 3-azido-2,2-dimethylpropane-1-sulfonamide (130 mg, 0.67 mmol) In THF (5 mL) was added PdC (20 mg, 10% Pd). The mixture was stirred for 64 hours under a hydrogen atmosphere. The mixture was filtered over Celite and evaporated to afford the title compound (0 mg, 80%) as an oil.

[0803] .sup.1H NMR (CDCl.sub.3) 2.95 (s, 2H), 2.87 (s, 2H), 1.27 (s, 6H).

Step C: 3-(Dimethylamino)-2,2-dimethylpropane-1-sulfonic acid triethylamine salt

[0804] ##STR00227##

[0805] To 3-amino-2,2-dimethylpropane-1-sulfonamide (160 mg, 0.6 mmol) in water (1 mL) and formic acid (1 mL, 6.6 mmol) was added formaldehyde (1 mL, 37% aqueous solution, 2.5 mmol). The mixture was refluxed for 6 hours. The solvents were evaporated. The residue was triturated in THF (10 mL) containing triethylamine (250 mg, 2.5 mmol). The solids were filtered to afford the title compound (80 mg, 45%) as a white solid.

[0806] .sup.1H NMR (CD.sub.3OD) 3.06 (s, 2H), 2.96 (s, 6H), 2.89 (s, 2H), 1.27 (s, 6H).

Step D: 3-(Dimethylamino)-2,2-dimethylpropane-1-sulfonamide

[0807] ##STR00228##

[0808] To 3-(dimethylamino)-2,2-dimethylpropane-1-sulfonic acid triethylamine salt (70 mg, 0.24 mmol) in dichloromethane (10 mL) was added DMF (2 drops). The mixture was cooled to 0 C. Then thionyl chloride (0.1 mL, 1.4 mmol) was added. The reaction was stirred for 18 hours at room temperature. The solvents were evaporated. The residue was triturated in THF. The THF layer was separated and added dropwise to a solution of ammonia in methanol (7 N). The mixture was stirred for 18 hours. The solvents were evaporated. The residue was triturated in THF. The solids were filtered. The THF was evaporated to afford the title compound (24 mg, 52%) as an off-white solid.

[0809] .sup.1H NMR (CDCl.sub.3) 3.51 (s, 2H), 3.29 (s, 2H), 2.37 (s, 6H), 1.19 (s, 6H).

Intermediate P47: 4-(Dimethylamino)butane-1-sulfonamide

[0810] ##STR00229##

[0811] To 4-chlorobutane-1-sulfonamide (200 mg, 1.2 mmol) in acetonitrile (4 mL) was added dimethylamine in THF (2.3 mL 2M, 4.6 mmol). The mixture was heated for 30 minutes at 100 C. in a microwave. The solvents were evaporated and the residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as a colourless oil (32 mg, 15%).

[0812] .sup.1H NMR (CD.sub.3OD) 4.19 (m, 4H), 3.37 (m, 4H), 2.49 (m, 2H), 1.90 (m, 2H), 1.75 (m, 2H).

Intermediate P48: (1-Methylpiperidin-3-yl)methanesulfonamide

[0813] ##STR00230##

[0814] To a suspension of piperidin-3-ylmethanesulfonamide (80 mg, 0.45 mmol) and formaldehyde (37% in water stabilized with methanol; 44 mg, 0.54 mmol, 1.2 equiv.) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (114 mg, 0.54 mmol, 1.2 equiv.). The reaction mixture was stirred overnight. Methanol was added and the mixture was concentrated to afford the crude title compound (300 mg), which was used without further purification.

Intermediate P49: (1-Ethylpiperidin-3-yl)methanesulfonamide

[0815] ##STR00231##

[0816] To a suspension of piperidin-3-ylmethanesulfonamide (70 mg, 0.39 mmol) and acetaldehyde (21 mg, 0.47 mmol, 1.2 equiv.) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (100 mg, 0.47 mmol, 1.2 equiv.). The reaction mixture was stirred overnight. Methanol was added and the mixture was concentrated to afford the crude title compound (300 mg), which was used without further purification.

Intermediate P50: tert-Butyl ((S)-1-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl) carbamate, Potassium Salt

Step A: ((1S)-2-Amino-7,7-dimethylbicyclo[2.2.1]heptan-1-yl)methanesulfonamide

[0817] ##STR00232##

[0818] A mixture of ((1S,E)-2-(hydroxyimino)-7,7-dimethylbicyclo[2.2.1] heptan-1-yl)methanesulfonamide (Intermediate P36) (365 mg, 1.48 mmol) and Raney-Ni (50 mg) in ethanol (7 mL) and 25% ammonia (1 mL) was equipped with a H.sub.2 balloon and stirred overnight at room temperature, followed by another 4 hours at 50 C. The reaction mixture was allowed to cool to room temperature, filtered through Celite and concentrated to afford the title compound (300 mg, 87%) as a white solid.

[0819] .sup.1H NMR (Chloroform-d) 3.72 (q, J=6.9 Hz, 1H), 3.46 (d, J=19.5 Hz, 1H), 3.26-3.15 (m, 1H), 2.97 (d, J=13.3 Hz, 1H), 2.86-2.64 (m, 1H), 2.41-1.10 (m, 9H), 1.01-0.76 (m, 6H).

Step B: tert-Butyl((1S)-7,7-dimethyl-1-(sulfamoylmethyl)bicyclo[2.2.1]heptan-2-yl) carbamate

[0820] ##STR00233##

[0821] A solution of ((1S)-2-amino-7,7-dimethylbicyclo[2.2.1]heptan-1-yl)methane-sulfonamide (180 mg, 0.77 mmol) in THF (5 mL) was treated with Et.sub.3N (0.11 mL, 0.77 mmol) and Boc.sub.2O (170 mg, 0.77 mmol) and stirred over the weekend. The mixture was concentrated and partitioned between DCM and water. The organic phase was separated and dried (Na.sub.2SO.sub.4), filtered and concentrated to afford the crude title compound (300 mg), which was used as such for the next step.

[0822] .sup.1H NMR (Chloroform-d) 3.17 (d, J=13.2 Hz, 1H), 2.96 (d, J=13.3 Hz, 1H), 2.86-2.67 (m, 1H), 2.50-1.67 (m, 10H), 1.52 (s, 9H), 1.16-0.80 (m, 6H).

Step C: tert-Butyl((1S)-1-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)carbamate, Potassium Salt

[0823] ##STR00234##

[0824] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and tert-butyl ((1S)-7,7-dimethyl-1-(sulfamoylmethyl)bicyclo[2.2.1]heptan-2-yl)carbamate to afford the title compound. The reaction mixture was concentrated to afford the crude product (200 mg) which was used as such.

[0825] LCMS: m/z 530 (MH).sup.(ES.sup.).

Intermediate P51: 4-(Azetidin-1-yl)butane-1-sulfonamide

[0826] ##STR00235##

[0827] Prepared as described for 3-(azetidin-1-yl)propane-1-sulfonamide (Intermediate P37) using 4-chlorobutane-1-sulfonamide to afford the title compound a colourless oil (6 mg, 3%).

[0828] .sup.1H NMR (CD.sub.3OD) 4.19 (m, 4H), 3.37 (m, 4H), 2.49 (m, 2H), 1.90 (m, 2H), 1.75 (m, 2H).

Intermediate P52: 1-(Azetidin-1-ylmethyl)cyclopropane-1-sulfonamide

Step A: 1-(Azetidin-1-ylmethyl)-N-(tert-butyl)cyclopropane-1-sulfonamide

[0829] ##STR00236##

[0830] To a suspension of cyclobutylamine (68 mg, 0.73 mmol) in THF (5 mL) was added triethylamine (120 mg, 1.2 mmol) and N-(tert-butyl)-1-(2-oxoethyl)cyclopropane-1-sulfonamide (100 mg, 0.49 mmol). Sodium cyanoborohydride (50 mg, 0.79 mmol) was added and the mixture was stirred for 18 hours at room temperature under nitrogen. Dichloromethane was added and the mixture was washed with water and brine. The organic layer was dried (on sodium sulfate), filtered and evaporated. The residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as a colourless oil (50 mg, 42%).

[0831] .sup.1H NMR (CD.sub.3OD) 3.30 (m, 4H), 2.80 (s, 2H), 2.10 (m, 2H), 1.35 (s, 9H), 1.24 (m, 2H), 0.89 (m, 2H).

Step B: 1-(Azetidin-1-ylmethyl)cyclopropane-1-sulfonamide

[0832] ##STR00237##

[0833] A solution of 1-(azetidin-1-ylmethyl)-N-(tert-butyl)cyclopropane-1-sulfonamide (50 mg, 0.2 mmol) in TFA (10 mL) was stirred for 64 hours at room temperature under nitrogen. Then the solvents were evaporated and the residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as a white solid (20 mg, 51%).

[0834] .sup.1H NMR (CD.sub.3OD) 3.36 (m, 4H), 2.87 (s, 2H), 2.12 (m, 2H), 1.26 (m, 2H), 0.89 (m, 2H).

Intermediate P53: 2-(Pyrrolidin-1-yl)ethane-1-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-2-(pyrrolidin-1-yl)ethane-1-sulfonamide

[0835] ##STR00238##

[0836] Prepared as described for N,N-bis(4-methoxybenzyl)-2-(2-methylazetidin-1-yl)ethane-1-sulfonamide (Intermediate P54, Step A) from N,N-bis(4-methoxybenzyl)ethene-sulfonamide and pyrrolidine to afford the title compound as an oil (361 mg, 100%).

[0837] .sup.1H NMR (CDCl.sub.3) 7.20 (d, 4H), 6.86 (d, 4H), 4.25 (s, 4H), 3.79 (s, 6H), 3.09 (m, 2H), 2.87 (m, 2H), 2.44 (m, 4H), 1.75 (m, 4H).

Step B: 2-(Pyrrolidin-1-yl)ethane-1-sulfonamide

[0838] ##STR00239##

[0839] Prepared as described for 2-(azetidin-1-yl)propane-1-sulfonamide (Intermediate P56, Step B) from N,N-bis(4-methoxybenzyl)-2-(pyrrolidin-1-yl)ethane-1-sulfonamide. The solvents were evaporated and the residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as a white solid (110 mg, 74%).

[0840] .sup.1H NMR (CDCl.sub.3) 3.32 (m, 2H), 2.96 (t, 2H), 2.61 (m, 4H), 1.84 (m, 4H).

Intermediate P54: 2-(2-Methylazetidin-1-yl)ethane-1-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-2-(2-methylazetidin-1-yl)ethane-1-sulfonamide

[0841] ##STR00240##

[0842] To methyl-azetidine HCl (55 mg, 0.52 mmol) in methanol (3 mL) was added N,N-bis(4-methoxybenzyl)prop-1-ene-1-sulfonamide (150 mg, 0.43 mmol) and triethylamine (0.7 g, 7 mmol). The mixture was stirred for 18 hours at room temperature under nitrogen. The solvents were evaporated and the residue was triturated in THF. The mixture was filtered and the solvent was evaporated to afford the title compound (170 mg, 94%) as a colourless oil.

[0843] .sup.1H NMR (CD.sub.3OD) 3.40 (m, 2H), 3.16 (m, 2H), 2.99 (m, 2H), 2.82 (m, 1H), 2.15 (m, 1H), 1.83 (m, 1H), 1.24 (d, 3H).

Step B: 2-(2-Methylazetidin-1-yl)ethane-1-sulfonamide

[0844] ##STR00241##

[0845] Prepared as described for 2-(azetidin-1-yl)-propane-1-sulfonamide (Intermediate P56, Step B) from N,N-bis(4-methoxybenzyl)-2-(2-methylazetidin-1-yl)ethane-1-sulfonamide. The solvents were evaporated and the residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as a colourless oil (41 mg, 54%).

[0846] .sup.1H NMR (CD.sub.3OD) 3.40 (m, 2H), 3.16 (m, 2H), 2.99 (m, 2H), 2.82 (m, 1H), 2.15 (m, 1H), 1.83 (m, 1H), 1.24 (d, 3H).

Intermediate P55: 2-(3-Fluoroazetidin-1-yl)ethane-1-sulfonamide

Step A: 2-(3-Fluoroazetidin-1-yl)-N,N-bis(4-methoxybenzyl)ethane-1-sulfonamide

[0847] ##STR00242##

[0848] To 3-fluoroazetidine HCl (60 mg, 0.52 mmol) in methanol (3 mL) was added potassium hydroxide (29 mg, 0.42 mmol) and N,N-bis(4-methoxybenzyl)ethenesulfonamide (150 mg, 0.43 mmol). The mixture was stirred for 30 minutes at 100 C. in a microwave. The solvents were evaporated to afford the crude title compound (250 mg, 100%) as an oil.

[0849] .sup.1H NMR (CDCl.sub.3) 7.23 (d, 4H), 6.91 (d, 4H), 5.08 (m, 1H), 4.27 (s, 4H), 3.83 (s, 6H), 3.61 (m, 4H), 3.18 (m, 2H), 3.08 (m, 2H).

Step B: 2-(3-Fluoroazetidin-1-yl)ethane-1-sulfonamide

[0850] ##STR00243##

[0851] Prepared as described for 2-(azetidin-1-yl)propane-1-sulfonamide (Intermediate P56, Step B) from 2-(3-fluoroazetidin-1-yl)-N,N-bis(4-methoxybenzyl)ethane-1-sulfonamide. The solvents were evaporated and the residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as a colourless oil (125 mg, 69%).

[0852] .sup.1H NMR (CD.sub.3OD) 5.14 (m, 1H), 3.75 (m, 4H), 3.34 (m, 2H), 3.14 (m, 2H), 3.04 (m, 2H).

Intermediate P56: 2-(Azetidin-1-yl)propane-1-sulfonamide

Step A: 2-(Azetidin-1-yl)-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide

[0853] ##STR00244##

[0854] To azetidine HCl (46 mg, 0.36 mmol) in methanol (3 mL) was added N,N-bis(4-methoxybenzyl)prop-1-ene-1-sulfonamide (150 mg, 0.41 mmol) and triethylamine (200 mg, 1.98 mmol). The mixture was stirred for 30 minutes at 100 C. in a microwave. The solvents were evaporated and the residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound as a colourless oil (100 mg, 58%).

[0855] .sup.1H NMR (CD.sub.3OD) 7.23 (m, 4H), 6.88 (m, 4H), 4.24 (s, 4H), 3.80 (s, 6H), 3.13 (m, 4H), 2.76 (m, 2H), 2.53 (m, 1H), 2.00 (m, 2H), 1.16 (d, 3H).

Step B: 2-(Azetidin-1-yl)propane-1-sulfonamide

[0856] ##STR00245##

[0857] A solution of 2-(azetidin-1-yl)-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (100 mg, 0.58 mmol) in trifluoroacetic acid (3 mL) was stirred for 18 hours at 21 C. The solvents were evaporated and the residue was triturated in methanol and filtered over Celite. The methanol layer was treated with Dowex strongly basic ion exchange resin. The mixture was filtered and the methanol was evaporated to afford the title compound as a colourless oil (50 mg, 50%).

[0858] .sup.1H NMR (CD.sub.3OD) 3.29 (m, 4H), 3.15 (m, 1H), 2.84 (m, 2H), 2.04 (m, 2H), 1.16 (d, 3H).

Intermediate P57: Methyl 3-sulfamoylpropanoate

[0859] ##STR00246##

[0860] To 3-sulfamoylpropanoic acid (200 mg, 1.3 mmol) in methanol (20 mL) was added sulfuric acid (30 mg, 0.3 mmol). The mixture was stirred for 18 hours at room temperature. The mixture was filtered through Celite and the solvent was evaporated to afford the title compound (225 mg, 100%) as a colourless oil, which crystallized upon standing.

[0861] .sup.1H NMR (CD.sub.3OD) 3.70 (s, 3H), 3.35 (m, 2H), 2.84 (m, 2H).

Intermediate P58: (1-Isopropylpiperidin-3-yl)methanesulfonamide

[0862] ##STR00247##

[0863] To a suspension of piperidin-3-ylmethanesulfonamide (70 mg, 0.39 mmol, 1.0 equiv.) and acetone (28 mg, 0.47 mmol, 1.2 equiv.) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (100 mg, 0.47 mmol, 1.2 equiv.). The reaction mixture was stirred overnight. Methanol was added and the mixture was concentrated to afford the crude title compound (200 mg), which was used without further purification.

Intermediate P59: 3-Methoxy-N-methyl-N-(3-sulfamoylpropyl) propanamide

[0864] ##STR00248##

[0865] Prepared as described for methyl methyl(3-sulfamoylpropyl)carbamate (Intermediate P64) from 3-(methylamino)propane-1-sulfonamide and 3-methoxypropionyl chloride. The title compound was obtained as a colourless oil (54 mg, 69%).

[0866] .sup.1H NMR (CD.sub.3OD) 3.66 (m, 2H), 3.54 (m, 2H), 3.30 (s, 3H), 3.05 (m, 2H), 3.05 (s, 3H), 2.51 (m, 2H), 2.05 (m, 2H).

Intermediate P60: N-Methyl-N-(3-sulfamoylpropyl)isobutyramide

[0867] ##STR00249##

[0868] Prepared as described for methyl methyl(3-sulfamoylpropyl)carbamate (Intermediate P64) from 3-(methylamino)propane-1-sulfonamide and isobutyryl chloride. The title compound was obtained as a colourless oil (64 mg, 88%).

[0869] .sup.1H NMR (CD.sub.3OD) 3.50 (m, 2H), 3.16 (m, 2H), 3.05 (s, 3H), 2.40 (m, 1H), 2.16 (m, 2H), 0.92 (m, 6H).

Intermediate P61: N-Methyl-N-(3-sulfamoylpropyl)formamide

[0870] ##STR00250##

[0871] Prepared as described for methyl methyl(3-sulfamoylpropyl)carbamate (Intermediate P64) from 3-(methylamino)propane-1-sulfonamide and acetic formic anhydride. The title compound was obtained as a colourless oil (100 mg, 100%).

[0872] .sup.1H NMR (CD.sub.3OD) 3.19 (m, 4H), 2.70 (s, 3H), 2.19 (m, 2H).

Intermediate P62: N,N-Dimethyl-3-sulfamoylpropanamide

[0873] ##STR00251##

[0874] Methyl 3-sulfamoylpropanoate (160 mg, 0.96 mmol) was added to dimethylamine in methanol (2 M, 5 mL, 10 mmol). The mixture was stirred for 1 hour at 120 C. in a microwave. The solvents were evaporated and the residue was purified over silica, using dichloromethane and methanol as the eluent, to afford the title compound as a white solid (28 mg, 16%).

[0875] .sup.1H NMR (CD.sub.3OD) 3.35 (m, 2H), 3.08 (s, 3H), 2.96 (s, 3H), 2.90 (t, 2H).

Intermediate P63: 3-(Benzyl(isopropyl)amino)propane-1-sulfonamide

[0876] ##STR00252##

[0877] To 3-chloropropane sulfonamide (250 mg, 1.6 mmol) in acetonitrile (5 mL) was added N-benzylpropan-2-amine (0.95 g, 6.34 mmol) and potassium iodide (50 mg, 0.3 mmol). The reaction was heated for 1 hour at 160 C. The solvents were evaporated and the residue was triturated in TBME. The organic layer was decanted and the residue was triturated in heptane. The organic layer was decanted to afford the title compound (190 mg, 44%) as a pale yellow oil.

[0878] .sup.1H NMR (CDCl.sub.3) 7.31 (m, 5H), 3.50 (s, 2H), 3.08 (m, 2H), 2.98 (m, 1H), 2.57 (m, 2H), 1.90 (m, 2H), 1.04 (d, 6H).

Intermediate P64: Methyl methyl(3-sulfamoylpropyl)carbamate

[0879] ##STR00253##

[0880] To 3-(methylamino)propane-1-sulfonamide (60 mg, 0.39 mmol) in dichloromethane (10 mL) was added triethylamine (60 mg, 0.6 mmol). The mixture was cooled to 0 C. A solution of methyl chloroformate (41 mg, 0.43 mmol) in dichloromethane (5 mL) was added dropwise. The mixture was stirred for 18 hours at room temperature. The solvents were evaporated and the residue was purified over silica, using dichloromethane/methanol as the eluent, to afford the title compound as a white solid (15 mg, 18%).

[0881] .sup.1H NMR (CD.sub.3OD) 3.70 (s, 3H), 3.69 (m, 2H), 3.55 (m, 2H), 3.07 (s, 3H), 2.54 (m, 3H).

Intermediate P65: 3-(Dimethylamino)propane-1-sulfonamide

[0882] ##STR00254##

[0883] To a solution of 3-chloropropane-1-sulfonamide (203 mg, 1.29 mmol) in 2M dimethylamine in THF (7 mL) was added triethylamine (0.18 mL, 1.29 mmol) and potassium iodide (214 mg, 1.29 mmol). The mixture was heated in a microwave at 80 C. for 90 minutes. The solvents were evaporated and the residue was purified over silica, using dichloromethane and a mixture of 3.5 M ammonia in methanol as the eluent, to afford the title compound (51 mg, 24%) as a white solid.

[0884] .sup.1H NMR (CD.sub.3OD) 3.20 (t, 2H), 2.44 (t, 2H), 2.24 (s, 6H), 2.04 (m, 2H).

Intermediate P66: 2-(2,2-Dimethylazetidin-1-yl)ethane-1-sulfonamide, TFA salt

Step A: 2-(2,2-Dimethylazetidin-1-yl)-N,N-bis(4-methoxybenzyl)ethane-1-sulfonamide

[0885] ##STR00255##

[0886] Prepared as described for 2-(azetidin-1-yl)-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (Intermediate P56, Step A) from N,N-bis(4-methoxybenzyl)ethene-sulfonamide and 2,2-dimethylazetidine to afford the title compound as an oil (125 mg, 100%).

[0887] .sup.1H NMR (CDC.sub.3) 7.17 (d, 4H), 6.87 (d, 4H), 4.22 (s, 4H), 3.77 (s, 6H), 3.00 (m, 2H), 2.84 (m, 2H), 2.73 (m, 2H), 1.82 (m, 2H), 1.10 (s, 6H).

Step B: 2-(2,2-Dimethylazetidin-1-yl)ethane-1-sulfonamide, TFA salt

[0888] ##STR00256##

[0889] Prepared as described for 2-(azetidin-1-yl)propane-1-sulfonamide (Intermediate P56, Step B) from 2-(2,2-dimethyllazetidin-1-yl)-N,N-bis(4-methoxybenzyl)ethane-1-sulfonamide to afford the title compound as colourless oil (83 mg, 92%).

[0890] .sup.1H NMR (CD.sub.3OD) 4.05 (m, 2H), 3.47 (m, 6H), 2.38 (m, 2H), 1.66 (d, 6H).

Intermediate P67: 2-(2,4-Dimethylazetidin-1-yl)ethane-1-sulfonamide, TFA salt

Step A: 2-(2,4-Dimethylazetidin-1-yl)-N,N-bis(4-methoxybenzyl)ethane-1-sulfonamide

[0891] ##STR00257##

[0892] Prepared as described for 2-(azetidin-1-yl)-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (Intermediate P56, Step A) from N,N-bis(4-methoxybenzyl)ethene-sulfonamide and 2,4-dimethylazetidine HCl salt to afford the title compound as a colourless oil (125 mg, 100%).

[0893] .sup.1H NMR (CDC.sub.3) 7.19 (d, 4H), 6.84 (d, 4H), 4.24 (s, 4H), 3.78 (s, 6H), 3.33 (m, 6H), 2.92 (m, 2H), 2.25 (m, 1H), 1.55 (d, 6H).

Step B: 2-(2,4-Dimethylazetidin-1-yl)ethane-1-sulfonamide, TFA salt

[0894] ##STR00258##

[0895] Prepared as described for 2-(azetidin-1-yl)propane-1-sulfonamide (Intermediate P56, Step B) from 2-(2,4-dimethylazetidin-1-yl)-N,N-bis(4-methoxybenzyl)ethane-1-sulfonamide. The solvents were evaporated and the residue was triturated in water. The water layer was filtered and lyophilized to afford the title compound as a white solid (120 mg, 133%) which was used as such.

[0896] .sup.1H NMR (CD.sub.3OD) 3.50 (m, 6H), 2.74 (m, 1H), 2.01 (m, 1H), 1.56 (d, 6H).

Intermediate P68:2-(2-Isopropylazetidin-1-yl)ethane-1-sulfonamide, TFA Salt

Step A: 2-(2-Isopropylazetidin-1-yl)-N,N-bis(4-methoxybenzyl)ethane-1-sulfonamide

[0897] ##STR00259##

[0898] Prepared as described for 2-(azetidin-1-yl)-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (Intermediate P56, Step A) from N,N-bis(4-methoxybenzyl)ethene-sulfonamide and 2-isopropylazetidine HCl salt to afford the title compound a colourless an oil (129 mg, 100%).

[0899] .sup.1H NMR (CDCl.sub.3) 7.19 (d, 4H), 6.87 (d, 4H), 4.25 (s, 4H), 3.78 (s, 6H), 3.76 (m, 2H), 3.32 (m, 2H), 3.09 (m, 2H), 2.28 (m, 2H), 1.55 (m, 1H), 0.92 (d, 6H).

Step B: 2-(2-Isopropylazetidin-1-yl)ethane-1-sulfonamide, TFA Salt

[0900] ##STR00260##

[0901] Prepared as described for 2-(azetidin-1-yl)propane-1-sulfonamide (Intermediate P56, Step B) from 2-(2-isopropylazetidin-1-yl)-N,N-bis(4-methoxybenzyl)ethane-1-sulfonamide to afford the title compound as colourless oil (120 mg, 136%).

[0902] .sup.1H NMR (CD.sub.3OD) 4.06 (m, 3H), 3.67 (m, 2H), 3.40 (m, 2H), 2.36 (m, 3H), 1.0 (d, 6H).

Intermediate P69: (1-Methylpyrrolidin-2-yl)methanesulfonamide

[0903] ##STR00261##

[0904] Prepared as described for 1-(oxetan-3-yl)pyrrolidin-3-yl)methanesulfonamide (Intermediate P31) from formaldehyde (37% in water stabilized with methanol) and pyrrolidin-2-ylmethanesulfonamide hydrochloride. The title compound (25 mg, 18%) was used without further purification.

[0905] .sup.1H NMR (CD.sub.3OD) 3.49 (dd, 1H), 3.25-3.16 (m, 1H), 3.09 (dd, 1H), 2.95-2.81 (m, 1H), 2.52-2.38 (m, 4H), 2.38-2.24 (m, 1H), 1.98-1.75 (m, 3H).

Intermediate P70: (1-Ethylpyrrolidin-2-yl)methanesulfonamide

[0906] ##STR00262##

[0907] Prepared as described for (1-(oxetan-3-yl)pyrrolidin-3-yl)methanesulfonamide (Intermediate P31) from acetaldehyde and pyrrolidin-2-ylmethanesulfonamide hydrochloride. The title compound (34 mg, 22%) was used without further purification.

[0908] .sup.1H NMR (CD.sub.3OD) 3.54-3.40 (m, 1H), 3.29-3.24 (m, 1H), 3.23-2.99 (m, 2H), 2.60-2.41 (m, 2H), 2.38-2.22 (m, 1H), 1.96-1.77 (m, 4H), 1.19 (t, 3H).

Intermediate P71: (1-Isopropylpyrrolidin-2-yl)methanesulfonamide

[0909] ##STR00263##

[0910] Prepared as described for (1-(oxetan-3-yl)pyrrolidin-3-yl)methanesulfonamide (Intermediate P31) from acetone and pyrrolidin-2-ylmethanesulfonamide hydrochloride. The title compound (98 mg, 60%) was used without further purification.

[0911] .sup.1H NMR (CD.sub.3OD) 3.53-3.32 (m, 2H), 3.25-3.04 (m, 2H), 2.99 (dt, 1H), 2.79-2.66 (m, 1H), 2.14 (dq, 1H), 2.03-1.76 (m, 3H), 1.21 (d, 3H), 1.13 (d, 3H).

Intermediate P72: (1-Isopropylpiperidin-2-yl)methanesulfonamide

[0912] ##STR00264##

[0913] Prepared as described for (1-(oxetan-3-yl)pyrrolidin-3-yl)methanesulfonamide (Intermediate P31) from acetone and piperidin-2-ylmethanesulfonamide hydrochloride. The title compound (33 mg, 19%) was used without further purification.

[0914] .sup.1H NMR (CD.sub.3OD) 3.27-3.05 (m, 4H), 2.82-2.67 (m, 2H), 1.83 (d, 2H), 1.74-1.56 (m, 1H), 1.55-1.41 (m, 2H), 1.41-1.25 (m, 1H), 1.15 (dd, 6H).

Intermediate P73: (1-Ethylpiperidin-2-yl)methanesulfonamide

[0915] ##STR00265##

[0916] Prepared as described for (1-(oxetan-3-yl)pyrrolidin-3-yl)methanesulfonamide (Intermediate P31) from acetaldehyde and piperidin-2-ylmethanesulfonamide hydrochloride. The title compound (9 mg, 5%) was used without further purification.

[0917] .sup.1H NMR (CD.sub.3OD) 3.25-3.04 (m, 4H), 2.73 (td, 1H), 2.53 (dd, 2H), 1.87-1.73 (m, 2H), 1.74-1.58 (m, 1H), 1.48 (m, 2H), 1.39-1.24 (m, 1H), 1.11 (t, 3H).

Intermediate P74: (1-Isopropyl-1H-pyrazol-3-yl)methanesulfonamide

Step A: Methyl 1-isopropyl-1H-pyrazole-3-carboxylate and methyl 1-isopropyl-1H-pyrazole-5-carboxylate

[0918] ##STR00266##

[0919] A mixture of methyl 1H-pyrazole-3-carboxylate (2 g, 15.86 mmol), 2-iodopropane (1.8 mL, 18.03 mmol) and K.sub.2CO.sub.3 (4.38 g, 31.7 mmol) in DMF (20 mL) was stirred at 60 C. for 3 days. The reaction was quenched with water (30 mL) and extracted with EtOAc (360 mL). The combined organic extracts were washed with brine (50 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (40 g column, 0-100% EtOAc/iso-hexane) to afford methyl 1-isopropyl-1H-pyrazole-3-carboxylate (1379 g, 51%) as a clear colourless oil and methyl 1-isopropyl-1H-pyrazole-5-carboxylate (951 mg, 35%) as a clear colourless oil.

Methyl 1-isopropyl-1H-pyrazole-3-carboxylate

[0920] .sup.1H NMR (DMSO-d6) 7.90 (d, J=2.3 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 4.59 (sept, J=6.7 Hz, 1H), 3.78 (s, 3H), 1.42 (d, J=6.7 Hz, 6H).

[0921] LCMS; m/z 169.5 (M+H).sup.+(ES.sup.+).

Methyl 1-isopropyl-1H-pyrazole-5-carboxylate

[0922] .sup.1H NMR (DMSO-d6) 7.57 (d, J=2.0 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 5.41 (sept, J=6.6 Hz, 1H), 3.82 (s, 3H), 1.40 (d, J=6.6 Hz, 6H).

[0923] LCMS; m/z 169.2 (M+H).sup.+(ES.sup.+).

Step B: (1-Isopropyl-H-pyrazol-3-yl)methanol

[0924] ##STR00267##

[0925] To a solution of methyl 1-isopropyl-1H-pyrazole-3-carboxylate (1.37 g, 7.98 mmol) in THF (20 mL) at 0 C. was slowly added LiAlH.sub.4 (2 M in THF, 6 mL, 12.0 mmol). The resulting mixture was stirred at 0 C. for 30 minutes and then at room temperature overnight. The reaction was sequentially quenched with water (0.3 mL), 2 M NaOH (0.75 mL) and water (2 mL). Na.sub.2SO.sub.4 was added, the mixture was stirred for 30 minutes and then filtered over a plug of Celite rinsing with EtOAc. The solvent was evaporated and the residue was purified by chromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford the title compound (779 mg, 70%) as a clear colourless oil.

[0926] .sup.1H NMR (DMSO-d6) 7.63 (d, J=2.2 Hz, 1H), 6.14 (d, J=2.2 Hz, 1H), 4.92 (t, J=5.8 Hz, 1H), 4.42 (sept, J=6.7 Hz, 1H), 4.38 (d, J=5.8 Hz, 2H), 1.38 (d, J=6.7 Hz, 6H).

[0927] LCMS; m/z 141.1 (M+H).sup.+(ES.sup.+).

Step C: 3-(Bromomethyl)-1-isopropyl-H-pyrazole

[0928] ##STR00268##

[0929] To a solution of (1-isopropyl-1H-pyrazol-3-yl)methanol (779 mg, 5.56 mmol) in DCM (50 mL) at 0 C. was slowly added tribromophosphine (0.55 mL, 5.85 mmol) in DCM (10 mL). The resulting mixture was warmed to room temperature and stirred overnight. The mixture was poured onto ice (50 g) and stirred until all ice was dissolved. Sat aq NaHCO.sub.3 (20 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (250 mL). The combined organic extracts were passed through a phase separator and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (24 g column, 0-50% EtOAc/iso-hexane) to afford the title compound (865 mg, 73%) as a clear colourless oil.

[0930] .sup.1H NMR (DMSO-d6) 7.71 (d, J=2.3 Hz, 1H), 6.28 (d, J=2.3 Hz, 1H), 4.60 (s, 2H), 4.46 (sept, J=6.7 Hz, 1H), 1.39 (d, J=6.7 Hz, 6H).

[0931] LCMS; m/z 203.1/205.1 (M+H).sup.+(ES.sup.+).

Step D: (1-Isopropyl-H-pyrazol-3-yl)methanesulfonamide

[0932] ##STR00269##

[0933] A mixture of methyl 3-(chlorosulfonyl)propanoate (1.0 g, 5.36 mmol), sodium sulfite (1.4 g, 11.11 mmol) and sodium bicarbonate (0.94 g, 11.19 mmol) in water (6 mL) was stirred at 80 C. overnight. The solvent was evaporated to give a white solid. Ethanol (30 mL) was added and the mixture was heated to 60 C. for 1 hour and subsequently filtered while being warm. The filtrate was evaporated to afford sodium 3-methoxy-3-oxopropane-1-sulfinate (588 mg, 50% purity by NMR) as a white solid which was used directly.

[0934] To a solution of sodium 3-methoxy-3-oxopropane-1-sulfinate (588 mg, 1.688 mmol) in DMSO (2.5 mL) was added 3-(bromomethyl)-1-isopropyl-1H-pyrazole (280 mg, 1.310 mmol) and the mixture was stirred at room temperature for 45 minutes. The mixture was diluted with water (5 mL) and extracted with EtOAC (430 mL). The combined organic extracts were washed with brine (25 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was dissolved in THF (5 mL) and MeOH (1.2 mL) and NaOMe (5.4 M in MeOH, 0.35 mL, 1.89 mmol) was added. The mixture was stirred at room temperature for 15 minutes. The solvent was removed in vacuo and the residue was dissolved in water (0.8 mL). (Aminooxy)sulfonic acid (1.2 g, 10.61 mmol) and sodium acetate (360 mg, 4.39 mmol) were added and the mixture was stirred at room temperature for 2 days. The mixture was diluted with sat aq NaHCO.sub.3 (30 mL) and extracted with EtOAc (240 mL). The combined organic extracts were washed with brine (30 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) and then further purified by preparative HPLC (Teledyne EZ Prep, basic (0.1% ammonium bicarbonate), basic, Waters X-Bridge Prep-C18, 5 m, 1950 mm column, 5-10% MeCN in water) to afford the title compound (31 mg, 11%) as a white solid.

[0935] .sup.1H NMR (DMSO-d6) 7.72 (d, J=2.3 Hz, 1H), 6.79 (s, 2H), 6.26 (d, J=2.3 Hz, 1H), 4.46 (sept, J=6.7 Hz, 1H), 4.23 (s, 2H), 1.40 (d, J=6.7 Hz, 6H).

[0936] LCMS; m/z 204.5 (M+H).sup.+(ES.sup.+).

Intermediate P75: N-Methyl-N-(3-sulfamoylpropyl)acetamide

[0937] ##STR00270##

[0938] Prepared as described for methyl methyl(3-sulfamoylpropyl)carbamate (Intermediate P64) from 3-(methylamino)propane-1-sulfonamide and acetic anhydride. The solvents were evaporated and the residue was triturated in THF. The THF was filtered (over Celite) and evaporated to afford the title compound as a colourless oil (100 mg, quant.) which was used without further purification.

[0939] .sup.1H NMR (Methanol-d.sub.4) 3.54 (t, 2H), 3.16 (t, 2H), 3.05 (s, 3H), 2.16 (m, 2H), 2.13 (s, 3H).

PREPARATION OF EXAMPLES

Example 1: 1-(1-Ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt

[0940] ##STR00271##

[0941] To a cooled (o C.) solution of (1-ethylpiperidin-4-yl)methanesulfonamide (Intermediate P1; 76 mg, 0.37 mmol) in THF (2.5 mL) was added potassium tert-butoxide (41 mg, 0.37 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; 73 mg, 0.37 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 (1 mL) was added. The suspension was filtered over cotton wool and subsequently submitted for purification by reversed phase column chromatography (see Experimental Methods) to afford the title compound (28 mg, 19%) as a white solid.

[0942] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.18 (m, 2H), 3.07 (m, 2H), 2.82 (m, 8H), 2.57 (m, 2H),2.24 (m, 2H), 2.04 (m, 7H), 1.44 (m, 2H) and 1.16 (t, 3H).

[0943] LCMS: m/z 406 (M+H).sup.+(ES.sup.+); 404 (MH).sup.(ES.sup.).

Example 2:3-(4-(Dimethylamino)piperidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propane-1-sulfonamide, potassium salt

[0944] ##STR00272##

[0945] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(4-(dimethylamino)piperidin-1-yl)propane-1-sulfonamide (Intermediate P2) to afford the title compound (13%) as a light yellow solid.

[0946] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.23 (m, 1H), 3.08 (m, 4H), 2.82 (m, 8H), 2.46 (m, 2H), 2.34 (s, 6H), 2.02 (m, 10H) and 1.58 (m, 2H).

[0947] LCMS: m/z 449 (M+H).sup.+(ES.sup.+); 447 (MH).sup.(ES.sup.).

Example 3: 3-(Diethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propane-1-sulfonamide, potassium salt

[0948] ##STR00273##

[0949] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(diethylamino)propane-1-sulfonamide (Intermediate P3) to afford the title compound (11%) as a light yellow solid.

[0950] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.28 (m, 4H), 2.95 (m, 2H), 2.82 (m, 10H), 2.02 (m, 6H) and 1.18 (t, 6H).

[0951] LCMS: m/z 394 (M+H).sup.+(ES.sup.+).

Example 4: 1-((1S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Potassium Salt

[0952] ##STR00274##

[0953] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1S)-10-camphorsulfonamide to afford the title compound (63%) as a white solid.

[0954] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.63 (d, 1H), 3.23 (d, 1H), 2.82 (m, 8H), 2.62 (m, 1H), 2.37 (m, 1H), 2.02 (m, 6H), 1.88 (d, 1H), 1.7 (m, 1H), 1.42 (m, 1H), 1.1 (s, 3H) and 0.85 (s, 3H).

[0955] LCMS: m/z 431 (M+H).sup.+(ES.sup.+); 429 (MH).sup.(ES.sup.).

Example 5: 2-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethane-1-sulfonamide, potassium salt

[0956] ##STR00275##

[0957] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isoevanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(dimethylamino)ethane-1-sulfonamide to afford the title compound (52%) as a white solid.

[0958] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.42 (m, 2H), 2.88 (m, 2H), 2.82 (m, 8H), 2.33 (s, 6H) and 2.02 (m, 4H).

[0959] LCMS: m/z 352 (M+H).sup.+(ES.sup.+); 350 (MH).sup.(ES.sup.).

Example 6: N-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)ethyl)acetamide, Potassium Salt

[0960] ##STR00276##

[0961] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-(2-sulfamoylethyl)acetamide to afford the title compound (67%) as a white solid.

[0962] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.61 (m, 2H), 3.37 (m, 2H), 2.82 (m, 8H), 2.02 (m, 4H) and 1.93 (s, 3H).

[0963] LCMS: m/z 366 (M+H).sup.+(ES.sup.+); 364 (MH).sup.(ES.sup.).

Example 7: 1-(1-(Dimethylamino)cyclopropyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt

[0964] ##STR00277##

[0965] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-(dimethylamino)cyclopropyl)methanesulfonamide to afford the title compound (57%) as a white solid.

[0966] .sup.1H NMR (CD.sub.3OD) 6.86 (s, 1H), 3.58 (s, 2H), 2.82 (m, 8H), 2.38 (s, 6H), 2.02 (m, 4H), 1.17 (m, 2H) and 1.66 (m, 2H).

[0967] LCMS: m/z 378 (M+H).sup.+(ES.sup.+); 376 (MH).sup.(ES.sup.).

Example 8: 3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propane-1-sulfonamide, potassium salt

[0968] ##STR00278##

[0969] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(dimethylamino)propane-1-sulfonamide (Intermediate P4) to afford the title compound (52%) as a white solid.

[0970] .sup.1H NMR (CD3OD) 6.87 (s, 1H), 3.24 (dd, 2H), 2.83 (m, 10H), 2.59 (t, 2H), 2.35 (s, 6H), 2.02 (m, 4H).

[0971] LCMS: m/z 366 (M+H).sup.+(ES.sup.+); 364 (MH).sup.(ES.sup.).

Example 9: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-4-morpholinobutane-1-sulfonamide, Potassium Salt

[0972] ##STR00279##

[0973] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4-morpholinobutane-1-sulfonamide (Intermediate P5) to afford the title compound (55%) as a white solid.

[0974] .sup.1H NMR (CD3OD) 6.87 (s, 1H), 3.73-3.62 (m, 4H), 3.28-3.18 (m, 2H), 2.82 (m, 8H), 2.46 (t, 4H), 2.44-2.32 (m, 2H), 2.03 (m, 4H), 1.93-1.74 (m, 2H), 1.66 (t, 2H).

[0975] LCMS: m/z 422 (M+H)+(ES+); 420 (MH)(ES).

Example 10: 4-(Diethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)butane-1-sulfonamide, potassium salt

[0976] ##STR00280##

[0977] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4-(diethylamino)butane-1-sulfonamide (Intermediate P6) to afford the title compound (61%) as a white solid.

[0978] .sup.1H NMR (CD3OD) 6.88 (s, 1H), 3.26 (dd, 2H), 3.04 (m, 6H), 2.83 (m, 9H), 2.13-1.92 (m, 4H), 1.91-1.73 (m, 3H), 1.22 (t, 6H).

[0979] LCMS: m/z 408 (M+H)+(ES+); 406 (MH)(ES).

Example 11: 2-(Benzyl(ethyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethane-1-sulfonamide, potassium salt

[0980] ##STR00281##

[0981] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(benzyl(ethyl)amino)ethane-1-sulfonamide (Intermediate P7) to afford the title compound (24%) as a white solid.

[0982] .sup.1H NMR (CD3OD) 7.42-7.11 (m, 5H), 6.86 (s, 1H), 3.63 (s, 2H), 3.51-3.40 (m, 2H), 3.11-2.95 (m, 2H), 2.81 (m, 8H), 2.55 (q, 2H), 2.02 (m, 4H), 1.16-0.99 (m, 3H).

[0983] LCMS: m/z 442 (M+H)+(ES+); 440 (MH)(ES).

Example 12: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-morpholinoethane-1-sulfonamide, Potassium Salt

[0984] ##STR00282##

[0985] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-morpholinoethane-1-sulfonamide (Intermediate P8) to afford the title compound (87%) as a white solid.

[0986] .sup.1H NMR (CD.sub.3OD) 6.87 (s, 1H), 3.68 (m, 4H), 3.53-3.38 (m, 2H), 2.96-2.74 (m, 10H), 2.51 (dd, 4H), 2.02 (m, 4H).

[0987] LCMS: m/z 394 (M+H)+(ES+); 392 (MH)(ES).

Example 13: 4-(Benzyl(ethyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)butane-1-sulfonamide, potassium salt

[0988] ##STR00283##

[0989] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4-(benzyl(ethyl)amino)butane-1-sulfonamide (Intermediate P9) to afford the title compound (22%) as a white solid.

[0990] .sup.1H NMR (CD3OD) 7.52-7.20 (m, 5H), 6.87 (s, 1H), 3.86 (s, 2H), 3.24 (t, 2H), 2.90-2.62 (m, 12H), 2.16-1.89 (m, 8H), 1.23-1.06 (m, 3H).

[0991] LCMS: m/z 470 (M+H)+(ES+); 468 (MH)(ES).

Example 14: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-methoxypropane-1-sulfonamide, Potassium Salt

[0992] ##STR00284##

[0993] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-methoxypropane-1-sulfonamide to afford the title compound (51%) as a white solid.

[0994] .sup.1H NMR (CD3OD) 6.87 (s, 1H), 3.50 (t, 2H), 3.33 (s, 3H), 3.30-3.16 (m, 2H), 2.82 (m, 8H), 2.17-1.91 (m, 6H).

[0995] LCMS: m/z 353 (M+H)+(ES+); 351 (MH)(ES).

Example 15: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-morpholinopropane-1-sulfonamide, Potassium Salt

[0996] ##STR00285##

[0997] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-morpholinopropane-1-sulfonamide (Intermediate P10) to afford the title compound (62%) as a white solid.

[0998] .sup.1H NMR (CD3OD) 6.87 (s, 1H), 3.79-3.59 (m, 4H), 3.28-3.18 (m, 2H), 2.82 (m, 8H), 2.58-2.41 (m, 6H), 2.02 (m, 6H).

[0999] LCMS: m/z 408 (M+H)+(ES+); 406 (MH)(ES).

Example 16: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-1-yl)propane-1-sulfonamide, Potassium Salt

[1000] ##STR00286##

[1001] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(piperidin-1-yl)propane-1-sulfonamide (Intermediate P11) to afford the title compound (28%) as a white solid.

[1002] .sup.1H NMR (CD3OD) 6.88 (s, 1H), 3.26 (t, 2H), 2.83 (m, 10H), 2.50 (t, 2H), 2.12 (q, 2H), 2.02 (m, 6H), 1.68 (q, 3H), 1.64-1.38 (m, 3H).

[1003] LCMS: m/z 406 (M+H)+(ES+); 404 (MH)(ES).

Example 17: 1-(1-Ethylazetidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt

[1004] ##STR00287##

[1005] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-ethylazetidin-3-yl)methanesulfonamide (Intermediate P14) to afford the title compound (11%) as a white solid.

[1006] .sup.1H NMR (CD3OD) 6.89 (s, 1H), 4.05 (t, 1H), 3.87 (t, 2H), 3.59 (m, 1H), 3.55-3.39 (m, 3H), 3.24-3.05 (m, 1H), 2.95-2.70 (m, 9H), 2.04 (m, 4H), 1.05 (t, 3H).

[1007] LCMS: m/z 378 (M+H)+(ES+); 376 (MH)(ES).

Example 18: 2-(Diethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethane-1-sulfonamide, potassium salt

[1008] ##STR00288##

[1009] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(diethylamino)ethane-1-sulfonamide (Intermediate P12) to afford the title compound (33%) as a white solid.

[1010] .sup.1H NMR (CD3OD) 6.88 (s, 1H), 3.48 (t, 2H), 2.83 (m, 14H), 2.02 (m, 4H), 1.19 (t, 6H).

[1011] LCMS: m/z 380 (M+H)+(ES+); 378 (MH)(ES).

Example 19: 2-(Ethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethane-1-sulfonamide, potassium salt

[1012] ##STR00289##

[1013] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(ethylamino)ethane-1-sulfonamide (Intermediate P13) to afford the title compound (8%) as a white solid.

[1014] .sup.1H NMR (CD3OD) 6.90 (s, 1H), 3.45 (t, 2H), 3.22 (t, 2H), 2.86 (t, 10H), 2.81 (s, 1H), 2.04 (m, 4H), 1.21 (t, 3H).

[1015] LCMS: m/z 352 (M+H)+(ES+); 350 (MH)(ES).

Example 20: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyridin-3-yl)methanesulfonamide, potassium salt

[1016] ##STR00290##

[1017] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and pyridin-3-ylmethanesulfonamide to afford the title compound (66%) as a white solid.

[1018] .sup.1H NMR (CD3OD) 8.61 (d, 1H), 8.46 (dd, 1H), 7.94 (d, 1H), 7.42 (dd, 1H), 6.90 (s, 1H), 4.54 (s, 2H), 2.85 (m, 8H), 2.06 (m, 4H).

[1019] LCMS: m/z 372 (M+H)+(ES+); 370 (MH)(ES).

Example 21: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyridin-2-yl)methanesulfonamide, potassium salt

[1020] ##STR00291##

[1021] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and pyridin-2-ylmethanesulfonamide to afford the title compound (67%) as a white solid.

[1022] .sup.1H NMR (CD3OD) 8.54-8.42 (m, 1H), 7.79 (td, 1H), 7.61 (d, 1H), 7.33 (ddd, 1H), 6.88 (s, 1H), 4.66 (s, 2H), 2.84 (m, 8H), 2.04 (m, 4H).

[1023] LCMS: m/z 372 (M+H).sup.+(ES.sup.+); 370 (MH).sup.(ES.sup.).

Example 22: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-methylpiperidin-4-yl)methanesulfonamide, Potassium Salt

[1024] ##STR00292##

[1025] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-methylpiperidin-4-yl)methanesulfonamide (Intermediate P15) to afford the title compound (27%) as a white solid.

[1026] .sup.1H NMR (CD3OD) 7.01 (s, 1H), 3.42 (m, 2H), 3.17 (m, 2H), 2.93 (m, 2H), 2.77-2.67 (m, 11H), 2.13-1.95 (m, 9H).

[1027] LCMS: m/z 392 (M+H)+(ES+); 390 (MH)(ES).

Example 23: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-methylpyrrolidin-3-yl)methanesulfonamide, Potassium Salt

[1028] ##STR00293##

[1029] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-methylpyrrolidin-3-yl)methanesulfonamide (Intermediate P16) to afford the title compound (70%) as a white solid.

[1030] .sup.1H NMR (CD.sub.3OD) 6.92 (s, 1H), 3.53-339 (m, 2H), 3.05 (dt, 2H), 2.86 (m, 10H), 2.70 (d, 4H), 2.30 (m, 1H), 2.06 (m, 4H), 1.95-1.74 (m, 1H).

[1031] LCMS: m/z 378 (M+H).sup.+(ES.sup.+); 376 (MH).sup.(ES.sup.).

Example 24: 1-(1-Ethylpyrrolidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt

[1032] ##STR00294##

[1033] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-ethylpyrrolidin-3-yl)methanesulfonamide (Intermediate P17) to afford the title compound (53%) as a white solid.

[1034] .sup.1H NMR (CD.sub.3OD) 6.90 (s, 1H), 3.54 (dd, 1H), 3.46-3.34 (m, 1H), 3.24-3.09 (m, 3H), 3.04 (q, 2H), 2.83 (m, 10H), 2.39-2.19 (m, 1H), 2.03 (m, 4H), 1.92-1.72 (m, 1H), 1.24 (t, 3H).

[1035] LCMS: m/z 392 (M+H).sup.+(ES.sup.+); 390 (MH).sup.(ES.sup.).

Example 25: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-isopropylpyrrolidin-3-yl)methanesulfonamide, Potassium Salt

[1036] ##STR00295##

[1037] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-isopropylpyrrolidin-3-yl)methanesulfonamide (Intermediate P18) to afford the title compound (44%) as a white solid.

[1038] .sup.1H NMR (CD.sub.3OD) 6.89 (s, 1H), 3.57 (dd, 1H), 3.49-3.34 (m, 1H), 3.26-3.12 (m, 3H), 3.06 (dd, 1H), 2.83 (m, 10H), 2.40-2.21 (m, 1H), 2.03 (m, 4H), 1.81 (dq, 1H), 1.28 (dd, 6H).

Example 26:1-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propane-2-sulfonamide, potassium salt

[1039] ##STR00296##

[1040] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(dimethylamino)propane-2-sulfonamide (Intermediate P19) to afford the title compound (17%) as a white solid.

[1041] .sup.1H NMR (CD.sub.3OD) 6.88 (s, 1H), 3.71 (d, 1H), 2.94 (s, 1H), 2.83 (m, 8H), 2.69 (d, 1H), 2.39 (s, 6H), 2.03 (m, 4H), 1.38 (d, 3H).

[1042] LCMS: m/z 366 (M+H)+(ES+); 364 (MH)(ES).

Example 27: 3-(Ethyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propane-1-sulfonamide, potassium salt

[1043] ##STR00297##

Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(ethyl(methyl)amino)propane-1-sulfonamide (Intermediate P22) to afford the title compound (44%) as a white solid.

[1044] .sup.1H NMR (CD.sub.3OD) 6.88 (s, 1H), 3.26 (t, 2H), 3.00-2.89 (m, 2H), 2.89-2.73 (m, 10H), 2.53 (s, 3H), 2.06 (m, 6H), 1.19 (t, 3H).

[1045] LCMS: m/z 380 (M+H).sup.+(ES.sup.+); 378 (MH).sup.(ES.sup.).

Example 28: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-1-yl)ethane-1-sulfonamide, Potassium Salt

[1046] ##STR00298##

[1047] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(piperidin-1-yl)ethane-1-sulfonamide (Intermediate P20) to afford the title compound (37%) as a white solid.

[1048] .sup.1H NMR (CD3OD) 6.87 (s, 1H), 3.55-3.40 (m, 2H), 3.03-2.92 (m, 2H), 2.83 (m, 8H), 2.60 (d, 4H), 2.02 (m, 4H), 1.64 (dq, 4H), 1.50 (t, 2H).

[1049] LCMS: m/z 392 (M+H)+(ES+); 390 (MH)(ES).

Example 20: 2-(Azetidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)ethane-1-sulfonamide, Potassium Salt

[1050] ##STR00299##

[1051] Prepared as described for 1-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(azetidin-1-yl)ethane-1-sulfonamide (Intermediate P21) to afford the title compound (1%) as a white solid.

[1052] LCMS: m/z 364 (M+H)+(ES+); 362 (MH)(ES).

Example 3o: 1-(4-Cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)methanesulfonamide, sodium salt

[1053] ##STR00300##

[1054] To a solution of (4-cyanophenyl)methanesulfonamide (Intermediate P23) (110 mg, 560.58 mol, 1 eq) in THF (5 mL) was added sodium methoxide (30.28 mg, 560.58 mol, 1 eq) at 20 C. After stirring for 15 minutes, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (111.69 mg, 560.58 mol, 1 eq) was added to the mixture. The mixture was stirred at 20 C. for 15 hours and then filtered. The collected solid was triturated with ethyl acetate (35 mL) and the combined layers were concentrated in vacuo to give the title compound (99 mg, 40%) as a white solid.

[1055] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.72 (d, 2H), 7.47 (d, 2H), 7.24 (br s, 1H), 6.78 (s, 1H), 4.34 (s, 2H), 2.77-2.69 (m, 8H) and 1.95-1.91 (m, 4H).

[1056] LCMS: m/z 396 (M+H).sup.+(ES.sup.+).

Example 31: Methyl 4-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)methyl)benzoate, sodium salt

[1057] ##STR00301##

[1058] Prepared as described for 1-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 30) to afford the title compound (125 mg, 72%) as a white solid.

[1059] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.84 (d, 2H), 7.44 (d, 2H), 7.26 (br s, 1H), 6.79 (s, 1H), 4.32 (s, 2H), 3.84 (s, 3H), 2.79-2.70 (m, 8H) and 1.95-1.91 (m, 4H).

[1060] LCMS: m/z 429 (M+H).sup.+(ES.sup.+).

Example 32: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(3-methoxyphenyl)methanesulfonamide, Sodium Salt

[1061] ##STR00302##

[1062] Prepared as described for 1-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 30) to afford the title compound (172 mg, 31%) as a white solid.

[1063] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.30-7.29 (m, 4H), 7.25 (br s, 1H), 6.78 (s, 1H), 4.21 (s, 2H), 3.33 (s, 3H), 2.77-2.72 (m, 8H) and 1.95-1.91 (m, 4H).

[1064] LCMS: m/z 401 (M+H).sup.+(ES.sup.+).

Example 33: Methyl 2-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)methyl)benzoate

[1065] ##STR00303##

[1066] To a solution of methyl 2-(sulfamoylmethyl)benzoate (100 mg, 436.20 mol) in THF (4 mL) was added sodium methoxide (23.56 mg, 436.20 mol). The mixture was stirred at 20 C. for 30 minutes before 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (104.29 mg, 523.44 mol, 1.2 eq) was added. The reaction mixture was stirred at 20 C. for 16 hours and then concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 m; mobile phase: [water (0.04% NH.sub.3H2O+10 mM NH.sub.4HCO.sub.3)-acetonitrile]; B %: 20%-50%,12 min) to give the title compound (46 mg, 25%) as a white solid.

[1067] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.17 (br s, 1H), 7.88-7.86 (m, 2H), 7.63-7.61 (m, 1H), 7.57-7.55 (m, 1H), 7.42-7.40 (m, 1H), 6.98 (s, 1H), 5.19 (s, 2H), 3.79 (s, 3H), 2.85-2.81 (m, 4H), 2.74-2.72 (m, 4H) and 2.05-1.99 (m, 4H).

[1068] LCMS: m/z 451 (M+Na).sup.+(ES.sup.+).

Example 34: 3-Azido-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) propane-1-sulfonamide, Potassium Salt

[1069] ##STR00304##

[1070] To a solution of 3-azidopropane-1-sulfonamide (Intermediate P30) (200 mg, 2.1 mmol) in THF (15 mL) was added potassium tert-butoxide (236 mg, 2.1 mmol). The mixture was stirred at room temperature for 45 minutes. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (419 mg, 2.1 mmol) was added and the mixture was stirred for 2 hours at room temperature. Then the reaction mixture was concentrated in vacuo and a part of the mixture was dissolved in DMSO (1 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method) to afford an initial amount of title compound (55 mg) as a white solid. The remainder of the batch was stored.

[1071] LCMS: m/z 364 (M+H).sup.+(ES.sup.+); 362 (MH).sup.(ES.sup.).

Example 35: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-methyl-1H-pyrazol-4-yl)methanesulfonamide

[1072] ##STR00305##

[1073] NaO.sup.tBu (2 M in THF, 0.17 mL, 0.34 mmol) was added to a solution of (1-methyl-1H-pyrazol-4-yl)methanesulfonamide (60 mg, 0.325 mmol) in a mixture of THF (3.5 mL) and DMF (0.5 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) (71 mg, 0.358 mmol) was added in a single portion and the reaction mixture was stirred for 21 hours at room temperature. EtOAc (10 mL) was added, followed by aq 2 M NaOH (0.2 mL) and water (3 mL). The phases were separated and the organic phase was washed with water (3 mL). The combined aqueous phases were filtered and purified by chromatography on RP Flash C18 (12 g column, 5-100% MeCN/10 mM ammonium bicarbonate) to afford the title compound (0.10 g, 81%) as a white solid.

[1074] .sup.1H NMR (DMSO-d6) 7.58 (s, 1H), 7.53 (br s, 1H), 7.30 (s, 1H), 6.86 (s, 1H), 4.31-4.23 (m, 2H), 3.80 (s, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.72 (t, J=7.3 Hz, 4H), 1.96 (p, J=7.5 Hz, 4H). NH not observed.

[1075] LCMS; m/z 397.3 (M+Na)+(ES+).

Example 36: 3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-methylpropane-1-sulfonamide, potassium salt

[1076] ##STR00306##

[1077] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(dimethylamino)-2-methylpropane-1-sulfonamide (Intermediate P29) to afford the title compound (2 mg, 3%) as a white solid.

[1078] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 3.29-3.06 (m, 2H), 2.83 (m, 9H), 2.77-2.59 (m, 1H), 2.46 (s, 6H), 2.45 (m, 1H), 2.02 (m, 4H), 1.15 (d, 3H).

[1079] LCMS: m/z 380 (M+H).sup.+(ES.sup.+); 378 (MH).sup.(ES.sup.).

Example 37:3-(Diethylamino)-N-((4-fluoro-2-isopropyl-6-(pyridin-3-yl) phenyl)carbamoyl)propane-1-sulfonamide

[1080] ##STR00307##

[1081] To a solution of 3-(diethylamino)propane-1-sulfonamide (Intermediate P3) (200 mg, 1.03 mmol, 1 eq) in THF (5 mL) was added NaOMe (56 mg, 1.03 mmol, 1 eq) and 3-(5-fluoro-2-isocyanato-3-isopropylphenyl)pyridine (Intermediate A6) (263.80 mg, 1.03 mmol, 1 eq). The reaction mixture was stirred at 70 C. for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini, 250 mm*25 mm*5 m; mobile phase: [A: water (0.04% ammonium hydroxide v/v); B: MeCN]; B %: 18%-39%, 10 min) to give the title compound (58.2 mg, 11% yield, 100% purity on LCMS) as a brown solid.

[1082] .sup.1H NMR (DMSO-d.sub.6): 8.59 (br s, 1H), 8.50 (dd, 1H), 7.83-7.81 (m, 1H), 7.38 (dd 2H), 7.12 (dd, 1H), 6.97 (d, 1H), 3.29-3.25 (m, 1H), 2.75-2.73 (m, 2H), 2.49-2.43 (m, 6H), 1.64-1.60 (m, 2H), 1.16 (d, 6H) and 0.97 (t, 6H).

[1083] LCMS: m/z 451.2 (M+H).sup.+(ES.sup.+).

Example 38: 2-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-azaspiro[3.3]heptane-6-sulfonamide, potassium salt

[1084] ##STR00308##

[1085] To a cooled (o C.) solution 2-ethyl-2-azaspiro[3.3]heptane-6-sulfonamide (Intermediate P24) (10 mg, 0.05 mmol) in THF (3 mL) was added potassium tert-butoxide (6 mg, 0.05 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) (10 mg, 0.05 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 (1 mL) was added. The suspension was filtered over cotton wool and subsequently submitted for purification by reversed phase column chromatography (see Experimental Methods) to afford the title compound (7 mg, 35%) as a white solid.

[1086] .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).

[1087] LCMS: m/z 404 (M+H).sup.+(ES.sup.+); 402 (MH).sup.(ES.sup.).

Example 39: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-isopropyl-2-azaspiro[3.3]heptane-6-sulfonamide, potassium salt

[1088] ##STR00309##

[1089] Prepared as described for 2-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-azaspiro[33]heptane-6-sulfonamide, potassium salt (Example 38) 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 P25) to afford the title compound (41%) as a white solid.

[1090] .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).

[1091] LCMS: m/z 418 (M+H)+(ES+); 416 (MH)(ES).

Example 40: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-methyl-2-azaspiro[3.3]heptane-6-sulfonamide, potassium salt

[1092] ##STR00310##

[1093] Prepared as described for 2-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-azaspiro[3.3]heptane-6-sulfonamide, potassium salt (Example 38) 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 P26) to afford the title compound (14%) as a white solid.

[1094] .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).

[1095] LCMS: m/z 390 (M+H)+(ES+); 388 (MH)(ES).

Example 41: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-3-(diethylamino)propane-1-sulfonamide

[1096] ##STR00311##

[1097] To a solution of 3-(diethylamino)propane-1-sulfonamide (Intermediate P3) (80 mg, 411.75 mol, 1 eq) in THF (1 mL) was added t-BuONa (40 mg, 411.75 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A3) (116 mg, 411.75 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The 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% ammonium hydroxide v/v); B: MeCN]; B %: 12%-42%,11.5 min) to give the title compound (105.29 mg, 55% yield, 100% purity on LCMS) as a white solid.

[1098] .sup.1H NMR (DMSO-d.sub.6): 8.75 (d, 1H), 8.08 (s, 1H), 7.79-7.73 (m, 2H), 7.23 (d, 1H), 7.13 (d, 1H), 3.09-3.06 (m, 1H), 3.03-2.88 (m, 8H), 1.75-1.72 (m, 2H), 1.16 (d, 6H) and 1.09 (t, 6H).

[1099] LCMS: m/z 476.3 (M+H).sup.+(ES.sup.+).

Example 42: 3-(Diethylamino)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)propane-1-sulfonamide

[1100] ##STR00312##

[1101] To a solution of 3-(diethylamino)propane-1-sulfonamide (Intermediate P3) (80 mg, 411.75 mol, 1 eq) in THF (1 mL) was added t-BuONa (40 mg, 411.75 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A4) (118 mg, 411.75 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The 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% ammonium hydroxide v/v); B: MeCN]; B %: 18%-48%,11.5 min) to give the title compound (59.65 mg, 30% yield, 100% purity on LCMS) as a white solid.

[1102] .sup.1H NMR (DMSO-d.sub.6): 8.15 (d, 1H), 7.64 (s, 1H), 7.19 (d, 1H), 7.09-6.95 (m, 2H), 6.85 (s, 1H), 3.87 (s, 3H), 3.23-3.20 (m, 1H), 3.04-2.75 (m, 8H), 1.77-1.72 (m, 2H), 1.16 (d, 6H) and 1.09-1.04 (m, 6H).

[1103] LCMS: m/z 481.3 (M+H).sup.+(ES.sup.+).

Example 43: 3-(Diethylamino)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)propane-1-sulfonamide

[1104] ##STR00313##

[1105] To a solution of 3-(diethylamino)propane-1-sulfonamide (Intermediate P3) (80 mg, 411.75 mol, 1 eq) in THF (1 mL) was added t-BuONa (40 mg, 411.75 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A5) (171 mg, 411.75 mol, purity: 64% on LCMS, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The 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% ammonium hydroxide v/v); B: MeCN]; B %: 15%-45%,11.5 min) to give the title compound (53.15 mg, 28% yield, 100% purity on LCMS) as a pink solid.

[1106] .sup.1H NMR (DMSO-d.sub.6): 8.13 (d, 1H), 7.64 (br s, 1H), 7.15 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 6.78 (s, 1H), 3.86 (s, 3H), 3.08 (t, 2H), 2.91 (t, 2H), 2.85-2.76 (m, 8H), 2.03-2.00 (m, 2H), 1.82-1.78 (m, 2H) and 1.05 (t, 6H).

[1107] LCMS: m/z 461.3 (M+H).sup.+(ES.sup.+).

Example 44: 3-(Diethylamino)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)propane-1-sulfonamide

[1108] ##STR00314##

[1109] A mixture of 3-(diethylamino)propane-1-sulfonamide (Intermediate P3) (60 mg, 308.81 mol, 1 eq) and t-BuONa (30 mg, 308.81 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 A2) (78 mg, 308.81 mol, 1 eq) was added. The resulting mixture was stirred at 25 C. for 10 minutes. 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% ammonium hydroxide v/v); B: MeCN]; B %: 10%-40%, 10 minutes) to give the title compound (18.1 mg, 13% yield, 100% purity on LCMS) as a white solid.

[1110] .sup.1H NMR (DMSO-d.sub.6): 8.58-8.56 (m, 2H), 7.61 (br s, 1H), 7.41 (d, 2H), 6.99 (d, 1H), 3.03 (t, 2H), 2.96 (t, 2H), 2.90-2.78 (m, 8H), 2.11-2.04 (m, 2H), 1.82-1.75 (m, 2H) and 1.07 (t, 6H).

[1111] LCMS: m/z 449.2 (M+H).sup.+(ES.sup.+).

Example 45: 3-(Benzyl(ethyl)amino)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)propane-1-sulfonamide

[1112] ##STR00315##

[1113] To a solution of 3-(benzyl(ethyl)amino)propane-1-sulfonamide (Intermediate P27) (90 mg, 351.06 mol, 1 eq) in THF (1 mL) was added t-BuONa (34 mg, 351.06 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A4) (101 mg, 351.06 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The 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% ammonium hydroxide v/v); B: MeCN]; B %: 20%-50%,11.5 min) to give the title compound (66.21 mg, 35% yield, 100% purity on LCMS) as a white solid.

[1114] .sup.1H NMR (DMSO-d.sub.6): 8.13 (d, 1H), 7.72 (s, 1H), 7.32-7.20 (m, 6H), 7.06-7.01 (m, 2H), 6.83 (s, 1H), 3.85 (s, 3H), 3.53 (s, 2H), 3.19-315 (m, 1H), 3.04-3.01 (m, 2H), 2.44-2.40 (m, 4H), 1.68-1.64 (m, 2H), 1.15 (d, 6H) and 0.96 (t, 3H).

[1115] LCMS: m/z 543.4 (M+H).sup.+(ES.sup.+).

Example 46: 3-(Benzyl(ethyl)amino)-N-((2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)propane-1-sulfonamide

[1116] ##STR00316##

[1117] To a solution of 3-(benzyl(ethyl)amino)propane-1-sulfonamide (Intermediate P27) (100 mg, 390.07 mol, 1 eq) in THF (1 mL) was added t-BuONa (37 mg, 390.07 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A3) (no mg, 390.07 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The 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% ammonium hydroxide v/v); B: MeCN]; B %: 28%-58%,11.5 min) to give the title compound (37.69 mg, 18% yield, 100% purity on LCMS) as a white solid.

[1118] .sup.1H NMR (DMSO-d.sub.6): 10.49 (br s, 1H), 8.76 (d, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.76 (dd, 1H), 7.34-7.20 (m, 7H), 3.74 (s, 2H), 3.18-3.09 (m, 3H), 2.47-2.42 (m, 4H), 1.65-1.62 (m, 2H), 1.17 (d, 6H) and 0.96 (t, 3H).

[1119] LCMS: m/z 538.4 (M+H).sup.+(ES.sup.+).

Example 47: 3-(Benzyl(ethyl)amino)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)propane-1-sulfonamide

[1120] ##STR00317##

[1121] To a solution of 3-(benzyl(ethyl)amino)propane-1-sulfonamide (Intermediate P27) (100 mg, 390.07 mol, 1 eq) in THF (1 mL) was added t-BuONa (37 mg, 390.07 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A5) (146 mg, 390.07 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The 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 (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 18%-48%,11.5 min) to give the title compound (35.98 mg, 17% yield, 98% purity on LCMS) as a white solid.

[1122] .sup.1H NMR (DMSO-d.sub.6): 10.31 (br s, 1H), 8.16 (d, 1H), 8.00 (s, 1H), 7.32-7.26 (m, 4H), 7.24 (d, 2H), 7.14 (d, 1H), 6.93 (d, 1H), 6.75 (s, 1H), 3.86 (s, 3H), 3.56 (s, 2H), 3.26-3.22 (m, 2H), 2.93 (t, 2H), 2.79 (t, 2H), 2.47-2.40 (m, 4H), 2.02-1.97 (m, 2H), 1.81-1.76 (m, 2H) and 0.96 (t, 3H).

[1123] LCMS: m/z 523.3 (M+H).sup.+(ES.sup.+).

Example 48: 3-(Benzyl(ethyl)amino)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)propane-1-sulfonamide

[1124] ##STR00318##

[1125] To a solution of 3-(benzyl(ethyl)amino)propane-1-sulfonamide (Intermediate P27) (101 mg, 393.30 mol, 1 eq) in THF (1 mL) was added t-BuONa (38 mg, 393.30 mol, 1 eq). The reaction mixture was stirred at 15 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-H-inden-5-yl)pyridine (Intermediate A2) (100 mg, 393.30 mol, 1 eq) was added. The resulting mixture was stirred at 15 C. for 10 minutes. 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% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (67.23 mg, 33% yield, 100% purity on LCMS) as a pink solid.

[1126] .sup.1H NMR (DMSO-d.sub.6): 8.57 (d, 2H), 7.86 (br s, 1H), 7.38 (d, 2H), 7.31 (d, 4H), 7.26-7.23 (m, 1H), 7.03 (d, 1H), 3.56 (s, 2H), 3.18-3.15 (m, 2H), 2.96 (t, 2H), 2.85 (t, 2H), 2.47-2.42 (m, 4H), 2.10-2.03 (m, 2H), 1.76-1.70 (m, 2H) and 0.96 (t, 3H).

[1127] LCMS: m/z 511.3 (M+H).sup.+(ES.sup.+).

Example 49: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-3-methoxypropane-1-sulfonamide

[1128] ##STR00319##

To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P28) (65 mg, 426.62 mol, 1.2 eq) in THF (1 mL) was added t-BuONa (34 mg, 355.51 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A3) (100 mg, 355.51 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The 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% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%,11.5 min) to give the title compound (113.93 mg, 74% yield, 100% purity on LCMS) as a white solid.

[1129] .sup.1HNMR (DMSO-d.sub.6): 8.71 (d, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.23-7.18 (m, 1H), 7.10 (d, 1H), 3.29-3.24 (m, 3H), 3.21 (s, 3H), 2.76-2.73 (m, 2H), 1.60-1.57 (m, 2H) and 1.16 (d, 6H).

[1130] LCMS: m/z 435.2 (M+H).sup.+(ES.sup.+).

Example 50: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) phenyl)carbamoyl)-3-methoxypropane-1-sulfonamide

[1131] ##STR00320##

[1132] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P28) (64 mg, 419.14 mol, 1.2 eq) in THF (1 mL) was added t-BuONa (34 mg, 349.28 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A4) (100 mg, 349.28 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The 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% ammonium hydroxide v/v); B: MeCN]; B %: 8%-38%,11.5 min) to give the title compound (130.95 mg, 85% yield, 99.7% purity on LCMS) as a white solid.

[1133] .sup.1H NMR (DMSO-d.sub.6): 8.11 (d, 1H), 7.51 (s, 1H), 7.16 (d, 1H), 7.02-6.95 (m, 2H), 6.84 (s, 1H), 3.86 (s, 3H), 3.34-3.27 (m, 3H), 3.21 (s, 3H), 2.90-2.86 (m, 2H), 1.72-1.61 (m, 2H) and 1.15 (d, 6H).

[1134] LCMS: m/z 440.2 (M+H).sup.+(ES.sup.+).

Example 51: 3-Methoxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)propane-1-sulfonamide

[1135] ##STR00321##

[1136] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P28) (72 mg, 469.98 mol, 1.2 eq) in THF (1 mL) was added t-BuONa (38 mg, 391.65 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A5) (163 mg, 391.65 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The 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% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%,11.5 min) to give the title compound (15.13 mg, 9% yield, 100% purity on LCMS) as a white solid.

[1137] .sup.1H NMR (DMSO-d.sub.6): 10.34 (br s, 1H), 8.17 (d, 1H), 7.97 (br s, 1H), 7.24 (d, 1H), 7.14 (d, 1H), 6.94 (d, 1H), 6.76 (s, 1H), 3.88 (s, 3H), 3.37 (t, 2H), 3.26-3.20 (m, 5H), 2.95 (t, 2H), 2.81 (t, 2H), 2.06-2.02 (m, 2H) and 1.84-1.78 (m, 2H).

[1138] LCMS: m/z 420.2 (M+H).sup.+(ES.sup.+).

Example 52: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-H-inden-4-yl) carbamoyl)-3-methoxypropane-1-sulfonamide

[1139] ##STR00322##

[1140] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P28) (60 mg, 393.30 mol, 1 eq) in THF (1 mL) was added t-BuONa (38 mg, 393.30 mol, 1 eq). The reaction mixture was stirred at 15 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A2) (100 mg, 393.30 mol, 1 eq) was added. The resulting mixture was stirred at 15 C. for 20 minutes. 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% ammonium hydroxide v/v); B: MeCN]; B %: 0%-30%, 10 min) to give the title compound (62.33 mg, 38% yield, 100% purity on LCMS) as a pink solid.

[1141] .sup.1H NMR (DMSO-d.sub.6): 8.57 (d, 2H), 7.63 (br s, 1H), 7.40 (d, 2H), 7.00 (d, 1H), 3.37-3.34 (m, 2H), 3.23 (s, 3H), 3.07-3.04 (m, 2H), 2.97 (t, H), 2.87 (t, 2H), 2.11-2.05 (m, 2H) and 1.79-1.72 (m, 2H).

[1142] LCMS: m/z 408.2 (M+H).sup.+(ES.sup.+).

Example 53: N-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)propyl)-N-methylacetamide, Potassium Salt

[1143] ##STR00323##

Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-methyl-N-(3-sulfamoylpropyl)acetamide (Intermediate P75) to afford the title compound (60 mg, 37%) as a white solid.

[1144] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.51 (q, 2H), 3.22 (m, 2H), 3.06 (s, 3H), 2.92 (s, 3H), 2.82 (m, 8H), 2.12-1.92 (m, 6H).

[1145] LCMS: m/z 394 (M+H).sup.+(ES.sup.+); 392 (MH).sup.(ES.sup.).

Example 54: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-(pyridin-3-yl)methanesulfonamide

[1146] ##STR00324##

[1147] To a solution of pyridin-3-ylmethanesulfonamide (60 mg, 348.42 mol, 1 eq) in THF (5 mL) was added t-BuONa (33 mg, 348.42 mol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A4) (100 mg, 348.42 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 8%-38%,11.5 min) to give the title compound (70 mg, 44% yield, 100% purity on LCMS) as a white solid.

[1148] .sup.1H NMR (DMSO-d.sub.6): 8.50 (d, 1H), 8.41 (s, 1H), 8.16 (d, 1H), 7.61 (br s, 1H), 7.50 (d, 1H), 7.33-7.30 (m, 1H), 7.21 (d, 1H), 7.06-7.00 (m, 2H), 6.87 (s, 1H), 4.33 (s, 2H), 3.85 (s, 3H), 3.22-3.17 (t, 1H) and 1.20-1.04 (m, 6H).

[1149] LCMS: m/z 459.3 (M+H).sup.+(ES.sup.+).

Example 55: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(pyridin-3-yl)methanesulfonamide

[1150] ##STR00325##

[1151] To a solution of pyridin-3-ylmethanesulfonamide (70 mg, 406.49 mol, 1 eq) in THF (5 mL) was added t-BuONa (39 mg, 406.49 mol, 1 eq) and 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A5) (108 mg, 406.49 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%,11.5 min) to give the title compound (65 mg, 36% yield, 100% purity on LCMS) as a white solid.

[1152] .sup.1H NMR (DMSO-d.sub.6): 8.52 (d, 1H), 8.46 (d, 1H), 8.16 (d, 1H), 7.61 (d, 1H), 7.37-734 (m, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 6.97-6.95 (m, 1H), 6.78 (s, 1H), 4.45 (s, 2H), 3.86 (s, 3H), 2.93 (t, 2H), 2.83 (t, 2H) and 2.07-1.98 (m, 2H).

[1153] LCMS: m/z 439.3 (M+H).sup.+(ES.sup.+).

Example 56: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(pyridin-3-yl)methanesulfonamide

[1154] ##STR00326##

[1155] To a solution of pyridin-3-ylmethanesulfonamide (68 mg, 393.30 mol, 1 eq) in THF (2 mL) was added t-BuONa (38 mg, 393.30 mol, 1 eq). Then the reaction mixture was stirred at 25 C. for 10 minutes. A solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-H-inden-5-yl)pyridine (Intermediate A2) (100 mg, 393.30 mol, 1 eq) in THF (2.5 mL) was added. The resulting mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 1%-31%, 10 min) to give the title compound (22.34 mg, 13%) as a white solid.

[1156] .sup.1H NMR (DMSO-d.sub.6): 8.57 (d, 2H), 8.49-845 (m, 2H), 7.59 (d, 1H), 7.39 (d, 2H), 7.34-730 (m, 1H), 6.96 (d, 1H), 4.34 (s, 2H), 2.95 (t, 2H), 2.87 (t, 2H) and 210-2.05 (m, 2H).

[1157] LCMS: m/z 427.2 (M+H).sup.+(ES.sup.+).

Example 57: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-(1-methylpyrrolidin-3-yl)methanesulfonamide

[1158] ##STR00327##

[1159] A solution of (1-methylpyrrolidin-3-yl)methanesulfonamide (Intermediate P16) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 mL) was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A3) (57 mg, 201.96 mol, 0.2 eq) was added. The resulting mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 10%-40%, 10.0 min) to give the title compound (17.51 mg, 4% yield, 100% purity on LCMS) as a white solid.

[1160] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): 8.70 (d, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.17 (dd, 1H), 7.06 (dd, 1H), 3.26-3.15 (m, 2H), 3.10-3.01 (m, 2H), 2.95-2.80 (m, 2H), 2.77-2.72 (m, 1H), 2.67 (s, 3H), 2.45-2.40 (m, 1H), 2.10-1.98 (m, 1H), 1.62-1.51 (m, 1H) and 1.13 (d, 6H).

[1161] LCMS: m/z 460.2 (M+H).sup.+(ES.sup.+).

Example 58: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) phenyl)carbamoyl)-1-(1-methylpyrrolidin-3-yl)methanesulfonamide

[1162] ##STR00328##

[1163] A solution of (1-methylpyrrolidin-3-yl)methanesulfonamide (Intermediate P16) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 mL) was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A4) (58 mg, 201.96 mol, 0.2 eq) was added. The resulting mixture was stirred at 25 C. for 30 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 12%-42%, 10.0 min) to give the title compound (4.92 mg, 1% yield, 100% purity on LCSM) as a white solid.

[1164] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): 8.12 (d, 1H), 7.14-7.11 (m, 1H), 7.04-7.02 (m, 1H), 6.96-6.93 (m, 1H), 6.85-6.83 (m, 1H), 3.86 (s, 3H), 3.30-3.14 (m, 2H), 3.05-2.98 (m, 3H), 2.92-2.83 (m, 2H), 2.63 (s, 3H), 2.60-2.57 (m, 1H), 2.04-2.00 (m, 1H), 1.61-1.57 (m, 1H) and 1.14 (d, 6H).

[1165] LCMS: m/z 465.2 (M+H).sup.+(ES.sup.+).

Example 59: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(1-methylpyrrolidin-3-yl)methanesulfonamide

[1166] ##STR00329##

[1167] A solution of (1-methylpyrrolidin-3-yl)methanesulfonamide (Intermediate P16) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 mL) was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-H-inden-5-yl)-2-methoxypyridine (Intermediate A5) (54 mg, 201.96 mol, 0.2 eq) was added. The resulting mixture was stirred at 25 C. for 30 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 10%-40%, 10.0 min) to give the title compound (5-47 mg, 1% yield, 100% purity on LCMS) as a white solid.

[1168] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): 8.09 (d, 1H), 7.11 (d, 1H), 7.04 (d, 1H), 6.98 (d, 1H), 6.78 (s, 1H), 3.84 (s, 3H), 3.28-3.21 (m, 1H), 3.15-3.01 (m, 3H), 2.95-2.90 (m, 1H), 2.89-2.86 (m, 3H), 2.84-2.78 (m, 2H), 2.64 (s, 3H), 2.61-255 (m, 1H), 2.11-1.96 (m, 3H) and 1.66-1.55 (m, 1H).

[1169] LCMS: m/z 445.2 (M+H).sup.+(ES.sup.+).

Example 60: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(1-methylpyrrolidin-3-yl)methanesulfonamide

[1170] ##STR00330##

[1171] To a solution of (1-methylpyrrolidin-3-yl)methanesulfonamide (Intermediate P16) (180 mg, 1.01 mmol, 5 eq) in THF (2 mL) was added t-BuONa (97 mg, 1.01 mmol, 5 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A2) (51 mg, 201.96 mol, 1 eq) in THF (1.5 mL) was added. The reaction mixture was stirred at 25 C. for 30 minutes. Most of the solvent was evaporated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex Gemini C18, 150 mm*25 mm*5 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN), B %: 8%-38%,10 min) to give the title compound (5.52 mg, 6% yield, 100% purity on LCMS) as a white solid.

[1172] .sup.1H NMR (DMSO-d.sub.6): 8.55 (d, 2H), 7.41 (d, 2H), 7.40 (br s, 1H), 6.95 (d, 1H), 3.12-3.08 (m, 2H), 2.97-2.85 (m, 7H), 2.75-2.71 (m, 1H), 2.58 (s, 3H), 2.53-2.50 (m, 1H), 2.09-2.00 (m, 3H) and 1.59-1.57 (m, 1H).

[1173] LCMS: m/z 433.2 (M+H).sup.+(ES.sup.+).

Example 61: 2-Isopropoxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethanesulfonamide, sodium salt

[1174] ##STR00331##

[1175] 2-Isopropoxyethanesulfonamide (50 mg, 0.299 mmol) was dissolved in dry THF (2 mL). Sodium tert-butoxide (2M in THF) (160 l, 0.320 mmol) was added and the mixture was stirred at room temperature for 30 minutes. A solution of 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A7) (80 mg, 0.299 mmol) in THF (1 mL) was added and the mixture was stirred for 2 hours at room temperature. The THF was removed in vacuo. The residue was dissolved in DMSO (2 mL) and then purified by basic prep-HPLC to afford to afford 2-isopropoxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethanesulfonamide as a colourless solid. The solid was dissolved in aq NaOH (0.1 M, 0.74 mL, 1 eq) and the solution was freeze dried overnight to afford the title compound (30 mg, 22%) as a colourless solid.

[1176] .sup.1H NMR (DMSO-d6) 8.10 (d, J=5.3 Hz, 1H), 7.13-7.02 (m, 3H), 7.00 (d, J=5.3 Hz, 1H), 6.81 (s, 1H), 3.86 (s, 3H), 3.57-3.48 (m, 3H), 3.14-3.06 (m, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 1.99 (p, J=7.5 Hz, 2H), 1.07 (d, J=6.1 Hz, 6H).

[1177] LCMS; m/z 434.2 (M+H).sup.+(ES.sup.+); 432.1 (MH).sup.(ES.sup.).

Example 62: 2-Isopropoxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-benzofuran-4-yl)carbamoyl)ethanesulfonamide, sodium salt

[1178] ##STR00332##

[1179] Prepared according to the general procedure 2-isopropoxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethanesulfonamide, Sodium (Example 61) from 2-isopropoxyethanesulfonamide and 4-(4-isocyanato-2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine (Intermediate A8) and 2-isopropoxyethanesulfonamide to afford the title compound (22 mg, 16%) as a white solid.

[1180] .sup.1H NMR (DMSO-d6) 8.09 (d, J=5.3 Hz, 1H), 7.20 (s, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.96 (dd, J=5.3, 1.4 Hz, 1H), 6.77 (d, J=1.3 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H), 4.54 (t, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.65-3.47 (m, 3H), 3.20-3.09 (m, 4H), 1.07 (d, J=6.1 Hz, 6H).

[1181] LCMS; m/z 436.1 (M+H).sup.+(ES.sup.+); 434.4 (MH).sup.(ES.sup.).

Example 63: N-Ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt

[1182] ##STR00333##

[1183] To a solution of N-ethyl-N-(4-sulfamoylcyclohexyl)acetamide (50 mg, 0.2 mmol) in THF (5 mL) was added potassium tert-butoxide (23 mg, 0.2 mmol). The mixture was stirred at room temperature for 45 minutes. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (40 mg, 0.2 mmol) was added and the mixture was stirred for 2 hours at room temperature. Then 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) to afford the title compound (5 mg, 6%) as a white solid.

[1184] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 4.22 (m, 1H), 3.65 (m, 1H), 2.82 (m, 10H), 2.29 (m, 2H), 2.12 (d, 2H), 2.12-1.88 (m, 6H), 1.72 (m, 5H), 1.20 (t, 3H).

[1185] LCMS: m/z 448 (M+H).sup.+(ES.sup.+); 446 (MH).sup.(ES.sup.).

Example 64: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-(oxetan-3-yl)pyrrolidin-3-yl)methanesulfonamide, Potassium Salt

[1186] ##STR00334##

[1187] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A11 and (1-(oxetan-3-yl)pyrrolidin-3-yl)methanesulfonamide (Intermediate P31) to afford the title compound (25 mg, 36%) as a white solid.

[1188] .sup.1H NMR (Deuterium Oxide) 6.95 (s, 1H), 4.73-4.58 (m, 2H), 4.56-4.37 (m, 2H), 3.80-3.57 (m, 1H), 3.21 (d, 2H), 3.01-2.82 (m, 1H), 2.68 (m, 9H), 2.46 (ddt, 2H), 2.16 (t, 1H), 2.07 (dd, 1H), 1.90 (m, 4H), 1.50 (dt, 1H).

[1189] LCMS: m/z 420 (M+H).sup.+(ES.sup.+); 418 (MH).sup.(ES.sup.).

Example 65: 3-Amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) propane-1-sulfonamide potassium salt

[1190] ##STR00335##

[1191] To 3-azido-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propane-1-sulfonamide, potassium salt (Example 34) (50 mg, 0.14 mmol) in methanol (5 mL) was added PdC (10%, 20 mg) in water (0.5 mL). The mixture was stirred for 18 hours under hydrogen atmosphere. Then the mixture was filtered through Celite and evaporated. DMSO (0.5-1 mL) was added and the mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method) to afford the title compound (50 mg, 100%) as a white solid.

[1192] .sup.1H NMR (Methanol-d.sub.4) 6.96 (s, 1H), 3.19 (t, 2H), 2.86 (t, 2H), 2.73 (m, 4H), 2.63 (m, 4H), 1.89 (m, 6H).

[1193] LCMS: m/z 338 (M+H)+(ES+); 336 (MH)(ES).

Example 66: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N,N-trimethylpropan-1-aminium, Potassium Salt

[1194] ##STR00336##

[1195] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N,N,N-trimethyl-3-sulfamoylpropan-1-aminium (Intermediate P32) to afford the title compound (6 mg, 5%) as a white solid.

[1196] .sup.1H NMR (Deuterium Oxide) 7.01 (s, 1H), 3.50-3.35 (m, 2H), 3.24 (t, 2H), 3.06 (s, 9H), 2.79-2.58 (m, 8H), 2.17 (p, 2H), 1.95 (p, 4H).

[1197] LCMS: m/z 380 (M+H).sup.+(ES.sup.+).

Example 67: 3-(Benzyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propane-1-sulfonamide, potassium salt

[1198] ##STR00337##

Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(benzyl(methyl)amino)propane-1-sulfonamide (Intermediate P33) to afford the title compound (39 mg, 31%) as a white solid.

[1199] .sup.1H NMR (Methanol-d.sub.4) 7.48-7.23 (m, 5H), 6.88 (s, 1H), 3.80 (s, 2H), 3.34 (m, 2H), 2.82 (m, 10H), 2.37 (s, 3H), 2.13 (p, 2H), 2.01 (p, 4H).

[1200] LCMS: m/z 442 (M+H).sup.+(ES.sup.+); 440 (MH).sup.(ES.sup.).

Example 68: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-methyl-3H-diazirin-3-yl)ethane-1-sulfonamide, Potassium Salt

[1201] ##STR00338##

[1202] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(3-methyl-3H-diazirin-3-yl)ethane-1-sulfonamide (Intermediate P34) to afford the title compound (134 mg, 81%) as a white solid.

[1203] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.22-3.02 (m, 2H), 2.82 (dt, 8H), 2.03 (p, 4H), 1.85-1.61 (m, 2H), 1.04 (s, 3H).

[1204] LCMS: m/z 363 (M+H).sup.+(ES.sup.+); 361 (MH).sup.(ES.sup.).

Example 69: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(methylamino)propane-1-sulfonamide, Potassium Salt

[1205] ##STR00339##

[1206] 3-(Benzyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-propane-1-sulfonamide, potassium salt (Example 67) (32 mg, 0.072 mmol) was stirred in water (1 mL). 10% Pd/C (5 mg) was added and a hydrogen balloon was applied. The mixture was stirred overnight, filtered through Celite and freeze-dried to afford the title compound (5 mg, 20%) as a white solid.

[1207] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 2.83 (m, 12H), 2.47 (s, 3H), 2.04 (m, 6H).

[1208] LCMS: m/z 352 (M+H).sup.+(ES.sup.+); 350 (MH).sup.(ES.sup.).

Example 70: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(methoxy(methyl)amino)propane-1-sulfonamide, Potassium Salt

[1209] ##STR00340##

[1210] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(methoxy(methyl)amino)propane-1-sulfonamide (Intermediate P35) to afford the title compound (14 mg, 52%) as a white solid.

[1211] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.49 (s, 3H), 2.83 (m, 10H), 2.80-2.67 (m, 2H), 2.54 (s, 3H), 2.03 (m, 6H).

[1212] LCMS: m/z 382 (M+H).sup.+(ES.sup.+); 380 (MH).sup.(ES.sup.).

Example 71: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,E)-2-(hydroxyimino)-7,7-dimethylbicyclo[2.2.1]heptan-1-yl)methane sulfonamide, Potassium Salt

[1213] ##STR00341##

[1214] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1), ((1S,E)-2-(hydroxyimino)-7,7-dimethylbicyclo[2.2.1]heptan-1-yl)methanesulfonamide (Intermediate P36) and KOtBu (2 equiv.) to afford the title compound (35 mg, 23%) as a white solid.

[1215] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 3.80 (d, 1H), 3.39 (d, 1H), 2.83 (m, 8H), 2.71-2.40 (m, 3H), 2.03 (p, 4H), 1.95-1.83 (m, 2H), 1.74 (m, 1H), 1.39-1.19 (m, 1H), 1.08 (s, 3H), 0.82 (s, 3H).

[1216] LCMS: m/z 446 (M+H).sup.+(ES.sup.+); 444 (MH).sup.(ES.sup.).

Example 72: 3-(Azetidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)propane-1-sulfonamide, Potassium Salt

[1217] ##STR00342##

##STR00343##

[1218] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(methyl(prop-2-yn-1-yl)amino)propane-1-sulfonamide (Intermediate P38) to afford the title compound (60 mg, 41%) as a white solid.

[1219] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 3.43-3.29 (m, 3H), 3.29-3.15 (m, 2H), 2.83 (q, 8H), 2.70-2.50 (m, 2H), 2.32 (s, 3H), 2.01 (m, 6H).

[1220] LCMS: m/z 390 (M+H).sup.+(ES.sup.+); 388 (MH).sup.(ES.sup.).

Example 74: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(4-methylmorpholin-2-yl)methanesulfonamide, Potassium Salt

[1221] ##STR00344##

[1222] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (4-methylmorpholin-2-yl)methanesulfonamide (Intermediate P39) to afford the title compound (9 mg, 13%) as a white solid.

[1223] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 4.05 (q, 1H), 3.94-3.77 (m, 1H), 3.65 (td, 1H), 3.40 (dd, 2H), 3.25-3.19 (m, 1H), 3.13 (d, 1H), 2.93-2.74 (m, 8H), 2.74-2.55 (m, 1H), 2.28 (d, 3H), 2.23-1.79 (m, 5H).

[1224] LCMS: m/z 394 (M+H).sup.+(ES.sup.+); 392 (MH).sup.(ES.sup.).

Example 75: 1-(4-Ethylmorpholin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt

[1225] ##STR00345##

[1226] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (4-ethylmorpholin-2-yl)methanesulfonamide (Intermediate P40) to afford the title compound (7 mg, 11%) as a white solid.

[1227] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 4.06 (s, 1H), 3.92-3.79 (m, 1H), 3.74-3.62 (m, 1H), 3.42 (dd, 2H), 3.22 (d, 2H), 2.83 (q, 9H), 2.46 (q, 2H), 2.21-1.86 (m, 5H), 1.11 (t, 3H).

[1228] LCMS: m/z 408 (M+H).sup.+(ES.sup.+); 406 (MH).sup.(ES.sup.).

Example 76: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(4-isopropylmorpholin-2-yl)methanesulfonamide, Potassium Salt

[1229] ##STR00346##

[1230] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (4-isopropylmorpholin-2-yl)methanesulfonamide (Intermediate P41) to afford the title compound (6 mg, 10%) as a white solid.

[1231] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 4.06 (s, 1H), 3.89 (d, 1H), 3.79-3.59 (m, 1H), 3.44 (dd, 2H), 3.21 (d, 1H), 2.83 (m, 10H), 2.38 (m, 1H), 2.28-2.12 (m, 1H), 2.03 (p, 4H), 1.22-1.00 (m, 6H).

[1232] LCMS: m/z 422 (M+H).sup.+(ES.sup.+); 420 (MH).sup.(ES.sup.).

Example 77: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-isopropyl-6-oxa-2-azaspiro[3.4]octan-7-yl)methanesulfonamide, Potassium Salt

[1233] ##STR00347##

[1234] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (2-isopropyl-6-oxa-2-azaspiro[3.4]octan-7-yl)methanesulfonamide (Intermediate P42) to afford the title compound (10 mg, 56%) as a white solid.

[1235] .sup.1H NMR (Methanol-d.sub.4) 6.89 (s, 1H), 4.47-4.22 (m, 1H), 3.98 (d, 1H), 3.89-3.67 (m, 5H), 3.55 (dd, 1H), 3.49-3.37 (m, 1H), 2.95 (m, 1H), 2.83 (m, 8H), 2.46 (td, 1H), 2.15 (dd, 1H), 2.10-1.85 (m, 4H), 1.08-0.99 (m, 6H).

[1236] LCMS: m/z 448 (M+H).sup.+(ES.sup.+); 446 (MH).sup.(ES.sup.).

Example 78: 3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)butane-1-sulfonamide, potassium salt

[1237] ##STR00348##

[1238] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(dimethylamino)butane-1-sulfonamide (Intermediate P43) to afford the title compound (3 mg, 10%) as a white solid.

[1239] .sup.1H NMR (Methanol-d.sub.4) 6.89 (s, 1H), 3.35 (m, 2H), 2.83 (m, 9H), 2.65 (s, 6H), 2.36-2.13 (m, 1H), 2.13-1.82 (m, 5H), 1.34-1.17 (m, 3H).

[1240] LCMS: m/z 380 (M+H).sup.+(ES.sup.+); 378 (MH).sup.(ES.sup.).

Example 79: 1-(2-Ethyl-6-oxa-2-azaspiro[3.4]octan-7-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt

[1241] ##STR00349##

[1242] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (2-ethyl-6-oxa-2-azaspiro[3.4]octan-7-yl)methanesulfonamide (Intermediate P44) to afford the title compound (8 mg, 30%) as a white solid.

[1243] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 4.36 (dd, 1H), 3.98 (d, 1H), 3.84 (dd, 1H), 3.69 (s, 3H), 3.53 (dd, 1H), 3.37 (d, 1H), 2.83 (m, 10H), 2.74-2.58 (m, 1H), 2.49 (dd, 1H), 2.23-2.12 (m, 1H), 2.04 (m, 4H), 1.03 (m, 3H).

[1244] LCMS: m/z 434 (M+H).sup.+(ES.sup.+); 432 (MH).sup.(ES.sup.).

Example 80: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-methyl-6-oxa-2-azaspiro[3.4]octan-7-yl)methanesulfonamide, Potassium Salt

[1245] ##STR00350##

[1246] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (2-methyl-6-oxa-2-azaspiro[3.4]octan-7-yl)methanesulfonamide (Intermediate P45) to afford the title compound (8 mg, 25%) as a white solid.

[1247] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 4.32 (p, 1H), 3.96 (d, 1H), 3.82 (d, 1H), 3.67-3.44 (m, 5H), 3.37 (m, 1H), 2.83 (m, 8H), 2.52-2.34 (m, 1H), 2.45 (s, 3H), 2.16-1.91 (m, 5H).

[1248] LCMS: m/z 420 (M+H).sup.+(ES.sup.+); 418 (MH).sup.(ES.sup.).

Example 81: 3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-2,2-dimethylpropane-1-sulfonamide, potassium salt

[1249] ##STR00351##

[1250] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(dimethylamino)-2,2-dimethylpropane-1-sulfonamide (Intermediate P46) to afford the title compound (7 mg, 15%) as a white solid.

[1251] .sup.1H NMR (Methanol-d.sub.4) 6.92 (s, 1H), 3.44 (s, 2H), 3.32 (m, 6H), 3.21 (s, 2H), 2.84 (m, 8H), 2.05 (m, 4H), 1.29 (s, 6H).

[1252] LCMS: m/z 394 (M+H).sup.+(ES.sup.+); 392 (MH).sup.(ES.sup.).

Example 82: 4-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)butane-1-sulfonamide, potassium salt

[1253] ##STR00352##

[1254] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4-(dimethylamino)butane-1-sulfonamide (Intermediate P47) to afford the title compound (18 mg, 27%) as a white solid.

[1255] .sup.1H NMR (Methanol-d.sub.4) 6.89 (s, 1H), 3.28 (m, 2H), 2.94 (t, 2H), 2.83 (m, 8H), 2.66 (s, 6H), 2.03 (m, 4H), 1.85 (m, 4H).

[1256] LCMS: m/z 380 (M+H).sup.+(ES.sup.+); 378 (MH).sup.(ES.sup.).

Example 83: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-methylpiperidin-3-yl)methanesulfonamide, Potassium Salt

[1257] ##STR00353##

[1258] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-methylpiperidin-3-yl)methanesulfonamide (Intermediate P48) to afford the title compound (19 mg, 11%) as a white solid.

[1259] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 3.29-3.06 (m, 2H), 3.01 (d, 2H), 2.83 (m, 9H), 2.55-2.29 (m, 1H), 2.30 (s, 3H), 2.16-1.82 (m, 5H), 1.82-1.57 (m, 2H), 1.31-1.13, 2H).

[1260] LCMS: m/z 392 (M+H).sup.+(ES.sup.+); 390 (MH).sup.(ES.sup.).

Example 84: 1-(1-Ethylpiperidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt

[1261] ##STR00354##

[1262] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-ethylpiperidin-3-yl)methanesulfonamide (Intermediate P49) to afford the title compound (45 mg, 28%) as a white solid.

[1263] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 3.26-3.11 (m, 2H), 3.00 (m, 3H), 2.83 (m, 9H), 2.74-2.29 (m, 2H), 2.04 (m, 4H), 1.97-1.55 (m, 3H), 1.34 (m, 1H), 1.28 (t, 3H), 1.13 (m, 1H).

[1264] LCMS: m/z 406 (M+H).sup.+(ES.sup.+); 404 (MH).sup.(ES.sup.).

Example 85: 1-((1S)-2-Amino-7,7-dimethylbicyclo[2.2.1]heptan-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, TFA Salt

[1265] ##STR00355##

[1266] Tert-butyl ((1S)-1-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl) methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)carbamate, potassium salt (Intermediate P50) (100 mg, 0.19 mmol) was stirred in DCM (0.3 mL) and TFA (0.3 mL) for 2.5 hours. Then the reaction mixture was concentrated and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method) to afford the title compound (1 mg, 1%) as a white solid.

[1267] .sup.1H NMR (Methanol-d.sub.4) 6.89 (s, 1H), 3.67-3.44 (m, 2H), 2.82 (m, 8H), 2.41 (m, 1H), 2.03 (m, 4H), 1.94-1.53 (m, 4H), 1.49-1.06 (m, 3H), 0.97 (m, 6H).

[1268] LCMS: m/z 432 (M+H).sup.+(ES.sup.+); 430 (MH).sup.(ES.sup.).

Example 86: 4-(Azetidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)butane-1-sulfonamide, Potassium Salt

[1269] ##STR00356##

[1270] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 4-(azetidin-1-yl)butane-1-sulfonamide (Intermediate P51) to afford the title compound (1 mg, 3%) as a white solid.

[1271] LCMS: m/z 392 (M+H).sup.+(ES.sup.+); 390 (MH).sup.(ES.sup.).

Example 87: 1-(Azetidin-1-ylmethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)cyclopropane-1-sulfonamide, potassium salt

[1272] ##STR00357##

[1273] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(azetidin-1-ylmethyl)cyclopropane-1-sulfonamide (Intermediate P52) to afford the title compound (15 mg, 37%) as a white solid.

[1274] .sup.1H NMR (Methanol-d.sub.4) 6.93 (s, 1H), 4.09 (m, 4H), 2.84 (m, 8H), 2.65 (s, 2H), 2.40 (m, 2H), 2.05 (m, 4H), 1.40 (s, 2H), 0.97 (s, 2H).

[1275] LCMS: m/z 390 (M+H).sup.+(ES.sup.+); 388 (MH).sup.(ES.sup.).

Example 88: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-1-yl)ethane-1-sulfonamide, Potassium Salt

[1276] ##STR00358##

[1277] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(pyrrolidin-1-yl)ethane-1-sulfonamide (Intermediate P53) to afford the title compound (25 mg, 20%) as a white solid.

[1278] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 3.46 (s, 2H), 3.09 (s, 2H), 2.81 (m, 12H), 2.03 (m, 4H), 1.86 (m, 4H).

[1279] LCMS: m/z 378 (M+H).sup.+(ES.sup.+); 376 (MH).sup.(ES.sup.).

Example 89: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylazetidin-1-yl)ethane-1-sulfonamide, Potassium Salt

[1280] ##STR00359##

[1281] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(2-methylazetidin-1-yl)ethane-1-sulfonamide (Intermediate P54) to afford the title compound (35 mg, 42%) as a white solid.

[1282] .sup.1H NMR (Methanol-d.sub.4) 6.91 (s, 1H), 4.21 (q, 1H), 3.90 (td, 1H), 3.84-3.63 (m, 2H), 3.56-3.33 (m, 3H), 2.84 (m, 8H), 2.52-2.30 (m, 1H), 2.18-1.95 (m, 5H), 1.45 (d, 3H).

[1283] LCMS: m/z 378 (M+H).sup.+(ES.sup.+); 376 (MH).sup.(ES.sup.).

Example 90: 2-(3-Fluoroazetidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethane-1-sulfonamide, Potassium Salt

[1284] ##STR00360##

[1285] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(3-fluoroazetidin-1-yl)ethane-1-sulfonamide (Intermediate P55) to afford the title compound (6 mg, 5%) as a white solid.

[1286] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.81-3.53 (m, 2H), 3.31 (m, 1H), 3.19-3.04 (m, 1H), 3.04-2.91 (m, 2H), 2.83 (s, 11H), 2.02 (m, 4H).

[1287] LCMS: m/z 382 (M+H).sup.+(ES.sup.+); 380 (MH).sup.(ES.sup.).

Example 91: 2-(Azetidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)propane-1-sulfonamide, Potassium Salt

[1288] ##STR00361##

[1289] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(azetidin-1-yl)propane-1-sulfonamide (Intermediate P56) to afford the title compound (21 mg, 20%) as a white solid.

[1290] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.58-3.38 (m, 4H), 3.07-2.93 (m, 2H), 2.83 (m, 9H), 2.05 (m, 6H), 1.22 (d, 3H).

[1291] LCMS: m/z 378 (M+H).sup.+(ES.sup.+); 376 (MH).sup.(ES.sup.).

Example 92: Methyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)propanoate, potassium salt

[1292] ##STR00362##

[1293] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and methyl 3-sulfamoylpropanoate (Intermediate P57) to afford the title compound (60 mg, 44%) as a white solid.

[1294] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.68 (s, 3H), 3.48 (t, 2H), 2.95-2.68 (m, 10H), 2.04 (m, 4H).

[1295] LCMS: m/z 367 (M+H).sup.+(ES.sup.+); 365 (MH).sup.(ES.sup.).

Example 43: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-isopropylpiperidin-3-yl)methanesulfonamide, Potassium Salt

[1296] ##STR00363##

[1297] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-isopropylpiperidin-3-yl)methanesulfonamide (Intermediate P58) to afford the title compound (34 mg, 34%) as a white solid.

[1298] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 3.58 (d, 1H), 3.25-3.06 (m, 2H), 2.83 (m, 10H), 2.77-2.50 (m 2H), 2.39 (m, 1H), 2.02 (m, 5H), 1.94-1.59 (m 2H), 1.33 (m, 1H), 1.25 (d, 6H).

[1299] LCMS: m/z 420 (M+H).sup.+(ES.sup.+); 418 (MH).sup.(ES.sup.).

Example 94: N-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)propyl)-3-methoxy-N-methylpropanamide, Potassium Salt

[1300] ##STR00364##

[1301] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-methoxy-N-methyl-N-(3-sulfamoylpropyl)propanamide (Intermediate P59) to afford the title compound (7 mg, 9%) as a white solid.

[1302] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.64 (m, 2H), 3.61-3.47 (m, 2H), 3.21 (m, 2H), 3.07 (s, 3H), 2.94 (s, 3H), 2.82 (m, 8H), 2.65 (m, 2H), 2.03 (m, 6H).

[1303] LCMS: m/z 438 (M+H).sup.+(ES.sup.+); 436 (MH).sup.(ES.sup.).

Example 95: N-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)propyl)-N-methylisobutyramide, Potassium Salt

[1304] ##STR00365##

[1305] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-methyl-N-(3-sulfamoylpropyl)isobutyramide (Intermediate P60) to afford the title compound (22 mg, 17%) as a white solid.

[1306] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.52 (q, 2H), 3.20 (dd, 1H), 3.09, 2.95 (d, 3H), 2.82 (m, 8H), 2.37 (dt, 2H), 2.02 (m, 7H), 1.62 (qd, 2H), 1.06-0.77 (m, 3H).

[1307] LCMS: m/z 422 (M+H).sup.+(ES.sup.+); 420 (MH).sup.(ES.sup.).

Example 96: N-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)propyl)-N-methylformamide, Potassium Salt

[1308] ##STR00366##

[1309] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N-methyl-N-(3-sulfamoylpropyl)formamide (Intermediate P61) to afford the title compound (29 mg, 13%) as a white solid.

[1310] .sup.1H NMR (Methanol-d.sub.4) 8.04 (d, 1H), 6.87 (s, 1H), 3.48 (td, 2H), 3.25-3.09 (m, 2H), 3.00, 2.95 (d, 3H), 2.95-2.70 (m, 8H), 2.03 (m, 6H).

[1311] LCMS: m/z 380 (M+H).sup.+(ES.sup.+); 378 (MH).sup.(ES.sup.).

Example 97: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N-dimethylpropanamide, Potassium Salt

[1312] ##STR00367##

[1313] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and N,N-dimethyl-3-sulfamoylpropanamide (Intermediate P62) to afford the title compound (19 mg, 41%) as a white solid.

[1314] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.58-3.38 (m, 2H), 3.09 (s, 3H), 2.93 (s, 3H), 2.83 (m, 10H), 2.02 (p, 4H).

[1315] LCMS: m/z 380 (M+H).sup.+(ES.sup.+); 378 (MH).sup.(ES.sup.).

Example 98: 3-(Benzyl(isopropyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propane-1-sulfonamide, potassium salt

[1316] ##STR00368##

[1317] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 3-(benzyl(isopropyl)amino)propane-1-sulfonamide (Intermediate P63) to afford the title compound (82 mg, 24%) as a white solid.

[1318] .sup.1H NMR (Methanol-d.sub.4) 7.55-7.16 (m, 5H), 6.89 (s, 1H), 3.59 (s, 2H), 3.28-3.17 (m, 1H), 3.12-3.00 (m, 2H), 2.81 (dt, 8H), 2.58 (t, 2H), 2.01 (m, 6H), 1.05 (d, 6H).

[1319] LCMS: m/z 470 (M+H).sup.+(ES.sup.+); 468 (MH).sup.(ES.sup.).

Example 99: Methyl (3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)propyl)(methyl)carbamate, potassium salt

[1320] ##STR00369##

[1321] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and methyl methyl(3-sulfamoylpropyl)carbamate (Intermediate P64) to afford the title compound (4 mg, 13%) as a white solid.

[1322] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.66 (s, 3H), 3.40 (t, 2H), 3.24-3.14 (m, 2H), 2.92 (s, 3H), 2.82 (m, 8H), 2.02 (p, 6H).

[1323] LCMS: m/z 410 (M+H).sup.+(ES.sup.+); 408 (MH).sup.(ES.sup.).

Example 100: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(isopropylamino)propane-1-sulfonamide, Potassium Salt

[1324] ##STR00370##

[1325] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(methylamino)propane-1-sulfonamide, potassium salt (Example 69), using 3-(benzyl(isopropyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propane-1-sulfonamide, potassium salt (Example 98) to afford the title compound (59 mg, 87%) as a white solid.

[1326] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 3.26-3.19 (m, 1H), 3.08 (m, 2H), 2.83 (m, 10H), 2.02 (td, 6H), 1.12 (d, 6H).

[1327] LCMS: m/z 380 (M+H).sup.+(ES.sup.+); 378 (MH).sup.(ES.sup.).

Example 101: 3-(Dimethylamino)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)propane-1-sulfonamide, potassium salt

[1328] ##STR00371##

[1329] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A10) and 3-(dimethylamino)propane-1-sulfonamide (Intermediate P65) to afford the title compound (10 mg, 24%) as a white solid.

[1330] .sup.1H NMR (Methanol-d.sub.4) 6.83 (d, 2H), 3.26 (m, 2H), 3.02 (t, 2H), 2.67 (s, 6H), 2.14 (m, 2H), 1.29 (m, 2H), 1.19 (d, 12H).

[1331] LCMS: m/z 388 (M+H).sup.+(ES.sup.+); 386 (MH).sup.(ES.sup.).

Example 102: 2-(2,2-Dimethylazetidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethane-1-sulfonamide, potassium salt

[1332] ##STR00372##

[1333] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(2,2-dimethylazetidin-1-yl)ethane-1-sulfonamide, TFA salt (Intermediate P66) to afford the title compound (66 mg, 56%) as a white solid.

[1334] .sup.1H NMR (Methanol-d.sub.4) 6.88 (s, 1H), 3.46 (t, 2H), 3.09 (dd, 2H), 2.83 (m, 10H), 2.03 (m, 6H), 1.38 (d, 6H).

[1335] LCMS: m/z 392 (M+H).sup.+(ES.sup.+); 390 (MH).sup.(ES.sup.).

Example 103: 2-(2,4-Dimethylazetidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethane-1-sulfonamide, potassium salt

[1336] ##STR00373##

[1337] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(2,4-dimethylazetidin-1-yl)ethane-1-sulfonamide, TFA salt (Intermediate P67) to afford the title compound (33 mg, 20%) as a white solid.

[1338] .sup.1H NMR (Methanol-d.sub.4) 6.89 (s, 1H), 3.51 (m, 2H), 3.12 (m, 4H), 2.84 (m, 8H), 2.06 (dt, 6H),1.26 (t, 6H).

[1339] LCMS: m/z 392 (M+H).sup.+(ES.sup.+); 390 (MH).sup.(ES.sup.).

Example 104: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-isopropylazetidin-1-yl)ethane-1-sulfonamide, Potassium Salt

[1340] ##STR00374##

[1341] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-(2-isopropylazetidin-1-yl)ethane-1-sulfonamide, TFA salt (Intermediate P68) to afford the title compound (17 mg, 11%) as a white solid.

[1342] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.45 (m, 1H), 3.26 (m, 1H), 3.03 (q, 2H), 2.83 (m, 11H), 2.15 (m, 1H), 2.03 (m, 4H), 1.95-1.68 (m, 2H), 0.95 (d, 3H), 0.82 (d, 3H).

[1343] LCMS: m/z 406 (M+H).sup.+(ES.sup.+); 404 (MH).sup.(ES.sup.).

Example 105: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-methylpyrrolidin-2-yl)methanesulfonamide, Potassium Salt

[1344] ##STR00375##

[1345] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-methylpyrrolidin-2-yl)methanesulfonamide (Intermediate P69) to afford the title compound (38 mg, 45%) as a white solid.

[1346] .sup.1H NMR (Methanol-d.sub.4) 6.87 (s, 1H), 3.71 (dd, 1H), 3.21-3.00 (m, 3H), 2.83 (m, 10H), 2.42 (d, 3H), 2.31 (m, 1H), 2.13-1.94 (m, 4H), 1.81 (m, 2H).

[1347] LCMS: m/z 378 (M+H).sup.+(ES.sup.+); 376 (MH).sup.(ES.sup.).

Example 106: 1-(1-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt

[1348] ##STR00376##

[1349] Prepare as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-ethylpyrrolidin-2-yl)methanesulfonamide (Intermediate P70) to afford the title compound (36 mg, 37%) as a white solid.

[1350] .sup.1H NMR (Methanol-d.sub.4) 6.89 (s, 1H), 3.78-3.56 (m, 1H), 3.26-3.14 (m, 3H), 2.94-2.75 (m, 10H), 2.60 (dt, 2H), 2.34 (m, 1H), 2.03 (m, 4H), 1.97-1.82 (m, 2H), 1.21 (td, 3H).

[1351] LCMS: m/z 392 (M+H).sup.+(ES.sup.+); 390 (MH).sup.(ES.sup.).

Example 107: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-isopropylpyrrolidin-2-yl)methanesulfonamide, Potassium Salt

[1352] ##STR00377##

[1353] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-isopropylpyrrolidin-2-yl)methanesulfonamide (Intermediate P71) to afford the title compound (101 mg, 40%) as a white solid.

[1354] .sup.1H NMR (Methanol-d.sub.4) 6.89 (s, 1H), 3.79-3.54 (m, 2H), 3.44 (q, 1H), 3.08 (dt, 1H), 2.94 (dd, 1H), 2.82 (m, 10H), 2.22 (ddt, 1H), 2.13-1.97 (m 4H), 1.89 (m 2H), 1.21 (ddd, 6H).

[1355] LCMS: m/z 406 (M+H).sup.+(ES.sup.+); 404 (MH).sup.(ES.sup.).

Example 108: 3-(Dimethylamino)-N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)propane-1-sulfonamide, potassium salt

[1356] ##STR00378##

[1357] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A9) and 3-(dimethylamino)propane-1-sulfonamide (Intermediate P65) to afford the title compound (15 mg, 34%) as a white solid.

[1358] .sup.1H NMR (Methanol-d.sub.4) 7.09 (d, 2H), 3.26 (m, 2H), 2.86 (t, 2H), 2.54 (s, 6H), 2.10 (m, 2H), 1.19 (d, 14H).

[1359] LCMS: m/z 404 (M+H).sup.+(ES.sup.+); 402 (MH).sup.(ES.sup.).

Example 109: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-isopropylpiperidin-2-yl)methanesulfonamide, Potassium Salt

[1360] ##STR00379##

[1361] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-isopropylpiperidin-2-yl)methanesulfonamide (Intermediate P72) to afford the title compound (11 mg, 8%) as a white solid.

[1362] .sup.1H NMR (Methanol-d.sub.4) 6.90 (s, 1H), 4.05 (m, 1H), 3.88-3.67 (m, 2H), 3.58 (dd, 1H), 3.04 (t, 1H), 2.83 (m, 9H), 2.23 (m, 1H), 2.03 (m, 5H), 1.81 (d, 3H), 1.62 (m, 1H), 1.33 (dd, 6H).

[1363] LCMS: m/z 420 (M+H).sup.+(ES.sup.+); 418 (MH).sup.(ES.sup.).

Example 110: 1-(1-Ethylpiperidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, potassium salt

[1364] ##STR00380##

[1365] Prepared as described for N-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)cyclohexyl)acetamide, potassium salt (Example 63) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and (1-ethylpiperidin-2-yl)methanesulfonamide (Intermediate P73) to afford the title compound (2 mg, 1%) as a white solid.

[1366] .sup.1H NMR (Methanol-d.sub.4) 6.89 (s, 1H), 4.07 (m, 1H), 3.79-3.48 (m, 2H), 3.21-2.99 (m, 3H), 2.83 (m, 9H), 2.03 (m, 6H), 1.74 (m, 3H), 1.59 (s, 1H), 1.26 (t, 3H).

[1367] LCMS: m/z 406 (M+H).sup.+(ES.sup.+); 404 (MH).sup.(ES.sup.).

[1368] Example 111: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-isopropyl-1H-pyrazol-3-yl)methanesulfonamide

##STR00381##

[1369] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-methyl-1H-pyrazol-4-yl)methanesulfonamide (Example 35) from (1-isopropyl-1H-pyrazol-3-yl)methanesulfonamide (Intermediate P74) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (14 mg, 24%) as a white solid.

[1370] .sup.1H NMR (DMSO-d6) 10.11 (s, 1H), 7.89 (s, 1H), 7.78 (d, J=2.3 Hz, 1H), 6.96 (s, 1H), 6.26 (d, J=2.3 Hz, 1H), 4.65 (s, 2H), 4.47 (sept, J=6.7 Hz, 1H), 2.82 (t, J=7.4 Hz, 4H), 2.74 (t, J=7.4 Hz, 4H), 1.99 (p, J=7.4 Hz, 4H), 1.40 (d, J=6.7 Hz, 6H).

[1371] LCMS; m/z 403.4 (M+H).sup.+(ES.sup.+).

Example 112: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-(pyridin-3-yl)methanesulfonamide

[1372] ##STR00382##

[1373] To a solution of pyridin-3-ylmethanesulfonamide (70 mg, 406.49 mol, 1 eq) in THF (5 mL) was added t-BuONa (39 mg, 406.49 mol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A3) (114 mg, 406.49 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%,11.5 min) to give the title compound (68 mg, 37% yield, 100% purity on LCMS) as a white solid.

[1374] .sup.1H NMR (DMSO-d.sub.6): 8.77 (d, 1H), 8.50 (d, 1H), 8.37 (s, 1H), 8.10 (s, 1H), 7.86 (br s, 1H), 7.79 (d, 1H), 7.61-7.45 (m, 1H), 7.33-7.27 (m, 2H), 7.19-7.02 (m, 1H), 4.31 (s, 2H), 3.24-3.18 (m, 1H) and 1.20-1.06 (m, 6H).

[1375] LCMS: m/z 454.3 (M+H).sup.+(ES.sup.+).

ExamplesBiological Studies

NLRP3 and Pyroptosis

[1376] 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-1) from the cell.

THP-1 Cells: Culture and Preparation

[1377] 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.6 cells/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

[1378] The following method step-by-step assay was followed for compound screening. [1379] 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) [1380] 2. Add 5 l compound (8 points half-log dilution, with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1381] 3. Incubate for 3 hrs at 37 C. in 5% CO.sub.2 [1382] 4. Add 5 l nigericin (Sigma # N7143) (FAC 5 M) to all wells [1383] 5. Incubate for 1 hr at 37 C. and 5% CO.sub.2 [1384] 6. At the end of the incubation period, spin plates at 300g for 3 mins and remove supernatant [1385] 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 [1386] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [1387] 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

[1388]

TABLE-US-00004 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

[1389] The results of the pyroptosis assay performed are summarised in Table 1 below as THP IC.sub.50.

Human Whole Blood IL1 Release Assay

[1390] 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.

[1391] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [1392] 1. Plate out 80 l of whole blood containing 1g/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [1393] 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 [1394] 3. Incubate for 3 hrs at 37 C., 5% CO.sub.2 [1395] 4. Add 10 l Nigericin (Sigma # N7143) (10 M FAC) to all wells [1396] 5. Incubate for 1 hr at 37 C., 5% CO.sub.2 [1397] 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) [1398] 7. IL-1 was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [1399] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[1400] The results of the human whole blood assay are summarised in Table 1 below as HWB IC.sub.50.

TABLE-US-00005 TABLE 1 NLRP3 inhibitory activity in THP-1 Cells EXAMPLE THP IC.sub.50 HWB IC.sub.50 1 +++ .circle-solid..circle-solid..circle-solid..circle-solid. 2 + ND 3 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 4 +++++ ND 5 +++ ND 6 + ND 7 +++ ND 8 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 9 + ND 10 ++++ ND 11 +++++ .circle-solid..circle-solid. 12 +++++ ND 13 +++++ .circle-solid..circle-solid..circle-solid. 14 +++++ .circle-solid..circle-solid..circle-solid. 15 ++ ND 16 ++ ND 17 +++ ND 18 + ND 19 +++ ND 20 +++++ .circle-solid..circle-solid..circle-solid. 21 ++++ ND 22 + ND 23 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 24 ++++ ND 25 + ND 26 + ND 27 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 28 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 29 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 30 +++++ .circle-solid..circle-solid..circle-solid. 31 +++++ .circle-solid..circle-solid..circle-solid. 32 +++++ ND 33 ++++ ND 34 +++++ .circle-solid..circle-solid..circle-solid. 35 +++++ .circle-solid..circle-solid..circle-solid. 36 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 37 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 38 + ND 39 + ND 40 + ND 41 +++++ ND 42 +++++ ND 43 +++++ ND 44 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 45 +++++ ND 46 + ND 47 +++++ ND 48 +++++ .circle-solid..circle-solid..circle-solid. 49 + ND 50 +++++ ND 51 +++++ ND 52 ++++ ND 53 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 54 + ND 55 + ND 56 + ND 57 + ND 58 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 59 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 60 + ND 61 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 62 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 63 + ND 64 + ND 65 + ND 66 + ND 67 +++++ .circle-solid. 68 ++++ ND 69 ++++ ND 70 +++++ .circle-solid..circle-solid..circle-solid. 71 +++++ .circle-solid. 72 +++ .circle-solid..circle-solid..circle-solid..circle-solid. 73 +++++ .circle-solid..circle-solid..circle-solid. 74 +++++ .circle-solid..circle-solid..circle-solid. 75 +++++ ND 76 +++ ND 77 + .circle-solid..circle-solid. 78 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 79 +++ ND 80 +++++ .circle-solid..circle-solid..circle-solid. 81 ++++ .circle-solid..circle-solid..circle-solid. 82 ++ .circle-solid..circle-solid..circle-solid. 83 ++++ .circle-solid..circle-solid..circle-solid..circle-solid. 84 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 85 + ND 86 + ND 87 ++ ND 88 +++ ND 89 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 90 +++++ .circle-solid..circle-solid..circle-solid. 91 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 92 +++++ .circle-solid..circle-solid. 93 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 94 ++ ND 95 +++++ .circle-solid..circle-solid..circle-solid. 96 ++++ ND 97 +++++ .circle-solid..circle-solid. 98 +++ ND 99 ++++ ND 100 ++++ ND 101 + ND 102 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 103 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 104 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 105 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 106 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 107 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 108 + ND 109 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 110 +++++ .circle-solid..circle-solid..circle-solid..circle-solid. 111 +++++ .circle-solid..circle-solid. 112 + ND (10 M = +, 2.0 M = ++, 1.6 M = +++, 1.2 M = +++, 0.8 M = ++++, 0.8 M = +++++, ND = not determined). NLRP3 inhibitory activity in HWB (10 M = .circle-solid., 7.5 M = .circle-solid..circle-solid., 5.0 M = .circle-solid..circle-solid..circle-solid., 1.0 M = .circle-solid..circle-solid..circle-solid..circle-solid., ND = not determined).

PK Protocol

[1401] Pharmacokinetic parameters were determined in male Sprague Dawley rats (Charles River, UK, 250-350 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.

[1402] 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 DMSO:water [10:90] in 5 mL/kg dosing volume and administered orally.

[1403] 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) or at each of 12 time-points post dose (0.03, 0.1, 0.17, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h) or pre-dose and at each of 9 time-points post dose (0.25, 0.5, 1, 2, 4, 6, 8, 12 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-00006 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/kg) 3 1 1181.1 1.5 0.79 14.2 8 1 2346.4 1.1 0.49 7.1 29 1 2776.5 1.3 0.53 6.0 37 1 591.0 0.9 0.55 28.2

TABLE-US-00007 TABLE 3 PK data (oral administration) Exam- AUC Cl/F ple Dose C.sub.max (ng .Math. T.sub.max T.sub.1/2 (mL/min/ Bioavail- No (mg/kg) (ng/mL) hr/mL) (hr) (hr) kg) ability 3 3 819.0 2271.3 0.42 1.8 22.6 64.1

[1404] 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.

[1405] 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.

[1406] 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.