NOVEL SULFONAMIDEUREA COMPOUNDS

Abstract

The present invention relates to compounds of formula (I): wherein Q is selected from O or S; R.sup.1 and R.sup.3 are each independently hydrogen or an optionally substituted hydrocarbyl group, or R.sup.1 and R.sup.3 together with the nitrogen atom to which they are attached may form a 3- to 12-membered optionally substituted cyclic group; and R.sup.2 is a cyclic group substituted at the position, wherein R.sup.2 may optionally be further substituted. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP3.

##STR00001##

Claims

1. A compound of formula (I): ##STR00244## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is selected from O or S; R.sup.1 and R.sup.3 are each independently hydrogen or a saturated or unsaturated 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 R.sup.1 and R.sup.3 together with the nitrogen atom to which they are attached may form a 3- to 12-membered cyclic group, wherein the cyclic group may optionally be substituted; and R.sup.2 is a cyclic group substituted at the α-position, wherein R.sup.2 may optionally be further substituted.

2. 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 α-position, and wherein R.sup.2 may optionally be further substituted.

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

4. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 3, 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 α,β positions and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α′,β′ positions, and wherein R.sup.2 may optionally be further substituted.

5. 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 α-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 α-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.

6. 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 α and α′ positions, wherein R.sup.2 may optionally be further substituted.

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

8. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, selected from the group consisting of: ##STR00245## ##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260##

9. (canceled)

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

11. (canceled)

12. 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.

13. The method as claimed in claim 12, wherein the disease, disorder or condition is selected from: (i) inflammation; (ii) an auto-immune disease; (iii) cancer; (iv) an infection; (v) a central nervous system disease; (vi) a metabolic disease; (vii) a cardiovascular disease; (viii) a respiratory disease; (ix) a liver disease; (x) a renal disease; (xi) an ocular disease; (xii) a skin disease; (xiii) a lymphatic condition; (xiv) a psychological disorder; (xv) graft versus host disease; (xvi) allodynia; and (xvii) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

14. The method as claimed in claim 12, 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).

15. (canceled)

16. The method as claimed in claim 12, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

17. 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.

18. 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

EXAMPLES—COMPOUND SYNTHESIS

[0479] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0480] 2-MeTHF 2-methyltetrahydrofuran [0481] Ac.sub.2O acetic anhydride [0482] AcOH acetic acid [0483] aq aqueous [0484] B.sub.2Pin.sub.2 bis(pinacolato)diboron [0485] Boc tert-butyloxycarbonyl [0486] br broad [0487] Cbz carboxybenzyl [0488] CDI 1,1-carbonyl-diimidazole [0489] conc concentrated [0490] d doublet [0491] DABCO 1,4-diazabicyclo[2.2.2]octane [0492] DCE 1,2-dichloroethane, also called ethylene dichloride [0493] DCM dichloromethane [0494] DIPEA N,N-diisopropylethylamine, also called Hünig's base [0495] DMA dimethylacetamide [0496] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0497] DME dimethoxyethane [0498] DMF N,N-dimethylformamide [0499] DMSO dimethyl sulfoxide [0500] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0501] eq or equiv equivalent [0502] (ES.sup.+) electrospray ionization, positive mode [0503] Et ethyl [0504] EtOAc ethyl acetate [0505] EtOH ethanol [0506] h hour(s) [0507] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0508] HPLC high performance liquid chromatography [0509] LC liquid chromatography [0510] m multiplet [0511] m-CPBA 3-chloroperoxybenzoic acid [0512] Me methyl [0513] MeCN acetonitrile [0514] MeOH methanol [0515] (M+H).sup.+ protonated molecular ion [0516] MHz megahertz [0517] min minute(s) [0518] MS mass spectrometry [0519] Ms mesyl, also called methanesulfonyl [0520] MsCl mesyl chloride, also called methanesulfonyl chloride [0521] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0522] m/z mass-to-charge ratio [0523] NaOtBu sodium tert-butoxide [0524] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0525] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0526] NMP N-methylpyrrolidine [0527] NMR nuclear magnetic resonance (spectroscopy) [0528] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone) dipalladium(0) [0529] Pd(dppf)Cl.sub.2 [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [0530] PE petroleum ether [0531] Ph phenyl [0532] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0533] prep-HPLC preparative high performance liquid chromatography [0534] prep-TLC preparative thin layer chromatography [0535] PTSA p-toluenesulfonic acid [0536] q quartet [0537] RP reversed phase [0538] RT room temperature [0539] s singlet [0540] sat saturated [0541] SCX solid supported cation exchange (resin) [0542] sept septuplet [0543] t triplet [0544] T3P propylphosphonic anhydride [0545] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0546] TEA triethylamine [0547] TFA 2,2,2-trifluoroacetic acid [0548] THF tetrahydrofuran [0549] TLC thin layer chromatography [0550] wt % weight percent or percent by weight [0551] Xphos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Experimental Methods

[0552] Nuclear Magnetic Resonance

[0553] NMR spectra were recorded at 300, 400 or 500 MHz. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Spectra were recorded using one of the following machines: [0554] a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe, [0555] a Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control, [0556] a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™, [0557] 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, or [0558] an Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

[0559] LC-MS

[0560] 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 2.1×30 mm, 5 μm.

[0561] Reversed Phase HPLC Conditions for the LCMS Analytical Methods

[0562] Methods 1a and 1b: Waters Xselect CSH C18 XP column (4.6×30 mm, 2.5 μm) at 40° C.; flow rate 2.5-4.5 mL min.sup.−1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 1a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 1b) over 4 min 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.

[0563] Method 1c: Agilent 1290 series with UV detector and HP 6130 MSD mass detector using Waters XBridge BEH C18 XP column (2.1×50 mm, 2.5 μm) at 35° C.; flow rate 0.6 mL/min; 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); over 4 min employing UV detection at 215 and 238 nm. Gradient information: 0-0.5 min, held at 80% A-20% B; 0.5-2.0 min, ramped from 80% A-20% B to 100% B.

[0564] Reversed Phase HPLC Conditions for the UPLC Analytical Methods

[0565] Methods 2a and 2b: Waters BEH C18 (2.1×30 mm, 1.7 μm) 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.

[0566] Preparative Reversed Phase HPLC General Methods

[0567] Method 1 (acidic preparation): Waters X-Select CSH column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a H.sub.2O-MeCN gradient containing 0.1% v/v formic acid over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 20% MeCN; 0.2-5.5 min, ramped from 20% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0568] Method 2 (basic preparation): Waters X-Bridge Prep column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 10% MeCN; 0.2-5.5 min, ramped from 10% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0569] Method 3: Phenomenex Gemini column, 10 μm (150×25 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.

[0570] Method 4: Revelis C18 reversed-phase 12 g cartridge [carbon loading 18%; surface area 568 m.sup.2/g; pore diameter 65 Angstrom; pH (5% slurry) 5.1; average particle size 40 μm], flow rate=30 mL/min eluting with a water-methanol gradient over 35 minutes using UV detection at 215, 235, 254 and 280 nm. Gradient information: 0-5 minutes, held at 0% methanol; 5-30 minutes, ramped from 0% to 70% methanol; 30-30.1 minutes, ramped from 70% to 100% methanol; 30.1-35 minutes, held at 100% methanol.

[0571] Synthesis of Intermediates

Intermediate A1: 7-Fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

Step A: N-(7-Fluoro-2,3-dihydro-1H-inden-4-yl)pivalamide

[0572] ##STR00053##

[0573] To an ice-cooled solution of N-(2,3-dihydro-1H-inden-4-yl)pivalamide (2.5 g, 11.50 mmol) in dry dichloromethane (50 mL) was added pyridine hydrofluoride (9 ml, 69.9 mmol). The pale yellow mixture was stirred for 30 minutes at 0° C. A solution of bis(tert-butylcarbonyloxy)iodobenzene (7.5, 17.91 mmol) in dichloromethane (10 mL) was then slowly added over 10 minutes to the mixture. The reaction was slowly allowed to reach room temperature and stirred overnight. It was then quenched with triethylamine (0.5 ml, 3.58 mmol) and the whole mixture was absorbed onto silica gel and purified by chromatography on silica gel (120 g column, 0-30% EtOAc/isohexane) to afford the title compound (0.635 g, 22%) as a yellow crystalline solid.

[0574] .sup.1H NMR (CDCl.sub.3) δ 7.68 (dd, J=8.8, 4.5 Hz, 1H), 7.14 (s, 1H), 6.87 (t, J=8.6 Hz, 1H), 3.01 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.18 (p, J=7.5 Hz, 2H), 1.34 (s, 9H).

[0575] LCMS m/z 236.3 (M+H).sup.+ (ES.sup.+); 234.2 (M−H).sup.− (ES.sup.−).

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

[0576] ##STR00054##

[0577] N-(7-Fluoro-2,3-dihydro-1H-inden-4-yl)pivalamide (0.632 g, 2.69 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) over the weekend. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and then basified with 2M aq. NaOH. The mixture was extracted with dichloromethane (3×100 mL). The combined organics were washed, dried by passing through a hydrophobic frit and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-30% EtOAc/isohexane) to afford the title compound (350 mg, 82%) as a pale pink oil that solidified on standing.

[0578] .sup.1H NMR (CDCl.sub.3) δ 6.71 (dd, J=9.0, 8.2 Hz, 1H), 6.46 (dd, J=8.5, 3.9 Hz, 1H), 3.45 (s, 2H), 2.96 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.16 (p, J=7.6 Hz, 2H).

[0579] LCMS m/z 152.3 (M+H).sup.+ (ES.sup.+).

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

[0580] ##STR00055##

[0581] 7-Fluoro-2,3-dihydro-1H-inden-4-amine (345 mg, 2.282 mmol) was dissolved in dichloromethane (10 mL). NBS (450 mg, 2.53 mmol) was added at room temperature in a single portion. The mixture turned dark brown immediately and was stirred for 15 minutes at room temperature. The reaction mixture was partitioned between dichloromethane and 1M aq. NaOH (20 mL) and stirred for 15 minutes. The organic phase was separated and washed with brine (10 mL), and then dried by passing through a hydrophobic frit. The solvent was removed in vacuo to give a dark brown oil. The crude product was purified by chromatography on silica gel (24 g column, 0-20% EtOAc/isohexane) to afford the title compound (323 mg, 55%) as a dark purple oil.

[0582] .sup.1H NMR (CDCl.sub.3) δ 7.08 (d, J=7.8 Hz, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.95 (t, J=7.5 Hz, 2H), 2.20 (p, J=7.6 Hz, 2H), NH.sub.2 not observed.

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

[0583] ##STR00056##

[0584] 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (320 mg, 1.391 mmol) was dissolved in dioxane (5 mL). A solution of potassium carbonate (600 mg, 4.34 mmol) in water (1 mL) and solid (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.2Cl.sub.2 (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80° C. (bath temperature) for 24 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 (0.185 g, 49%) as a pale brown oil that crystallized on standing.

[0585] .sup.1H NMR (CDCl.sub.3) δ 8.27 (d, J=5.4 Hz, 1H), 7.06 (d, J=5.3 Hz, 1H), 6.95 (s, 1H), 6.73 (d, J=9.0 Hz, 1H), 4.03 (s, 3H), 3.00 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.23 (p, J=7.5 Hz, 2H), NH.sub.2 not observed.

[0586] LCMS m/z 259.3 (M+H).sup.+ (ES.sup.+).

Intermediate A2: 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

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

[0587] ##STR00057##

[0588] 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 (2×10 mL), water (2×10 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.

[0589] LCMS m/z 296.3/298.3 (M+H).sup.+ (ES.sup.+).

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

[0590] ##STR00058##

[0591] 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 (3×20 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%).

[0592] .sup.1H NMR (CDCl.sub.3) δ 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

[0593] ##STR00059##

[0594] 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.2Cl.sub.2 (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.

[0595] .sup.1H NMR (CDCl.sub.3) δ 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.

[0596] LCMS m/z 241.3 (M+H).sup.+ (ES.sup.+).

Intermediate A3: 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

[0597] ##STR00060##

[0598] To a solution of phosgene (4.45 mL, 20% weight in toluene, 8.4 mmol) in EtOAc (90 mL) was added drop-wise a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in EtOAc (45 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 3 hours and upon cooling was filtered and concentrated in vacuo to afford the title compound as a brown oil (756 mg, 100%). The crude product was used directly in the next step without further purification.

[0599] .sup.1H NMR (CDCl.sub.3) δ 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m, 4H).

Intermediate A4: ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl chloride

[0600] ##STR00061##

[0601] A stirred solution of chlorosulfonyl isocyanate (0.53 ml, 6.1 mmol) in tert-butyl methyl ether (10 mL) was cooled to −20° C., then a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (1 g, 5.8 mmol) in tert-butyl methyl ether (20 mL) was added slowly over 10 minutes. The reaction was stirred for 1 hour at −20° C. and then allowed to reach room temperature overnight. Subsequently most of the solvent was removed in vacuo and the material was dried overnight to afford the crude title compound (1.5 g, 82%), which was used without additional purification.

[0602] .sup.1H NMR (CDCl.sub.3) δ 7.95 (s, 1H), 7.10 (s, 1H), 2.93 (t, J=7.5 Hz, 4H), 2.86 (t, 4H), 2.11 (m, 4H).

Intermediate A5: 1,2,3,5-Tetrahydro-s-indacen-4-amine

Step A: 4-Nitro-1,2,3,5-tetrahydro-s-indacene

[0603] ##STR00062##

[0604] To a suspension of 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-ol (174 mg, 0.794 mmol) in anhydrous toluene (2 mL) were added 3 molecular sieves 3A and p-toluenesulfonic acid monohydrate (29 mg, 0.151 mmol). The reaction mixture was refluxed for 1.5 hours, and then diluted with EtOAc and washed with saturated aq. NaHCO.sub.3 (5 mL) and brine (5 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (heptane: EtOAc) to afford the title compound (92 mg, 59%) as a yellow solid.

[0605] .sup.1H NMR (CDCl.sub.3) δ 7.50 (s, 1H), 6.85 (m, 1H), 6.66 (m, 1H), 3.83 (s, 2H), 3.38 (t, 2H), 3.02 (t, 2H), 2.18 (m, 2H).

Step B: 1,2,3,5-Tetrahydro-s-indacen-4-amine

[0606] ##STR00063##

[0607] To a solution of 4-nitro-1,2,3,5-tetrahydro-s-indacene (85 mg, 42 mmol) in a 1/0.6/0.4 mixture of 1,4-dioxane/EtOH/H.sub.2O (11.9 mL) was added Fe (144.5 mg, 2.55 mmol) and ammonium chloride (110.5 mg, 2.12 mmol). The reaction mixture was stirred at reflux for 1 hour, and then filtered through a plug of Celite® and concentrated under reduced pressure. The residue was purified by flash column chromatography (heptane:EtOAc) to afford the title compound (29 mg, 40%) as a yellow solid.

[0608] .sup.1H NMR (CDCl.sub.3) δ 6.94 (s, 1H), 6.82 (m, 1H), 6.50 (m, 1H), 3.32 (d, 2H), 2.92 (dd, 4H), 2.17 (q, 2H).

Intermediate A6: 6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

Step A: N-(6-Bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide

[0609] ##STR00064##

[0610] Nitric acid (150 mL, 2350 mmol) was slowly added to sulfuric acid (150 mL) cooled to 0° C., while keeping the temperature below 20° C. The mixture was stirred for 10 minutes and then added dropwise to a stirred mixture of N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide (58 g, 228 mmol) in AcOH (300 mL) and sulfuric acid (150 mL), while keeping the temperature below 30° C. The mixture was stirred at room temperature for 4 hours and then poured onto ice/water (4.5 L total volume, 2.5 kg ice) and left to stand at room temperature for 18 hours. The solid was filtered, washed with water (2.5 L) and dried to afford the title compound (55 g, 80%) as an ochre powder.

[0611] .sup.1H NMR (DMSO-d6) δ 9.99 (s, 1H), 7.85 (s, 1H), 3.01-2.88 (m, 4H), 2.07 (p, J=7.5 Hz, 2H), 2.00 (s, 3H).

[0612] LCMS m/z 299.0/301.0 (M+H).sup.+ (ES.sup.+).

Step B: N-(6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide

[0613] ##STR00065##

[0614] A mixture of N-(6-bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (30 g, 100 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (14.02 mL, 100 mmol) and K.sub.2CO.sub.3 (34.7 g, 251 mmol) in dioxane (500 mL) and H.sub.2O (140 mL) was degassed with N.sub.2 for 15 minutes. Then PdCl.sub.2(dppf).DCM (4.10 g, 5.01 mmol) was added and the reaction was heated at 100° C. for 16 hours, diluted with brine (300 mL) and extracted with EtOAc (2×800 mL). The organic layers were dried (MgSO.sub.4) and evaporated. The residue was triturated with EtOAc/isohexanes (1:1 mixture, 400 mL) and the resultant solid was filtered, rinsing with hexanes, and dried in vacuo to afford the title compound (15.33 g, 56%) as a brown solid.

[0615] .sup.1H NMR (DMSO-d6) δ 9.65 (s, 1H), 7.41 (s, 1H), 2.98-2.87 (m, 4H), 2.20 (s, 3H), 2.07-2.03 (m, 2H), 1.99 (s, 3H).

[0616] LCMS m/z 235.2 (M+H).sup.+ (ES.sup.+).

Step C: 6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-amine

[0617] ##STR00066##

[0618] N-(6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (15.33 g, 65.4 mmol) was suspended in a mixture of EtOH (126 mL) and concentrated aqueous HCl (126 mL). The mixture was heated to reflux overnight and concentrated in vacuo. The residue was basified by portionwise addition of 2M aq NaOH (˜500 mL). The aqueous layer was extracted with DCM (5×200 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (15.18 g, 84%) as a brown solid.

[0619] .sup.1H NMR (DMSO-d6) δ 7.21 (s, 1H), 6.61 (s, 2H), 3.16 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.16 (s, 3H), 2.00-1.94 (m, 2H).

[0620] LCMS m/z 193.4 (M+H).sup.+ (ES.sup.+).

Step D: 5-Bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene

[0621] ##STR00067##

[0622] A solution of 6-methyl-4-nitro-2,3-dihydro-1H-inden-5-amine (4.9 g, 20.39 mmol) and isopentyl nitrite (3 mL, 22.33 mmol) in MeCN (400 mL) was heated to 55° C., whereupon CuBr.sub.2 (4.56 g, 20.39 mmol) was added. The mixture was heated to 70° C. and stirred for 1 hour. Then the reaction was allowed to cool to room temperature and 1M HCl (200 mL) was added. The reaction mixture was extracted with DCM (3×200 mL). The organic phases were concentrated in vacuo and the crude product was purified by chromatography on silica gel (220 g column, 0-20% EtOAc/isohexane) to afford the title compound (3.2 g, 60%) as a pale yellow solid.

[0623] .sup.1H NMR (DMSO-d6) δ 7.50 (s, 1H), 2.94-2.86 (m, 4H), 2.41 (s, 3H), 2.09 (p, J=7.6 Hz, 2H).

[0624] LCMS m/z 279.2 (M+Na)+(ES.sup.+).

Step E: 4-Bromo-2-((1-methylpiperidin-4-yl)oxy)pyridine

[0625] ##STR00068##

[0626] 1-Methylpiperidin-4-ol (0.75 g, 6.51 mmol) was added to a mixture of KO.sup.tBu (0.96 g, 8.56 mmol) in THF (10 mL) at room temperature. The mixture was stirred for 1 hour, cooled to 0° C. and then a solution of 4-bromo-2-fluoropyridine (1.00 g, 5.68 mmol) in THF (5 mL) was added. The mixture was warmed to room temperature, stirred for 22 hours, and then partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with water (50 mL), dried (MgSO.sub.4) and evaporated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (1.43 g, 76%) as a pale yellow oil.

[0627] .sup.1H NMR (DMSO-d6) δ 8.05 (d, J=5.5 Hz, 1H), 7.19 (dd, J=5.5, 1.7 Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 5.12-4.86 (m, 1H), 2.71-2.56 (m, 2H), 2.21-2.08 (m, 5H), 1.99-1.86 (m, 2H), 1.76-1.59 (m, 2H).

[0628] LCMS m/z 271.0/273.0 (M+H).sup.+ (ES.sup.+).

Step F: 4-(6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)-2-((1-methylpiperidin-4-yl)oxy)pyridine

[0629] ##STR00069##

[0630] To a solution of 4-bromo-2-((1-methylpiperidin-4-yl)oxy)pyridine (step E) (2.485 g, 9.17 mmol) in dioxane (42 mL) was added B.sub.2Pin.sub.2 (2.56 g, 10.08 mmol) followed by KOAc (3.60 g, 36.7 mmol). The reaction mixture was heated to 60° C. and degassed with N.sub.2. PdCl.sub.2(dppf).DCM (0.374 g, 0.458 mmol) was added to the reaction mixture and the temperature was increased to 100° C. for 2 hours. 5-Bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene (step D) (2.42 g, 9.17 mmol) was added, followed by a solution of K.sub.2CO.sub.3 (5.07 g, 36.7 mmol) in water (10 mL). The solution was stirred at 100° C. for 1 hour, cooled to room temperature, filtered through a plug of Celite®, diluted with EtOAc (200 mL) and washed with brine (100 mL). The organic layers were dried (MgSO.sub.4), concentrated in vacuo and purified by chromatography on silica gel (120 g column, 0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (1.88 g, 51 20%) as a brown gum.

[0631] .sup.1H NMR (DMSO-d6) δ 8.20 (d, J=5.2 Hz, 1H), 7.49 (s, 1H), 6.81 (dd, J=5.2, 1.5 Hz, 1H), 6.60 (s, 1H), 5.07-4.85 (m, 1H), 3.03-2.89 (m, 4H), 2.74-2.57 (m, 2H), 2.25-2.03 (m, 9H), 2.04-1.95 (m, 3H), 1.75-1.59 (m, 2H).

[0632] LCMS m/z 368.3 (M+H).sup.+ (ES.sup.+).

Step G: 6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0633] ##STR00070##

[0634] A mixture of 4-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)-2-((1-methylpiperidin-4-yl)oxy)pyridine (1.88 g, 4.66 mmol) and 5% Pd—C(Type 87L, 58-5% moisture) (0.478 g, 0.093 mmol) in EtOH (30 mL) was hydrogenated at 1 bar for 22 hours. The mixture was filtered through a pad of Celite®, rinsing with MeOH (2×30 mL). The filtrate was concentrated in vacuo to afford the title compound (1.70 g, 94%) as a sticky brown tar.

[0635] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J=5.1 Hz, 1H), 6.73 (dd, J=5.2, 1.4 Hz, 1H), 6.55-6.47 (m, 1H), 6.45 (s, 1H), 5.01 (tt, J=8.8, 4.2 Hz, 1H), 4.14 (s, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.74-2.58 (m, 4H), 2.27-2.09 (m, 5H), 2.06-1.93 (m, 4H), 1.88 (s, 3H), 1.76-1.63 (m, 2H).

[0636] LCMS m/z 338.2 (M+H).sup.+ (ES.sup.+).

Intermediate A7: 5-(2-Methoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

Step A: 2-Methoxy-4-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)pyridine

[0637] ##STR00071##

[0638] A mixture of 5-bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene (Intermediate A6, Step D) (910 mg, 3.55 mmol) and (2-methoxypyridin-4-yl)boronic acid (652 mg, 4.26 mmol) was dissolved in dioxane (20 mL) and a solution of K.sub.2CO.sub.3 (1473 mg, 10.66 mmol) in water (4 mL) was added. The reaction mixture was degassed with N.sub.2 for 15 minutes. Pd(dppf)Cl.sub.2.DCM (290 mg, 0.355 mmol) was added and the reaction mixture was heated to 80° C. for 4 hours. The reaction was cooled to room temperature and partitioned between EtOAc (100 mL) and brine (50 mL). The organic layers were concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-20% EtOAc/isohexane) to afford the title compound (888 mg, 83%) as a yellow oil.

[0639] .sup.1H NMR (DMSO-d6) δ 8.24 (d, J=5.2 Hz, 1H), 7.51 (s, 1H), 6.86 (dd, J=5.3, 1.4 Hz, 1H), 6.68-6.66 (m, 1H), 3.89 (s, 3H), 3.04-2.90 (m, 4H), 2.17-2.04 (m, 5H).

[0640] LCMS m/z 285.0 (M+H).sup.+ (ES.sup.+).

Step B: 5-(2-Methoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

[0641] ##STR00072##

[0642] A mixture of 2-methoxy-4-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)pyridine (186 mg, 0.536 mmol) and 5% Pd—C(Type 87L, 58-5% moisture) (55 mg, 10.72 μmol) in EtOH (2 mL) was hydrogenated at 1 bar for 6 hours. Then the mixture was filtered through Celite® and evaporated to afford the title compound (120 mg, 77%) as a solid.

[0643] .sup.1H NMR (DMSO-d6) δ 8.24 (d, J=5.2 Hz, 1H), 6.77 (dd, J=5.2, 1.5 Hz, 1H), 6.58 (s, 1H), 6.45 (s, 1H), 4.16 (s, 2H), 3.89 (s, 3H), 2.78 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.4 Hz, 2H), 1.99 (p, J=7.4 Hz, 2H), 1.88 (s, 3H).

[0644] LCMS m/z 255.1 (M+H).sup.+ (ES.sup.+).

Intermediate A8: 4-Isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-amine

Step A: 2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0645] ##STR00073##

[0646] To a solution of NaH (9.74 g, 243.59 mmol, 60 wt % in mineral oil, 1 eq) in DMF (200 mL) was added in portions 2-methyl-1H-imidazole (20 g, 243.59 mmol, 1 eq) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. Then (2-(chloromethoxy)ethyl) trimethylsilane (48.73 g, 292.31 mmol, 1.2 eq) was added. The resulting mixture was stirred at 0° C. for 2 hours. The reaction mixture was quenched with ice-water (300 mL), diluted with ethyl acetate (1 L), and washed with saturated aqueous NH.sub.4C1 solution (3×300 mL) and brine (3×300 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 5:1 to 1:1) to give the title compound (40 g, 76% yield, 98% purity on LCMS) as a yellow oil.

[0647] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.90 (s, 2H), 5.18 (s, 2H), 3.47 (t, 2H), 2.43 (s, 3H), 0.89 (t, 2H) and 0.01 (s, 9H).

[0648] LCMS: m/z 213.0 (M+H).sup.+ (ES.sup.+).

Step B: 4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0649] ##STR00074##

[0650] To a solution of 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (20 g, 94.18 mmol, 1 eq) in DMF (200 mL) was added NBS (16.76 g, 94.18 mmol, 1 eq) at −20° C. Then the reaction mixture was stirred at −20° C. for 2 hours. The reaction mixture was quenched with saturated aqueous Na.sub.2SO.sub.3 solution (100 mL), diluted with EtOAc (200 mL), and washed with saturated aqueous NH.sub.4Cl solution (3×100 mL) and brine (3×100 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 10:1 to 5:1) to give the title compound (13.5 g, 41% yield, 84% purity on LCMS) as a yellow oil.

[0651] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.88 (s, 1H), 5.25 (s, 2H), 3.55 (t, 2H), 2.42 (s, 3H), 0.91 (t, 2H) and 0.02 (s, 9H).

[0652] LCMS: m/z 292.9 (M+H).sup.+ (ES.sup.+).

Step C: 2-Methyl-4-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0653] ##STR00075##

[0654] A solution of 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (10 g, 28.84 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.33 g, 31.72 mmol, 1.1 eq), Pd(dppf)Cl.sub.2 (1.06 g, 1.44 mmol, 0.05 eq) and Na.sub.2CO.sub.3 (6.11 g, 57.68 mmol, 2 eq) in dioxane (100 mL) and H.sub.2O (20 mL) was stirred at 100° C. for 12 hours under N.sub.2. The reaction mixture was diluted with water (100 mL), and then extracted with ethyl acetate (3×100 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 5:1 to 1:1) to give the title compound (7 g, 96%) as a yellow oil.

[0655] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.88 (s, 1H), 5.23 (s, 2H), 5.20 (s, 1H), 5.14 (s, 1H), 3.52 (t, 2H), 2.48 (s, 3H), 2.08 (s, 3H), 0.93 (t, 2H) and 0.01 (s, 9H).

[0656] LCMS: m/z 253.0 (M+H).sup.+ (ES.sup.+).

Step D: 4-Isopropyl-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0657] ##STR00076##

[0658] To a solution of 2-methyl-4-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (7.18 g, 28.44 mmol, 1 eq) in MeOH (100 mL) was added Pd/C (700 mg, 10 wt % loading on activated carbon) under N.sub.2. The suspension was degassed in vacuo and purged with H.sub.2 several times. The mixture was stirred at 25° C. for 12 hours under H.sub.2 (15 psi). Then the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (8 g, 99% yield, 90% purity on LCMS) as a yellow oil.

[0659] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.66 (s, 1H), 5.15 (s, 2H), 3.49 (t, 2H), 2.95-2.84 (m, 1H), 2.43 (s, 3H), 1.26 (d, 6H), 0.91 (t, 2H) and 0.02 (s, 9H).

[0660] LCMS: m/z 255.2 (M+H).sup.+ (ES.sup.+).

Step E: 4-Isopropyl-2-methyl-1H-imidazole

[0661] ##STR00077##

[0662] To a solution of 4-isopropyl-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (8 g, 31.44 mmol, 1 eq) in DCM (80 mL) was added TFA (123.20 g, 1.08 mol, 34.37 eq) at 25° C. Then the mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched with ice-water (10 mL) and saturated aqueous NaHCO.sub.3 solution (300 mL). The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, ethyl acetate: methanol, 1:0 to 20:1) to give the title compound (3.7 g, 95%) as a yellow oil.

[0663] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.71 (s, 1H), 2.99-2.93 (m, 1H), 2.53 (s, 3H) and 1.27 (d, 6H).

[0664] LCMS: m/z 125.3 (M+H).sup.+ (ES.sup.+).

Step F: 4-(4-Isopropyl-2-methyl-1H-imidazol-1-yl)pyridine

[0665] ##STR00078##

[0666] To a solution of 4-isopropyl-2-methyl-1H-imidazole (1.4 g, 11.27 mmol, 1 eq) and 4-iodopyridine (1.85 g, 9.02 mmol, 0.8 eq) in DMF (14 mL) was added with Cu.sub.2O (81 mg, 563.68 μmol, 0.05 eq) and Cs.sub.2CO.sub.3 (7-35 g, 22.55 mmol, 2 eq). The reaction mixture was stirred at 100° C. for 15 hours. Then the reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated aqueous NH.sub.4Cl solution (3×30 mL) and brine (3×30 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 5:1 to 0:1) to give the title compound (600 mg, 26% yield, 97% purity on LCMS) as a yellow solid.

[0667] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.73 (dd, 2H), 7.27 (dd, 2H), 6.77 (s, 1H), 2.93-2.86 (m, 1H), 2.48 (s, 3H) and 1.29 (d, 6H).

[0668] LCMS: m/z 202.0 (M+H).sup.+ (ES.sup.+).

Step G: 4-(4-Isopropyl-2-methyl-5-nitro-1H-imidazol-1-yl)pyridine

[0669] ##STR00079##

[0670] To a solution of 4-(4-isopropyl-2-methyl-1H-imidazol-1-yl)pyridine (400 mg, 1.93 mmol, 1 eq) in H.sub.2SO.sub.4 (71.33 mmol, 3.88 mL, 98% purity in solution, 37 eq) was added with HNO.sub.3 (5.78 mmol, 400 μL, 65% purity in aqueous solution, 3 eq) at 0° C. Then the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched with ice-water (20 mL), and adjusted to pH=8-9 with saturated aqueous NaHCO.sub.3 solution. The mixture was extracted with ethyl acetate (3×20 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The yellow solid was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 2:1 to 1:1) to give the title compound (400 mg, 84%) as a yellow solid.

[0671] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.83 (d, 2H), 7.22 (d, 2H), 3.75-3.69 (m, 1H), 2.25 (s, 3H) and 1.36 (d, 6H).

[0672] LCMS: m/z 247.1 (M+H).sup.+ (ES.sup.+).

Step H: 4-Isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-amine

[0673] ##STR00080##

[0674] A mixture of 4-(4-isopropyl-2-methyl-5-nitro-1H-imidazol-1-yl)pyridine (400 mg, 1.62 mmol, 1 eq) and Pd/C (40 mg, 10 wt % loading on activated carbon) in MeOH (20 mL) was hydrogenated at 20° C. for 1 hour under H.sub.2 (15 psi). Then the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in THF (10 mL), and adjusted to pH=3-4 with 4M HCl/dioxane. The resulting mixture was concentrated in vacuo to give the title compound (400 mg, 97%, HCl salt) as a yellow solid, which was used in the next step without further purification.

[0675] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 15.02 (s, 1H), 8.99 (d, 2H), 7.90 (d, 2H), 3.25-3.15 (m, 1H), 2.45 (s, 3H) and 1.27 (d, 6H).

[0676] LCMS: m/z 217.1 (M+H).sup.+ (ES.sup.+).

Intermediate P1: N1,N1,N2-Trimethylpropane-1,2-diamine

[0677] ##STR00081##

[0678] N1,N1-dimethylpropane-1,2-diamine (153 mg, 1.5 mmol) was dissolved in DCM (50 mL) and cooled to 0° C. Ethyl chloroformate (162 mg, 1.5 mmol) was added dropwise and the mixture was allowed to reach room temperature overnight. The reaction mixture was washed with aqueous 1 N NaOH (20 mL), dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in THF (20 mL) and added dropwise to a suspension of lithium aluminium hydride (0.5, 13 mmol) in THF (20 mL) at 0° C. The reaction was refluxed overnight, and subsequently cooled to room temperature and carefully quenched with water. The suspension was filtered and the residue was washed with methanol (10 mL). The filtrates were combined and evaporated to near dryness. The crude product was dissolved in DCM (20 mL), dried over sodium sulfate and evaporated to dryness to yield the title compound (140 mg, 86%) as a yellow oil.

[0679] .sup.1H NMR (CDCl.sub.3) δ 2.59 (m, 1H), 2.39 (s, 3H), 2.05 (m, 1H), 2.19 (s, 6H), 2.01 (m, 1H), 1.40 (s, 1H), 0.95 (d, 3H).

[0680] LCMS: m/z 117 (M+H).sup.+ (ES.sup.+).

Intermediate P2: (1-Isopropylazetidin-2-yl)methanamine dihydrochloride

Step A: tert-Butyl ((1-isopropylazetidin-2-yl)methyl)carbamate

[0681] ##STR00082##

[0682] To a solution of tert-butyl (azetidin-2-ylmethyl)carbamate (200 mg, 1.07 mmol) and acetone (84 μL, 1.13 mmol) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (283 mg, 1.34 mmol). The reaction mixture was stirred overnight and then concentrated in vacuo. The crude product was coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and was submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol as eluent to afford the title compound (222 mg, 90%) which was used without further purification.

[0683] .sup.1H NMR (CDCl.sub.3) δ 5-75 (bs, 1H), 3.60 (bs, 2H), 3.48-3.34 (m, 1H), 3.18 (d, 1H), 2.98 (q, 1H), 2.71-2.54 (m, 1H), 2.06-1.92 (m, 2H), 1.44 (s, 9H), 1.02 (dd, 6H).

Step B: (1-Isopropylazetidin-2-yl)methanamine dihydrochloride

[0684] ##STR00083##

[0685] To a solution of tert-butyl ((1-isopropylazetidin-2-yl)methyl)carbamate (83 mg, 0.36 mmol) in dichloromethane (10 mL) was added 4M hydrochloric acid in dioxane (0.9 mL, 36 mmol). After stirring for 6 hours, additional 4M hydrochloric acid in dioxane (0.9 mL, 36 mmol) was added and the reaction stirred over the weekend. The suspension was concentrated in vacuo to afford the title compound (72 mg, quantitative yield) which was used without further purification.

[0686] .sup.1H NMR (CD.sub.3OD) δ 4.83-4.68 (m, 1H), 4.20-3.99 (m, 2H), 3.64-3.45 (m, 3H), 2.73-2.38 (m, 2H), 1.33 (dd, 6H).

Intermediate P3: 3-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

Step A: tert-Butyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0687] ##STR00084##

[0688] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (84 mg, 0.40 mmol) and formaldehyde (37% in water, stabilized with methanol; 32 μL, 42 mmol) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (0.50 mmol, 106 mg). After stirring overnight, an extra equivalent of formaldehyde (37% in water, stabilized with methanol; 32 μL, 42 mmol) and sodium triacetoxyborohydride (0.50 mmol, 106 mg) were added. After stirring for 3 hours, the reaction mixture was concentrated in vacuo. The crude product was coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and was submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol as eluent to afford the title compound (86 mg, 94%).

[0689] .sup.1H NMR (CDCl.sub.3) δ 4.14 (bs, 2H), 2.67 (d, 2H), 2.35-2.13 (m, 5H), 1.91-1.78 (m, 4H), 1.46 (s, 9H).

Step B: 3-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

[0690] ##STR00085##

[0691] To a solution of tert-butyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (86 mg, 0.38 mmol) in dichloromethane (10 mL) was added 4M hydrochloric acid in dioxane (1.9 mL, 7.6 mmol). After stirring over the weekend, the reaction mixture was concentrated in vacuo to afford the title compound (70 mg, 92%) which was used without further purification.

[0692] .sup.1H NMR (CD.sub.3OD) δ 4.34 (s, 2H), 3.73 (d, 2H), 3.55 (d, 2H), 2.94 (s, 3H), 2.37-2.29 (m, 4H).

Intermediate P4: 3-Ethyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

Step A: tert-Butyl 3-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0693] ##STR00086##

[0694] Prepared as described for tert-butyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate P3, step A) using acetaldehyde instead of formaldehyde to afford the title compound (165 mg, 85%).

[0695] .sup.1H NMR (CDCl.sub.3) δ 3.70 (dd, 2H), 3.35 (d, 2H), 3.20 (dd, 2H), 2.55 (q, 2H), 1.98-1.84 (m, 2H), 1.76-1.56 (m, 2H), 1.44 (s, 9H), 1.15 (t, 3H).

Step B: 3-Ethyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

[0696] ##STR00087##

[0697] Prepared as described for 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P3, step B) from tert-butyl 3-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate to afford the title compound (140 mg, 95%) which was used without further purification.

[0698] .sup.1H NMR (CD.sub.3OD) δ 4.36 (d, 2H), 3.89-3.74 (m, 2H), 3.73-3.63 (m, 2H), 3.62-3.51 (m, 2H), 2.53 (d, 1H), 2.47-2.38 (m, 1H), 2.36-2.19 (m, 2H), 1.40 (t, 3H).

Intermediate P5: 3-Isopropyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

Step A: tert-Butyl 3-isopropyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0699] ##STR00088##

[0700] Prepared as described for tert-butyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate P3, step A) using acetone instead of formaldehyde to afford the title compound (95 mg, 46%).

[0701] .sup.1H NMR (CDCl.sub.3) δ 4.14 (d, 2H), 2.60 (dd, 3H), 2.42 (s, 2H), 1.90-1.70 (m, 4H), 1.45 (d, 9H), 0.98 (d, 6H).

Step B: 3-Isopropyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

[0702] ##STR00089##

[0703] Prepared as described for 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P3, step B) from tert-butyl 3-isopropyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate to afford the title compound (72 mg, quantitative yield) which was used without further purification.

[0704] .sup.1H NMR (CD.sub.3OD) δ 4.35 (d, 2H), 3.73 (d, 2H), 3.61-3.51 (m, 3H), 2.47-2.20 (m, 4H), 1.44 (d, J=6.6 Hz, 6H).

Intermediate P6: 8-Ethyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

[0705] ##STR00090##

[0706] Prepared as described for tert-butyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate P3, step A) from tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate and acetaldehyde. The intermediate Boc-protected compound was dissolved in dichloromethane (10 mL) and then 4M hydrochloric acid in dioxane (3.3 mL, 13.3 mmol) was added. After stirring over the weekend, the reaction mixture was concentrated in vacuo to afford the title compound (144 mg, 84% yield over two steps).

[0707] .sup.1H NMR (CD.sub.3OD) δ 4.33 (s, 2H), 3.86 (d, 2H), 3.59 (d, 2H), 3.21 (q, 2H), 2.56-2.44 (m, 2H), 2.35-2.22 (m, 2H), 1.43 (t, 3H).

Intermediate P7: 8-Isopropyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

Step A: tert-Butyl 8-isopropyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0708] ##STR00091##

[0709] Prepared as described for tert-butyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate P3, step A) from tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate and acetone. The title compound (173 mg, 85%) was used without further purification.

[0710] .sup.1H NMR (CDCl.sub.3) δ 3.81-3.55 (m, 4H), 3.34 (dd, 2H), 2.80 (q, 1H), 1.98 (m, 2H), 1.81-1.66 (m, 2H), 1.45 (s, 9H), 1.25 (d, 6H).

Step B: 8-Isopropyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

[0711] ##STR00092##

[0712] Prepared as described for 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P3, step B) from tert-butyl 8-isopropyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate to afford the title compound (143 mg, 91%) which was used without further purification.

[0713] .sup.1H NMR (CD.sub.3OD) δ 4.51 (bs, 2H), 3.89 (d, 2H), 3.57 (d, 2H), 3.43-3.32 (m, 1H), 2.55-2.38 (m, 2H), 2.27 (d, 2H), 1.48 (d, 6H).

Intermediate P8: 8-Cyclopropyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

Step A: tert-Butyl 8-cyclopropyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0714] ##STR00093##

[0715] To a solution of tert-butyl (1R′,5S′)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (100 mg, 471 μmol) and (1-ethoxycyclopropoxy)trimethylsilane (189 μL, 942 μmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added acetic acid (62.2 mg, 59.3 μL, 1.04 mmol) followed by sodium cyanoborohydride (44.4 mg, 707 μmol). The reaction mixture was stirred at 50° C. After stirring overnight, more (1-ethoxycyclopropoxy)trimethylsilane (189 μL, 942 μmol), acetic acid (62.2 mg, 59.3 μL, 1.04 mmol) and sodium cyanoborohydride (44.4 mg, 707 μmol) were added. After stirring for 3 days at 50° C., the reaction mixture was concentrated in vacuo. The crude product was coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and was submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol as eluent to afford the title compound (118 mg, quantitative yield).

[0716] .sup.1H NMR (CDCl.sub.3) δ 3.87 (td, 1H), 3.82-3.70 (m, 2H), 3.68-3.56 (m, 1H), 3.21 (dd, 2H), 2.02-1.90 (m, 1H), 1.83-1.63 (m, 2H), 1.44 (s, 9H), 1.33-1.16 (m, 2H), 0.78 (s, 2H), 0.54 (d, 2H).

Step B: 8-Cyclopropyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride

[0717] ##STR00094##

[0718] Prepared as described for 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P3, step B) from tert-butyl 8-cyclopropyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate to afford the title compound (106 mg, quantitative yield) which was used without further purification.

[0719] .sup.1H NMR (CD.sub.3OD) δ 4.38 (d, 2H), 3.94 (d, 2H), 3.55 (d, 2H), 2.99 (s, 1H), 2.64 (d, 2H), 2.40-2.24 (m, 2H), 1.35 (d, 2H), 1.01 (d, 2H).

Intermediate P9: (1R,3s,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

Step A: tert-Butyl ((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate

[0720] ##STR00095##

[0721] tert-Butyl ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (0.20 g, 0.88 mmol) was dissolved in dry acetonitrile (15 mL) and formaldehyde (0.16 ml, 4.41 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes at room temperature, then sodium triacetoxyborohydride (0.56 g, 2.65 mmol) was added. The solvent was evaporated in vacuo. Purification by silica based column chromatography (DCM:7N NH.sub.3 in methanol; 9:1) gave the title compound (0.11 g, 52%) as an off-white solid.

[0722] .sup.1H NMR (CDCl.sub.3) δ 4.46 (s, 1H), 3.76 (s, 1H), 3.20 (s, 2H), 2.30 (s, 3H), 2.17-1.90 (m, 2H), 1.88-1.50 (m, 6H), 1.38 (s, 9H).

Step B: (1R,3s,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

[0723] ##STR00096##

[0724] tert-Butyl ((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate (0.11 g, 0.42 mmol) was dissolved in a 4N solution of hydrogen chloride in 1,4-dioxane (5 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo. The crude product (74 mg, 99%) was used in the next step without further purification.

[0725] .sup.1H NMR (CD.sub.3OD) δ 4.06-3.98 (m, 2H), 3.80-3.56 (m, 1H), 2.81 (s, 3H), 2.48-2.33 (m, 2H), 2.31-2.17 (m, 5H), 2.16-1.96 (m, 3H).

Intermediate P10: (1R,3r,5S)-8-Isopropyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

Step A: tert-Butyl ((1R,3r,5S)-8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate

[0726] ##STR00097##

[0727] tert-Butyl ((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (0.10 g, 0.44 mmol) was dissolved in acetone (8 mL) and sodium triacetoxyborohydride (0.12 g, 0.55 mmol) was added at room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo. Purification by silica based column chromatography (DCM:7N NH.sub.3 in methanol; 9:1) gave the title compound as an off-white solid (0.11 g, 92%).

[0728] .sup.1H NMR (CDCl.sub.3) δ 4.12-3.93 (m, 2H), 3.90-3.70 (m, 1H), 3.23-3.03 (m, 1H), 2.60-2.38 (m, 2H), 2.35-2.20 (m, 2H), 2.14-2.02 (m, 3H), 1.92-1.76 (m, 2H), 1.49-1.34 (m, 15H).

Step B: (1R,3r,5S)-8-Isopropyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

[0729] ##STR00098##

[0730] tert-Butyl ((1R,3r,5S)-8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate (0.11 g, 0.37 mmol) was dissolved in a 4N solution of hydrogen chloride in 1,4-dioxane (5 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo. The crude product (84 mg, quantitative yield) was used in the next step without further purification.

[0731] .sup.1H NMR (CD.sub.3OD) δ 4.31 (s, 1H), 4.16 (s, 1H), 3.83-3.60 (m, 2H), 2.80-2.56 (m, 3H), l0 2.48-2.33 (m, 2H), 2.27-2.07 (m, 4H), 2.03-1.90 (m, 1H), 1.43-1.40 (m, 6H).

Intermediate P11: (1R,3s,5S)—N,N-Diethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

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

[0732] ##STR00099##

[0733] tert-Butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (0.21 g, 0.93 mmol) was dissolved in dry acetonitrile (12 mL) and acetaldehyde (0.12 g, 0.16 mL, 2.8 mmol) was added at room temperature. After 20 minutes sodium triacetoxyhydroborate (0.59 g, 2.8 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvents were evaporated and the crude mixture was purified by silica based column chromatography (DCM:7N NH.sub.3 in DCM, 9:1) to give the title compound (0.22 g, 84%) as a colourless oil.

[0734] .sup.1H NMR (CDCl.sub.3) δ 4.39-3.98 (m, 2H), 3.19-2.98 (m, 1H), 2.62-2.32 (m, 4H), 1.95-1.80 (m, 2H), 1.69-1.48 (m, 6H), 1.41 (s, 9H), 1.07-0.91 (m, 6H).

Step B: (1R,3s,5S)—N,N-Diethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

[0735] ##STR00100##

[0736] tert-Butyl (1R,3s,5S)-3-(diethylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.22 g, 0.78 mmol) was dissolved in a 4N solution of hydrogen chloride in 1,4-dioxane (8 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The crude product (0.17 g, 99%) was used in the next step without further purification.

[0737] .sup.1H NMR (CD.sub.3OD) δ 4.03-3.81 (m, 2H), 3.62-3.39 (m, 1H), 3.15-2.78 (m, 5H), 2.02-1.90 (m, 4H), 1.89-1.72 (m, 4H), 1.09-0.98 (m, 6H).

Intermediate P12: tert-Butyl (1R,3s,5S)-3-(dimethylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0738] ##STR00101##

[0739] tert-Butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (0.20 g, 0.88 mmol) was dissolved in dry acetonitrile (12 mL) and formaldehyde (80 mg, 98 μL, 2.7 mmol) was added at room temperature. After 20 minutes sodium triacetoxyhydroborate (0.56 g, 2.7 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvents were evaporated and the crude mixture was purified by silica based column chromatography (DCM:7N NH.sub.3 in MeOH; 9:1) to give the title compound (0.23 g, 92%) as a colourless oil.

[0740] .sup.1H NMR (CDCl.sub.3) δ 4.38-4.02 (m, 2H), 2.63-2.45 (m, 1H), 2.16 (s, 6H), 1.93-1.79 (m, 2H), 1.73-1.45 (m, 6H), 1.40 (s, 9H).

Intermediate P13: 1-Isopropylimidazolidine

[0741] ##STR00102##

[0742] N-Isopropylethylenediamine (0.50 g, 4.89 mmol) was added to a suspension of paraformaldehyde (0.15 g, 4.89 mmol), K.sub.2CO.sub.3 (2.3 g, 16.6 mmol), and MgSO.sub.4 (2.3 g, 19.08 mmol) in CHCl.sub.3 (16 mL), under a nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight. The solid was filtered off and solvent was evaporated to give the title compound (0.51 g, 91%). This material was used in the next step without further purification.

[0743] .sup.1H NMR (CDCl.sub.3) δ 3.47 (s, 2H), 3.13-3.01 (m, 2H), 2.68-2.55 (m, 2H), 2.43-2.29 (m, 1H), 1.18-1.03 (m, 6H).

Intermediate P14: (1R,3r,5S)-3-(Pyrrolidin-1-yl)-8-azabicyclo[3.2.1]octane hydrochloride

Step A: tert-Butyl (1R,3r,5S)-3-(pyrrolidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0744] ##STR00103##

[0745] tert-Butyl (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (0.20 g, 0.88 mmol) was dissolved in dry acetonitrile (12 mL). Then potassium iodide (33 mg, 0.20 mmol), potassium carbonate (0.14 g, 1.0 mmol) and 1,4-dibromobutane (0.19 g, 0.10 mL, 0.86 mmol) were added successively. The reaction mixture was heated for 6 hours under reflux. The reaction mixture was cooled down to room temperature and the solvent was evaporated in vacuo. Purification by silica based column chromatography (DCM:7N NH.sub.3 in methanol; 9:1) afforded the title compound (0.145 g, 58%) as a colourless oil.

[0746] .sup.1H NMR (CDCl.sub.3) δ 4.23-3.95 (m, 2H), 2.60-2.39 (m, 4H), 2.33-2.15 (m, 1H), 2.15-1.79 (m, 6H), 1.78-1.61 (m, 6H), 1.41 (s, 9H).

Step B: (1R,3r,5S)-3-(Pyrrolidin-1-yl)-8-azabicyclo[3.2.1]octane hydrochloride

[0747] ##STR00104##

[0748] tert-Butyl (1R,3r,5S)-3-(pyrrolidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (145 mg, 0.517 mmol) was dissolved in a 4N solution of hydrogen chloride in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The crude product (112 mg, quantitative yield) was used in the next step without further purification.

[0749] .sup.1H NMR (CD.sub.3OD) δ 4.22-4.05 (m, 2H), 3.85-3.69 (m, 3H), 3.25-3.07 (m, 2H), 2.93-2.66 (m, 2H), 2.37-1.92 (m, 11H).

Intermediate P15: (1R,3r,5S)—N,N-Diethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

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

[0750] ##STR00105##

[0751] tert-Butyl (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (0.20 g, 0.88 mmol) was dissolved in dry acetonitrile (12 mL) and acetaldehyde (0.16 g, 0.20 mL, 3.5 mmol) was added at room temperature. After 20 minutes sodium triacetoxyhydroborate (0.56 g, 2.65 mmol) was added and the reaction mixture was stirred at room temperature overnight. The crude mixture was purified by silica based column chromatography (DCM:7N NH.sub.3 in MeOH; 9:1) to give the title compound (0.17 g, 71%) as a colourless oil.

[0752] .sup.1H NMR (CDCl.sub.3) δ 4.24-4.00 (m, 2H), 2.68-2.42 (m, 5H), 2.31-2.08 (m, 2H), 1.97-1.83 (m, 2H), 1.71-1.57 (m, 2H), 1.40 (s, 9H), 1.40-1.19 (m, 2H), 1.04-0.85 (m, 6H).

Step B: (1R,3r,5S)—N,N-Diethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

[0753] ##STR00106##

[0754] tert-Butyl (1R,3r,5S)-3-(diethylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.17 g, 0.60 mmol) was dissolved in a 4N solution of hydrogen chloride in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The crude product (0.13 g, 99%) was used in the next step without further purification.

[0755] .sup.1H NMR (CD.sub.3OD) δ 4.25-4.11 (m, 2H), 3.40-3.17 (m, 6H), 2.88-2.73 (m, 2H), 2.30-2.15 (m, 2H), 2.12-2.01 (m, 2H), 1.99-1.86 (m, 2H), 1.43-1.31 (m, 6H).

Intermediate P16: (1R,3r,5S)—N,N-Dimethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

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

[0756] ##STR00107##

[0757] tert-Butyl (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (0.20 g, 0.88 mmol) was dissolved in dry acetonitrile (12 mL) and formaldehyde (0.11 g, 0.13 mL, 3.5 mmol) was added at room temperature. After 20 minutes sodium triacetoxyhydroborate (0.56 g, 2.65 mmol) was added and the reaction mixture was stirred at room temperature overnight. The crude mixture was purified by silica based column chromatography (DCM:7N NH.sub.3 in MeOH, 9:1) to afford the title compound (0.15 g, 68%) as a colourless oil.

[0758] .sup.1H NMR (CDCl.sub.3) δ 4.28-4.01 (m, 2H), 2.21 (s, 6H), 2.17-1.99 (m, 3H), 1.94-1.75 (m, 4H), 1.72-1.51 (m, 2H), 1.44 (s, 9H).

Step B: (1R,3r,5S)—N,N-Dimethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

[0759] ##STR00108##

[0760] tert-Butyl (1R,3r,5S)-3-(dimethylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.13 g, 0.51 mmol) was dissolved in a 4N solution of hydrogen chloride in 1,4-dioxane (8 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The crude product (97 mg, quantitative yield) was used in the next step without further purification.

[0761] .sup.1H NMR (CD.sub.3OD) δ 4.24-4.07 (m, 2H), 3.64-3.50 (m, 1H), 2.94 (s, 6H), 2.83-2.66 (m, 2H), 2.33-2.14 (m, 3H), 2.13-1.97 (m, 4H).

Intermediate P17: (1R,3s,5S)-8-Isopropyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

Step A: tert-Butyl ((1R,3s,5S)-8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate

[0762] ##STR00109##

[0763] tert-Butyl ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (0.20 g, 0.88 mmol) was dissolved in acetone (12 mL) and sodium triacetoxyhydroborate (0.56 g, 2.65 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvents were evaporated and the crude mixture was purified by silica based column chromatography (DCM:7N NH.sub.3 in MeOH; 9:1) to afford the title compound (0.19 g, 79%) as a colourless oil.

[0764] .sup.1H NMR (CDCl.sub.3) δ 5.21-4.89 (m, 1H), 4.24-3.79 (m, 3H), 3.21-2.82 (m, 1H), 2.34-2.03 (m, 4H), 2.01-1.78 (m, 4H), 1.50-1.30 (m, 15H).

Step B: (1R,3s,5S)-8-Isopropyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

[0765] ##STR00110##

[0766] tert-Butyl ((1R,3s,5S)-8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate (0.19 g, 0.71 mmol) was dissolved in a 4N solution of hydrogen chloride in 1,4-dioxane (7 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The crude product (0.14 g, 96%) was used in the next step without further purification.

[0767] .sup.1H NMR (CD.sub.3OD) δ 4.51-4.32 (m, 1H), 4.29-4.18 (m, 1H), 4.14-3.99 (m, 1H), 3.83-3.65 (m, 1H), 2.48-1.91 (m, 10H), 1.59-1.37 (m, 6H).

Intermediate P18: (1R,3s,5S)-8-Ethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

Step A: tert-Butyl ((1R,3s,5S)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate

[0768] ##STR00111##

[0769] tert-Butyl ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (0.20 g, 0.88 mmol) was dissolved in dry acetonitrile (12 mL) and acetaldehyde (0.12 g, 0.15 mL, 2.65 mmol) was added at room temperature. After 20 minutes sodium triacetoxyhydroborate (0.56 g, 2.65 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvents were evaporated and the crude mixture was purified by silica based column chromatography (DCM:7N NH.sub.3 in MeOH; 9:1) to afford the title compound (0.18 g, 82%) as a yellow oil.

[0770] .sup.1H NMR (CDCl.sub.3) δ 3.37 (s, 2H), 3.32-3.21 (m, 2H), 2.56-2.45 (m, 2H), 1.99-1.88 (m, 4H), 1.84-1.76 (m, 4H), 1.74-1.61 (m, 9H), 1.19-1.10 (m, 3H).

Step B: (1R,3s,5S)-8-Ethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride

[0771] ##STR00112##

[0772] tert-Butyl ((1R,3s,5S)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate (0.10 g, 0.42 mmol) was dissolved in a 4N solution of hydrogen chloride in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The crude product (79 mg, 97%) was used in the next step without further purification.

[0773] .sup.1H NMR (CD.sub.3OD) δ 4.23-4.08 (m, 2H), 3.80-3.68 (m, 2H), 3.19-3.04 (m, 2H), 2.40-2.21 (m, 6H), 2.13-2.05 (m, 2H), 1.48-1.34 (m, 3H).

Intermediate P1: 6-Methyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride

Step A: tert-Butyl 6-methyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

[0774] ##STR00113##

[0775] Prepared as described for tert-butyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate P3, step A) from tert-butyl 3,6-diazabicyclo[3.2.0]heptane-3-carboxylate to afford the title compound (68 mg, 64%).

[0776] .sup.1H NMR (CDCl.sub.3) δ 3.79 (dd, 1H), 3.69 (s, 2H), 3.39 (t, 1H), 3.24 (dd, 2H), 3.08 (dd, 1H), 2.97 (dt, 1H), 2.34 (s, 3H), 1.47 (s, 9H).

Step B: 6-Methyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride

[0777] ##STR00114##

[0778] Prepared as described for 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P3, step B) from tert-butyl 6-methyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate to afford the title compound (59 mg, quantitative yield) which was used without further purification.

[0779] .sup.1H NMR (CD.sub.3OD) δ 5.01 (s, 1H), 4.41-4.21 (m, 1H), 4.14 (s, 1H), 3.89-3.66 (m, 2H), 3.62 (t, 2H), 3.49-3.35 (m, 1H), 3.05 (s, 3H).

Intermediate P20: 6-Ethyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride

Step A: tert-Butyl 6-ethyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

[0780] ##STR00115##

[0781] To a solution of tert-butyl 3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (100 mg, 0.50 mmol) and ethyl iodide (40 μL, 0.50 mmol) in acetonitrile (10 mL) was added potassium carbonate (209 mg, 1.50 mmol). After stirring overnight at room temperature, the suspension was filtered. The residue was washed with methanol. The filtrates were combined and concentrated in vacuo. The crude product was coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and was submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol as eluent to afford the title compound (68 mg, 60%).

[0782] .sup.1H NMR (CDCl.sub.3) δ 3.78-3.53 (m, 3H), 3.52-3.40 (m, 1H), 3.23-3.07 (m, 3H), 3.00-2.89 (m, 1H), 2.58-2.46 (m, 2H), 1.46 (s, 9H), 0.96 (t, 3H).

Step B: 6-Ethyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride

[0783] ##STR00116##

[0784] Prepared as described for 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P3, step B) from tert-butyl 6-ethyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate to afford the title compound (59 mg, quantitative yield) which was used without further purification.

[0785] .sup.1H NMR (CD.sub.3OD) δ 5.07 (s, 1H), 4.30-4.13 (m, 2H), 3.85 (d, 1H), 3.75-3.57 (m, 3H), 3.53-3.35 (m, 3H), 1.27 (t, 3H).

Intermediate P21: 6-Isopropyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride

Step A: tert-Butyl 6-isopropyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

[0786] ##STR00117##

[0787] Prepared as described for tert-butyl 3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate P3, step A) from tert-butyl 6-methyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate and acetone to afford the title compound (79 mg, 65%).

[0788] .sup.1H NMR (CDCl.sub.3) δ 3.94 (bs, 1H), 3.67 (bs, 2H), 3.45-3.29 (m, 2H), 3.27-3.13 (m, 2H), 2.97 (bs, 1H), 2.60 (bs, 1H), 1.47 (s, 9H), 0.97 (dd, 6H).

Step B: 6-Isopropyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride

[0789] ##STR00118##

[0790] Prepared as described for 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P3, step B) from tert-butyl 6-isopropyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate to afford the title compound (70 mg, quantitative yield) which was used without further purification. 1H NMR (CD.sub.3OD) δ 5.22 (t, 1H), 4.42-4.01 (m, 3H), 3.88 (d, 1H), 3.71-3.42 (m, 4H), 1.32 (dd, J=18.5, 6.5 Hz, 6H).

Intermediate P22: 6-Methyl-3,6-diazabicyclo[3.1.1]heptane hydrochloride

Step A: tert-Butyl 6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0791] ##STR00119##

[0792] To a solution of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (100 mg, 1 eq, 504 μmol) and formaldehyde (31 μL, 2.2 eq, 1.10 mmol) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (107 mg, 1 eq, 504 μmol). The suspension was stirred at room temperature overnight and then concentrated in vacuo. The crude product was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (83 mg, 78%).

[0793] .sup.1H NMR (CDCl.sub.3) δ 3.66-3.48 (m, 4H), 3.37 (dd, 2H), 2.71-2.49 (m, 1H), 2.19 (d, 3H), 1.89 (s, 1H), 1.55-1.43 (m, 9H).

Step B: 6-Methyl-3,6-diazabicyclo[3.1.1]heptane hydrochloride

[0794] ##STR00120##

[0795] To a solution of tert-butyl 6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (83 mg, 039 mmol, 1 eq) in dichloromethane (8 mL) was added hydrochloric acid in dioxane (4 M, 4.0 mL, 16.0 mmol, 40 eq). The reaction mixture was stirred at room temperature. After stirring for 1.5 hours, a few drops of methanol were added. After stirring overnight, the reaction mixture was concentrated in vacuo to afford the title compound (72 mg, 99%).

[0796] .sup.1H NMR (DMSO-d.sub.6) δ 4.41-4.10 (m, 2H), 3.96 (m, 1H), 3.82 (m, 1H), 3.74-3.58 (m, 2H), 3.30 (s, 3H), 3.04-2.79 (m, 2H).

Intermediate P23: (R)—N-Methyl-1-(1-methylpyrrolidin-2-yl)methanamine

Step A: Methyl methyl-D-prolinate

[0797] ##STR00121##

[0798] Pd/C (10%) (1.1 g, 0.012 eq, 1.0 mmol) was added to a solution of D-proline (10.0 g, 1 eq, 86.9 mmol) and formaldehyde (37% in water) (7.5 mL, 1 eq, 86.9 mmol) in methanol (200 mL). The mixture was stirred overnight under 2 bar hydrogen. Then the mixture was filtered over Celite® and the filtrate was treated with thionyl chloride (11.4 g, 6.97 mL, 1.1 eq, 95.5 mmol) and refluxed overnight. The reaction mixture was evaporated to dryness, treated with cold 1M Na.sub.2CO.sub.3 solution (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (20 mL), dried over sodium sulfate and evaporated to dryness to yield the title compound (12.4 g, 100%) as a colourless oil.

[0799] .sup.1H NMR (CDCl.sub.3) δ 3.72 (s, 3H), 3.13 (dt, 1H), 2.93 (dd, 1H), 2.38 (s, 3H), 2.25 (q, 1H), 2.12 (m, 1H), 1.91 (m, 2H), 1.79 (m, 1H).

[0800] LCMS: m/z 144 (M+H).sup.+ (ES.sup.+).

Step B: (R)—N,1-Dimethylpyrrolidine-2-carboxamide

[0801] ##STR00122##

[0802] Methyl methyl-D-prolinate (5.5 g, 1 eq, 38 mmol) was dissolved in methylamine (200 mL) in ethanol (33 wt %) and stirred overnight. Removal of the volatiles by rotary evaporation yielded the title compound (5.5 g, 100%) as a clear oil that crystallized upon standing.

[0803] .sup.1H NMR (CDCl.sub.3) δ 7.22 (bs, 1H), 3.03 (m, 1H), 2.83 (dd, 1H), 2.79 (d, 3H), 2.34 (s, 3H), 2.33 (m, 1H), 2.18 (m, 2H), 1.71 (m, 2H).

[0804] LCMS: m/z 143 (M+H).sup.+ (ES.sup.+).

Step C: (R)—N-Methyl-1-(1-methylpyrrolidin-2-yl)methanamine

[0805] ##STR00123##

[0806] (R)—N,1-Dimethylpyrrolidine-2-carboxamide (5.50 g, 1 eq, 38.7 mmol) was dissolved in THF (80 mL) and cooled to 0° C. Lithium aluminium hydride (2.20 g, 1.5 eq, 58.0 mmol) was carefully added and the mixture was refluxed overnight. The mixture was cooled to 0° C., water (4.18 g, 4.18 mL, 6 eq, 232 mmol) was added dropwise and 33% NaOH solution (2 mL) was added. The suspension was allowed to reach room temperature, stirred for 1 hour and filtered. The filtrate was dried over sodium sulfate and evaporated to dryness, yielding the title compound (5.0 g, 100%) as a clear liquid.

[0807] .sup.1H NMR (CDCl.sub.3) δ 3.03 (dt, 1H), 2.70 (dd, 1H), 2.50 (dd, 1H), 2.41 (s, 3H), 2.35 (s, 3H), 2.22 (m, 1H), 2.18 (m, 2H), 1.92 (m, 1H), 1.63 (m, 2H), 1.20 (bs, 1H).

[0808] LCMS: m/z 129 (M+H).sup.+ (ES.sup.+).

Intermediate P24: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)(N,N-dimethyl-sulfamoyl)amide

[0809] ##STR00124##

[0810] A solution of dimethylaminosulfonamide (993 mg, 8.00 mmol) and DMAP (1.954 g, 16.00 mmol) in MeCN (10 mL) was stirred at room temperature for 10 minutes. Then diphenyl carbonate (1.885 g, 8.80 mmol) was added and the resulting solution was stirred at room temperature for 5 days. The precipitate was filtered off and washed with MTBE. The resulting solid was dried in vacuo (50° C.) to afford the crude title compound (1.45 g, 67%) which was used without further purification.

Intermediate P25: (S)—N-Methyl-1-(1-methylpyrrolidin-2-yl)methanamine

[0811] ##STR00125##

[0812] Prepared as described for (R)—N-methyl-1-(1-methylpyrrolidin-2-yl)methanamine (Intermediate P23). 1H NMR (400 MHz, CDCl.sub.3) δ 3.05-3.01 (m, 1H), 2.72-2.68 (m, 1H), 2.53-2.48 (m, 1H), 2.44 (s, 3H), 2.32 (s, 3H), 2.28-2.23 (m, 1H), 2.19-2.14 (m, 1H), 1.95-1.88 (m, 1H) and 1.76-1.60 (m, 3H). 1×NH was missing.

Intermediate P26: 1-Methyl-3-[methyl(sulfamoyl)amino]pyrrolidine

[0813] ##STR00126##

[0814] To a solution of N,1-dimethylpyrrolidin-3-amine (4 g, 35.03 mmol, 1 eq) in 1,2-dimethoxyethane (80 mL) was added sulfuric diamide (4.04 g, 42.04 mmol, 1.2 eq) in one portion. The reaction mixture was heated to 90° C. and stirred for 12 hours under N.sub.2. Then the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, EtOAc: EtOH, 20:1 to 5:1) to give the title compound (3.5 g, 43% yield, 83% purity on LCMS) as a brown oil.

[0815] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.65 (s, 2H), 4.31-4.23 (m, 1H), 2.62 (s, 3H), 2.61-2.56 (m, 2H), 2.41-2.36 (m, 1H), 2.20 (s, 3H), 2.18-2.12 (m, 1H), 2.05-1.98 (m, 1H) and 1.78-1.71 (m, 1H).

[0816] LCMS: m/z 194.0 (M+H).sup.+ (ES.sup.+).

PREPARATION OF EXAMPLES

Example 1: 3-(N-Methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea

[0817] ##STR00127##

[0818] To a cooled (0° C.) solution of chlorosulfonyl isocyanate (59 mg, 0.41 mmol) in DCM (5 mL) was added 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A2; 100 mg, 0.41 mmol). The mixture was stirred for 10 minutes at 0° C. N,1-dimethylpyrrolidin-3-amine (95 mg, 0.83 mmol) in DCM (5 mL) was added and the reaction was allowed to reach room temperature over 30 minutes. The mixture was evaporated to dryness in vacuo and purified by reversed phase chromatography to afford the title compound (9 mg; 5%) as a white solid.

[0819] .sup.1H NMR (CD.sub.3OD) δ 8.12 (d, 1H), 7.19 (d, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 6.83 (s, 1H), 4.48 (m, 1H), 3.92 (s, 3H), 2.92 (m, 6H), 2.82 (m, 2H), 2.71 (s, 3H), 2.50 (s, 3H), 2.10 (m, 3H) and 1.92 (m, 1H).

[0820] LCMS: m/z 460 (M+H).sup.+ (ES.sup.+); 458 (M−H).sup.− (ES.sup.−).

Example 2: 3-(N-Methyl-N-((1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea

[0821] ##STR00128##

[0822] Prepared as described for 3-(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea (Example 1), using chlorosulfonyl isocyanate (59 mg, 0.41 mmol), 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A2; 100 mg, 0.41 mmol) and N-methyl-1-(1-methylpyrrolidin-2-yl)methanamine (racemic Intermediate P23; 107 mg, 0.83 mmol) to afford the title compound (2 mg; 1%) as a white solid.

[0823] .sup.1H NMR (CD.sub.3OD) δ 8.12 (d, 1H), 7.19 (m, 2H), 7.09 (d, 1H), 6.93 (s, 1H), 3.92 (s, 3H), 3.88 (m, 1H), 3.65 (m, 1H), 3.09 (m, 1H), 2.98 (m, 6H), 2.79 (s, 3H), 2.69 (s, 3H), 2.10 (m, 3H), 1.97 (m, 2H) and 1.60 (m, 1H).

[0824] LCMS: m/z 474 (M+H).sup.+ (ES.sup.+).

Example 3: 3-(N-Methyl-N-((1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea

[0825] ##STR00129##

[0826] Prepared as described for 3-(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea (Example 1), using chlorosulfonyl isocyanate (55 mg, 0.38 mmol), 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A1; 100 mg, 0.38 mmol) and N,1-dimethylpyrrolidin-3-amine (95 mg, 0.83 mmol) to afford the title compound (12 mg; 10%) as a white solid.

[0827] .sup.1H NMR (CD.sub.3OD) δ 8.14 (d, 1H), 7.08 (d, 1H), 6.98 (m, 2H), 4.48 (m, 1H), 3.92 (s, 3H), 2.98 (m, 8H), 2.71 (s, 3H), 2.60 (s, 3H), 2.10 (m, 3H) and 1.92 (m, 1H).

[0828] LCMS: m/z 479 (M+H).sup.+ (ES.sup.+).

Example 4: 3-(N-Methyl-N-((1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea

[0829] ##STR00130##

[0830] Prepared as described for 3-(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea (Example 1), using chlorosulfonyl isocyanate (55 mg, 0.38 mmol), 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A1; 100 mg, 0.38 mmol) and N-methyl-1-(1-methylpyrrolidin-2-yl)methanamine (racemic Intermediate P23; 139 mg, 1.16 mmol) to afford the title compound (23 mg; 12%) as a white solid.

[0831] .sup.1H NMR (CD.sub.3OD) δ 8.12 (d, 1H), 7.00 (d, 1H), 6.90 (d, 1H), 6.83 (s, 1H), 3.92 (s, 3H), 3.78 (m, 1H), 3.55 (m, 1H), 3.00 (m, 7H), 2.79 (s, 3H), 2.67 (s, 3H), 2.19 (m, 3H), 2.01 (m, 2H) and 1.62 (m, 1H).

[0832] LCMS: m/z 492 (M+H).sup.+ (ES.sup.+); 490 (M−H).sup.− (ES.sup.−).

Example 5: (1R,4R)—N-((7-Fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamide

[0833] ##STR00131##

[0834] (1R,4R)-2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (50 mg, 0.18 mmol) and sodium hydride (60%) (150 mg, 3.7 mmol) were refluxed for 1 hour in THF (10 mL). The mixture was cooled to room temperature and filtered over Celite®. The filtrate was evaporated to dryness in vacuo and the residue was dissolved in DCM (10 mL), after which DABCO was added (20 mg, 0.18 mmol).

[0835] Meanwhile, to a cooled (0° C.) solution of chlorosulfonyl isocyanate (35 mg, 0.25 mmol) in DCM (5 mL) was added 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A1; 66 mg, 0.26 mmol). The mixture was stirred for 10 minutes at 0° C.

[0836] Both DCM mixtures were combined and allowed to reach room temperature after 1 hour. The mixture was evaporated to dryness in vacuo and purified by reversed phase chromatography to afford the title compound (4 mg; 5%) as a white solid.

[0837] .sup.1H NMR (CD.sub.3OD) δ 8.12 (d, 1H), 7.02 (d, 1H), 6.90 (m, 2H), 4.54 (m, 1H), 4.24 (m, 1H), 3.92 (s, 3H), 3.39 (m, 2H), 2.98 (m, 4H), 2.75 (s, 3H), 2.20 (m, 2H), and 1.64 (m, 2H).

[0838] LCMS: m/z 476 (M+H).sup.+ (ES.sup.+); 474 (M−H).sup.− (ES.sup.−).

Example 6: 3-Methyl-((2-(dimethylamino)ethyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0839] ##STR00132##

[0840] To a solution of [(2-dimethylamino)ethyl](methyl)sulfamoyl-amine (57 mg, 0.31 mmol) in THF (3 mL) was added potassium tert-butoxide (35 mg, 0.31 mmol). The mixture was stirred for 40 minutes. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A3) (63 mg, 0.31 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 resulting suspension was filtered over cotton wool and subsequently submitted for purification by reversed phase column chromatography (see “Experimental Methods”) to afford the title compound (84 mg, 70%) as a white solid.

[0841] .sup.1H NMR (CD.sub.3OD) δ 6.89 (s, 1H), 3.44 (t, 2H), 3.04 (t, 2H), 2.95-2.74 (m, 11H), 2.67 (s, 6H), 2.03 (m, 4H).

[0842] LCMS: m/z 381 (M+H).sup.+ (ES.sup.+); 379 (M−H).sup.− (ES.sup.−).

Example 7: 3-Methyl-((2-Methoxyethyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0843] ##STR00133##

[0844] Prepared as described for 3-methyl-((2-(dimethylamino)ethyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 6) using [(2-methoxyethyl)(methyl)sulfamoyl]amine (52 mg, 0.31 mmol), KOtBu (35 mg, 0.31 mmol) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A3) (62 mg, 0.31 mmol) to afford the title compound (80 mg, 71%) as a white solid.

[0845] .sup.1H NMR (CD.sub.3OD) δ 6.88 (s, 1H), 3.56 (t, 2H), 3.33 (m, 5H), 2.82 (m, 11H), 2.03 (m, 4H).

[0846] LCMS: m/z 368 (M+H).sup.+ (ES.sup.+); 366 (M−H).sup.− (ES.sup.−).

Example 8: 3-(N-(2-(Dimethylamino)ethyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea

[0847] ##STR00134##

[0848] To a cooled (0° C.) solution of N1,N1-dimethylethane-1,2-diamine (102 mg, 1.0 mmol) in THF (10 mL) was added ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol). The ice bath was removed and the reaction mixture was stirred whilst being allowed to warm to room temperature overnight. The solvent was removed 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 (12 mg, 10%) as a white solid.

[0849] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.23 (m, 2H), 3.07 (m, 2H), 2.82 (m, 8H), 2.70 (s, 6H), 2.03 (m, 4H).

[0850] LCMS: m/z 367 (M+H).sup.+ (ES.sup.+); 365 (M−H).sup.− (ES.sup.−).

Example 9: 3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)pyrrolidine-1-sulfonamide, potassium salt

[0851] ##STR00135##

[0852] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N,N-dimethylpyrrolidin-3-amine (114 mg, 1.00 mmol) to afford the title compound (5 mg, 4%) as a white solid.

[0853] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.80 (dd, 1H), 3.62 (t, 1H), 3.43 (q, 1H), 3.25 (m, 1H), 3.03 (p, 1H), 2.82 (m, 8H), 2.38 (s, 6H), 2.20 (m, 1H), 2.03 (m, 4H), 1.95 (m, 1H).

[0854] LCMS: m/z 393 (M+H).sup.+ (ES.sup.+); 391 (M−H).sup.− (ES.sup.−).

Example 10: 3-(N-Benzyl-N-(2-(dimethylamino)ethyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0855] ##STR00136##

[0856] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1-benzyl-N2,N2-dimethylethane-1,2-diamine (178 mg, 1.00 mmol) to afford the title compound (10 mg, 7%) as a white solid.

[0857] .sup.1H NMR (CD.sub.3OD) δ 7.48 (d, 2H), 7.38 (m, 3H), 6.91 (s, 1H), 4.31 (s, 2H), 3.46 (t, 2H), 2.82 (m, 8H), 2.71 (t, 2H), 2.59 (s, 6H), 2.03 (m, 4H).

[0858] LCMS: m/z 457 (M+H).sup.+ (ES.sup.+); 455 (M−H).sup.− (ES.sup.−).

Example 11: 3-(N-Methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0859] ##STR00137##

[0860] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N,1-dimethylpyrrolidin-3-amine (115 mg, 1.00 mmol) to afford the title compound (11 mg, 9%) as a white solid.

[0861] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.60 (m, 1H), 2.82 (m, 11H), 2.74 (m, 2H), 2.61 (m, 1H), 2.50 (m, 1H), 2.38 (s, 3H), 2.03 (m, 6H).

[0862] LCMS: m/z 393 (M+H).sup.+ (ES.sup.+); 391 (M−H).sup.− (ES.sup.−).

Example 12: 3-(N-(2-(Dimethylamino)ethyl)-N-isobutylsulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0863] ##STR00138##

[0864] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1-isobutyl-N2,N2-dimethylethane-1,2-diamine (144 mg, 1.00 mmol) to afford the title compound (7 mg, 5%) as a white solid.

[0865] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.51 (t, 2H), 3.10 (t, 2H), 2.95 (d, 2H), 2.82 (m, 14H), 2.03 (m, 4H), 1.90 (m, 1H), 0.99 (m, 6H).

[0866] LCMS: m/z 423 (M+H).sup.+ (ES.sup.+); 421 (M−H).sup.− (ES.sup.−).

Example 13: 3-(N-(2-(Dimethylamino)ethyl)-N-phenethylsulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0867] ##STR00139##

[0868] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N1-dimethyl-N2-phenethylethane-1,2-diamine (192 mg, 1.00 mmol) to afford the title compound (24 mg, 5%) as a white solid.

[0869] .sup.1H NMR (CD.sub.3OD) δ 7.21 (m, 5H), 6.91 (s, 1H), 3.60 (m, 2H), 3.41 (m, 2H), 3.10 (t, 2H), 3.01 (t, 2H) 2.82 (m, 8H), 2.76 (s, 6H), 2.03 (m, 4H).

[0870] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (M−H).sup.− (ES.sup.−).

Example 14: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3-sulfonamide, potassium salt

[0871] ##STR00140##

[0872] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 8-methyl-3,8-diazabicyclo[3.2.1]octane (128 mg, 1.00 mmol) with triethylamine (0.3 mL, 2.0 mmol) to afford the title compound (0.8 mg, 1%) as a white solid.

[0873] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.50 (m, 2H), 3.05 (m, 4H), 2.82 (m, 8H), 2.38 (s, 3H) 2.03 (m, 4H), 1.97 (m, 4H).

[0874] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (M−H).sup.− (ES.sup.−).

Example 15: 3-(N-(1-(Dimethylamino)propan-2-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0875] ##STR00141##

[0876] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N,N-dimethylpiperidin-3-amine (130 mg, 1.00 mmol) to afford the title compound (18 mg, 14%) as a white solid.

[0877] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.79 (m, 1H), 3.52 (m, 1H), 2.98 (m, 2H), 2.82 (m, 8H), 2.58 (m, 1H), 2.40 (s, 6H) 2.03 (m, 4H), 1.92 (m, 1H), 1.80 (m, 1H), 1.60 (m, 1H), 1.42 (m, 1H).

[0878] LCMS: m/z 407 (M+H).sup.+ (ES.sup.+); 405 (M−H).sup.− (ES.sup.−).

Example 16: 3-(N-(1-(Dimethylamino)propan-2-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0879] ##STR00142##

[0880] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N1-dimethylpropane-1,2-diamine (102 mg, 1.00 mmol) to afford the title compound (6 mg, 5%) as a white solid.

[0881] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.79 (m, 1H), 2.98 (m, 2H), 2.82 (m, 8H), 2.75 (s, 6H) 2.03 (m, 4H), 1.24 (d, 3H).

[0882] LCMS: m/z 381 (M+H).sup.+ (ES.sup.+); 379 (M−H).sup.− (ES.sup.−).

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

[0883] ##STR00143##

[0884] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N,N-dimethylazetidin-3-amine dihydrochloride (178 mg, 1.00 mmol) with triethylamine (0.25 mL, 2 mmol) to afford the title compound (16 mg, 13%) as a white solid.

[0885] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.79 (m, 4H), 3.06 (m, 1H), 2.82 (m, 8H), 2.18 (s, 6H) 2.03 (m, 4H).

[0886] LCMS: m/z 379 (M+H).sup.+ (ES.sup.+); 377 (M−H).sup.− (ES.sup.−).

Example 18: 3-(N-(2-(Diethylamino)ethyl)-N-ethylsulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0887] ##STR00144##

[0888] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N1,N2-triethylethane-1,2-diamine (148 mg, 1.00 mmol) to afford the title compound (2 mg, 1%) as a white solid.

[0889] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.54 (t, 2H), 3.24 (t, 2H), 3.04 (m, 6H), 2.82 (m, 8H), 2.03 (m, 4H), 1.21 (t, 9H).

[0890] LCMS: m/z 423 (M+H).sup.+ (ES.sup.+); 421 (M−H).sup.− (ES.sup.−).

Example 10: 3-(N-(1-Ethylpiperidin-3-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0891] ##STR00145##

[0892] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 1-ethylpiperidin-3-amine (125 mg, 1.00 mmol) to afford the title compound (4 mg, 3%) as a white solid.

[0893] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.41 (m, 1H), 3.20 (m, 1H), 2.82 (m, 8H), 2.43 (m, 4H), 2.03 (m, 7H), 1.95 (s, 1H), 1.79 (m, 1H), 1.60 (m, 1H), 1.22 (m, 1H), 1.10 (t, 3H).

[0894] LCMS: m/z 407 (M+H).sup.+ (ES.sup.+); 405 (M−H).sup.− (ES.sup.−).

Example 20: 3-(N-((1-Methylpiperidin-2-yl)methyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0895] ##STR00146##

[0896] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and (1-methylpiperidin-2-yl)methanamine (128 mg, 1.00 mmol) to afford the title compound (8 mg, 6%) as a white solid.

[0897] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.51 (m, 1H), 3.18 (m, 1H), 2.82 (m, 14H), 2.03 (m, 4H), 1.95 (s, 1H), 1.70 (m, 6H).

[0898] LCMS: m/z 407 (M+H).sup.+ (ES.sup.+); 405 (M−H).sup.− (ES.sup.−).

Example 21: 4-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) piperazine-1-sulfonamide

[0899] ##STR00147##

[0900] To a solution of 1-ethylpiperazine (36 mg, 0.32 mmol) in dry DCM (6 mL) was added ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 1 hour at 0° C. to reach full conversion. The solvent was evaporated in vacuo. Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (40 mg, 33%) as a white solid.

[0901] .sup.1H NMR (CD.sub.3OD) δ 6.89 (s, 1H), 3.56 (s, 1H), 3.21 (s, 1H), 3.02-2.92 (m, 2H), 2.91-2.75 (m, 6H), 2.74-2.62 (m, 1H), 2.64-2.37 (m, 9H), 2.18-1.91 (m, 4H), 1.19-1.00 (m, 3H).

[0902] LCMS: m/z 393 (M+H).sup.+ (ES.sup.+); 391 (M−H).sup.− (ES.sup.−).

Example 22: 3-(N-methyl-N-((1-methylpiperidin-2-yl)methyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0903] ##STR00148##

[0904] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol), N-methyl-1-(1-methylpiperidin-2-yl)methanamine (70 mg, 0.50 mmol) and triethylamine (50 mg, 0.5 mmol) to afford the title compound (18 mg, 13%) as a white solid.

[0905] LCMS: m/z 421 (M+H).sup.+ (ES.sup.+); 419 (M−H).sup.− (ES.sup.−).

Example 23: 3-(N-(3-(Pyrrolidin-1-yl)azetidin-1-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0906] ##STR00149##

[0907] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol), 1-(azetidin-3-yl)pyrrolidine dihydrobromide (125 mg, 0.50 mmol) and triethylamine (0.15 mL, 1.0 mmol) to afford the title compound (8 mg, 6%) as a white solid.

[0908] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.02 (m, 4H), 3.48 (m, 1H), 2.82 (m, 8H), 2.78 (m, 4H), 2.03 (m, 4H), 1.95 (s, 1H), 1.83 (m, 4H).

[0909] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (M−H).sup.− (ES.sup.−).

Example 24: 3-(N-(2-Oxoindolin-5-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0910] ##STR00150##

[0911] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 5-aminoindolin-2-one (145 mg, 1.00 mmol) with triethylamine (86 mg, 0.85 mmol) to afford the title compound (31 mg, 23%) as a white solid.

[0912] .sup.1H NMR (CD.sub.3OD) δ 7.21 (s, 1H), 7.13 (d, 1H), 6.91 (s, 1H), 6.80 (d, 1H), 4.82 (s, 2H), 2.82 (t, 4H), 2.62 (t, 4H), 2.03 (m, 4H).

[0913] LCMS: m/z 427 (M+H).sup.+ (ES.sup.+); 425 (M−H).sup.− (ES.sup.−).

Example 25: 3-(N-((1-Methylpyrrolidin-2-yl)methyl))sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0914] ##STR00151##

[0915] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and (1-methylpyrrolidin-2-yl)methanamine (114 mg, 1.00 mmol) to afford the title compound (4 mg, 3%) as a white solid.

[0916] LCMS: m/z 393 (M+H).sup.+ (ES.sup.+); 391 (M−H).sup.− (ES.sup.−).

Example 26: 3-((N-(2-Isopropyl))ethyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea

[0917] ##STR00152##

[0918] To a solution of 1-isopropylimidazolidine (Intermediate P13) (36 mg, 0.32 mmol) in dry THF (6 mL) at 0° C. was added ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol). The mixture was stirred for 1 hour at 0° C. to reach full conversion. The solvent was evaporated in vacuo. Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (2 mg, 2%) as a white solid.

[0919] .sup.1H NMR (CD.sub.3OD) δ 6.89 (s, 1H), 4.82 (s, 2H), 4.60 (s, 2H), 3.17-3.02 (m, 3H), 2.92-2.71 (m, 8H), 2.14-1.94 (m, 4H), 1.91 (s, 1H), 1.28 (d, J=6.5 Hz, 6H).

[0920] LCMS: m/z 381 (M+H).sup.+ (ES.sup.+); 379 (M−H).sup.− (ES.sup.−).

Example 27: 3-(N-(1-(dimethylamino)propan-2-yl)-N-methyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0921] ##STR00153##

[0922] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N1,N2-trimethylpropane-1,2-diamine (Intermediate P1) (140 mg, 1.10 mmol) to afford the title compound (5 mg, 4%) as a white solid.

[0923] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.42 (m, 1H), 3.02 (m, 2H), 2.82 (m, 17H), 2.03 (m, 4H), 1.93 (s, 1H), 1.29 (d, 3H).

[0924] LCMS: m/z 395 (M+H).sup.+ (ES.sup.+); 393 (M−H).sup.− (ES.sup.−).

Example 28: 3-(N-Isopropyl-N-(2-(isopropylamino)ethyl))sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0925] ##STR00154##

[0926] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N2-diisopropylethane-1,2-diamine (140 mg, 1.0 mmol) to afford the title compound (5 mg, 4%) as a white solid.

[0927] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.62 (m, 2H), 3.38 (m, 2H), 3.18 (m, 2H), 2.82 (m, 8H), 2.17 (s, 1H), 2.03 (m, 4H), 1.90 (s, 1H), 1.35 (d, 12H).

[0928] LCMS: m/z 423 (M+H).sup.+ (ES.sup.+); 421 (M−H).sup.− (ES.sup.−).

Example 20: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-8-isopropyl-3,8-diazabicyclo[3.2.1]octane-3-sulfonamide, potassium salt

[0929] ##STR00155##

[0930] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (98 mg, 0.31 mmol) and 8-isopropyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P7) (71 mg, 0.31 mmol) to afford the title compound (5 mg, 3%) as a white solid.

[0931] .sup.1H NMR (CD.sub.3OD) δ 6.93 (s, 1H), 3.99 (bs, 2H), 3.48 (d, 2H), 3.39-3.32 (m, 2H), 3.20-3.06 (m, 1H), 2.83 (dt, 8H), 2.11-1.98 (m, 8H), 1.27 (d, 6H).

[0932] LCMS: m/z 433 (M+H).sup.+ (ES.sup.+); 431 (M−H).sup.− (ES.sup.−).

Example 30: 3-(N-(2-(Dimethylamino)propyl))sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0933] ##STR00156##

[0934] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N2,N2-dimethylpropane-1,2-diamine (102 mg, 1.00 mmol) to afford the title compound (14 mg, 12%) as a white solid.

[0935] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.13 (m, 1H), 2.98 (m, 1H), 2.82 (m, 9H), 2.37 (s, 6H), 2.17 (s, 1H), 2.03 (m, 4H), 1.05 (d, 3H).

[0936] LCMS: m/z 381 (M+H).sup.+ (ES.sup.+); 379 (M−H).sup.− (ES.sup.−).

Example 31: 3-(N-((1-Methylazetidin-2-yl)methyl))sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0937] ##STR00157##

[0938] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and (1-methylazetidin-2-yl)methanamine (100 mg, 1.00 mmol) to afford the title compound (8 mg, 7%) as a white solid.

[0939] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.93 (m, 1H), 3.72 (m, 1H), 3.40 (m, 1H), 3.06 (m, 1H), 2.82 (m, 9H), 2.64 (s, 3H), 2.12 (m, 2H), 2.03 (m, 4H), 1.90 (s, 1H).

[0940] LCMS: m/z 379 (M+H).sup.+ (ES.sup.+); 377 (M−H).sup.− (ES.sup.−).

Example 32: 3-(N-Methyl-N-(2-(methylamino)ethyl))sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0941] ##STR00158##

[0942] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N2-dimethylethane-1,2-diamine (88 mg, 1.00 mmol) to afford the title compound (12 mg, 10%) as a white solid.

[0943] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.63 (t, 2H), 3.18 (t, 1H), 3.00 (t, 1H), 2.96 (s, 3H), 2.82 (m, 8H), 2.64 (s, 3H), 2.16 (s, 1H), 2.03 (m, 4H).

[0944] LCMS: m/z 367 (M+H).sup.+ (ES.sup.+); 365 (M−H).sup.− (ES.sup.−).

Example 33: (1R,3r,5S)-8-Isopropyl-8-azabicyclo[3.2.1]octan-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-sulfonamide)

[0945] ##STR00159##

[0946] (1R,3r,5S)-8-Isopropyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride (Intermediate P10) (84 mg, 0.41 mmol) was dissolved in dry THF (10 mL) at 0° C. under a nitrogen atmosphere. Et.sub.3N (0.17 mL, 1.23 mmol) was added, followed by ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (0.13 g, 0.41 mmol). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was evaporated in vacuo. Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (5 mg, 5%) as a white solid.

[0947] .sup.1H NMR (CD.sub.3OD) δ 6.89 (s, 1H), 4.57 (s, 1H), 4.10 (s, 2H), 3.65-3.50 (m, 1H), 3.18-2.98 (m, 1H), 2.93-2.71 (m, 8H), 2.69-2.45 (m, 2H), 2.44-1.93 (m, 10H), 1.90 (s, 2H), 1.36-1.30 (m, 6H).

[0948] LCMS: m/z 447 (M+H).sup.+ (ES.sup.+); 445 (M−H).sup.− (ES.sup.−).

Example 34: 3-(N-(1-Methylazetidin-3-yl))sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0949] ##STR00160##

[0950] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) and (100 mg, 0.32 mmol) 1-methylazetidin-3-amine (80 mg, 1.00 mmol) to afford the title compound (16 mg, 14%) as a white solid.

[0951] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.00 (m, 1H), 3.78 (t, 2H), 3.00 (t, 2H), 2.82 (m, 8H), 2.32 (s, 3H), 2.03 (m, 4H).

[0952] LCMS: m/z 365 (M+H).sup.+ (ES.sup.+); 363 (M−H).sup.− (ES.sup.−).

Example 35: 3-(N-(2-(Azetidin-1-yl)ethyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0953] ##STR00161##

[0954] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 2-(azetidin-1-yl)ethan-1-amine (100 mg, 1.00 mmol) to afford the title compound (19 mg, 16%) as a white solid.

[0955] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.59 (t, 4H), 3.02 (t, 2H), 2.82 (m, 9H), 2.60 (m, 1H), 2.20 (m, 2H), 2.03 (m, 4H).

[0956] LCMS: m/z 379 (M+H).sup.+ (ES.sup.+); 377 (M−H).sup.− (ES.sup.−).

Example 16: 3-(N-(1-isopropylpyrrolidin-3-yl)-N-methylsulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0957] ##STR00162##

[0958] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 1-isopropyl-N-methylpyrrolidin-3-amine (142 mg, 1.00 mmol) to afford the title compound (20 mg, 15%) as a white solid.

[0959] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.55 (m, 1H), 3.24 (m, 1H), 3.03 (t, 2H), 2.82 (m, 8H), 2.70 (m, 2H), 2.60 (m, 1H), 2.40 (s, 3H), 2.10 (m, 1H), 2.03 (m, 4H), 1.18 (d, 6H).

[0960] LCMS: m/z 421 (M+H).sup.+ (ES.sup.+); 419 (M−H).sup.− (ES.sup.−).

Example 17: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-methyl-3,8-diazabicyclo[3.2.1]octane-8-sulfonamide, potassium salt

[0961] ##STR00163##

[0962] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (110 mg, 0.35 mmol) and 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P3) (70 mg, 0.35 mmol) to afford the title compound (1 mg, 0.6%) as a white solid.

[0963] .sup.1H NMR (CD.sub.3OD) δ 6.92 (s, 1H), 4.15 (bs, 2H), 2.92-2.62 (m, 10H), 2.40 (d, 2H), 2.26 (s, 3H), 2.16-1.98 (m, 6H), 1.92-1.74 (m, 2H).

[0964] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (M−H).sup.− (ES.sup.−).

Example 38: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-isopropyl-3,8-diazabicyclo[3.2.1]octane-8-sulfonamide, potassium salt

[0965] ##STR00164##

[0966] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (147 mg, 0.46 mmol) and 3-isopropyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P5) (72 mg, 0.46 mmol) to afford the title compound (4 mg, 1%) as a white solid.

[0967] .sup.1H NMR (CD.sub.3OD) δ 6.96 (s, 1H), 4.20 (s, 2H), 2.91-2.56 (m, 13H), 2.05 (p, 6H), 1.94-1.81 (m, 2H), 1.04 (d, 6H).

[0968] LCMS: m/z 433 (M+H).sup.+ (ES.sup.+); 431 (M−H).sup.− (ES.sup.−).

Example 39: 3-(N-(2-(Dimethylamino)ethyl)-N-ethylsulfamoyl))-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0969] ##STR00165##

[0970] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1-ethyl-N2,N2-dimethylethane-1,2-diamine (155 mg, 1.3 mmol) to afford the title compound (2 mg, 2%) as a white solid.

[0971] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.52 (t, 2H), 3.25 (t, 2H), 3.10 (m, 2H), 2.82 (m, 8H), 2.70 (s, 6H), 2.03 (m, 4H), 1.21 (t, 3H).

[0972] LCMS: m/z 395 (M+H).sup.+ (ES.sup.+); 393 (M−H).sup.− (ES.sup.−).

Example 40: 3-(N-(2-(Diethylamino)ethyl)sulfamoyl))-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0973] ##STR00166##

[0974] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N1-diethylethane-1,2-diamine (115 mg, 1.00 mmol) to afford the title compound (10 mg, 8%) as a white solid.

[0975] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.27 (m, 2H), 3.20 (s, 1H), 3.00 (m, 5H), 2.82 (m, 8H), 2.03 (m, 4H), 1.19 (t, 6H).

[0976] LCMS: m/z 395 (M+H).sup.+ (ES.sup.+); 393 (M−H).sup.− (ES.sup.−).

Example 41: N-(2-((N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)(methyl)amino)ethyl)-N-methylacetamide, potassium salt

[0977] ##STR00167##

[0978] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N-methyl-N-(2-(methylamino)ethyl)acetamide (130 mg, 1.00 mmol) to afford the title compound (7 mg, 6%) as a white solid.

[0979] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.55 (m, 2H), 3.39 (m, 2H), 3.10 (s, 3H), 2.90 (s, 3H), 2.82 (m, 8H), 2.03 (m, 7H).

[0980] LCMS: m/z 409 (M+H).sup.+ (ES.sup.+); 407 (M−H).sup.− (ES.sup.−).

Example 42: 3-((Dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-1-sulfonamide, potassium salt

[0981] ##STR00168##

[0982] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N,N-dimethyl-1-(piperidin-2-yl)methanamine (142 mg, 1.00 mmol) to afford the title compound (11 mg, 8%) as a white solid.

[0983] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.42 (m, 1H), 3.95 (m, 1H), 3.70 (d, 1H), 3.45 (t, 1H), 3.05 (t, 1H), 2.82 (m, 8H), 2.66 (s, 6H), 2.21 (s, 1H), 2.03 (m, 4H), 1.80 (m, 1H), 1.60 (m, 4H).

[0984] LCMS: m/z 421 (M+H).sup.+ (ES.sup.+); 419 (M−H).sup.− (ES.sup.−).

Example 43: (1R,4R)—N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamide, potassium salt

[0985] ##STR00169##

[0986] To a solution of (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (100 mg, 0.36 mmol) in THF (10 mL) under N.sub.2 atmosphere was added sodium hydride (40%) (30 mg, 0.75 mmol). The reaction mixture was refluxed for 30 minutes. After cooling to room temperature, DABCO (100 mg, 89 mmol), triethylamine (0.5 g, 0.7 mL, mmol) and ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) were added. The mixture was stirred for 4 hours at room temperature. Potassium tert-butoxide (100 mg, 0.89 mmol) was added and the mixture was stirred for 5 minutes. The solvent was removed 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 (21 mg, 18%) as a white solid.

[0987] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.29 (s, 1H), 3.62 (s, 1H), 3.42 (dd, 2H), 3.05 (m, 2H), 2.82 (m, 11H), 2.03 (m, 4H), 1.56 (s, 2H).

[0988] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+); 389 (M−H).sup.− (ES.sup.−).

Example 44: 3-(N-(1-Methylpyrrolidin-3-yl))sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0989] ##STR00170##

[0990] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 1-methylpyrrolidin-3-amine (100 mg, 1.00 mmol) to afford the title compound (38 mg, 31%) as a white solid.

[0991] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.95 (m, 1H), 3.01 (dd, 1H), 2.82 (m, 8H), 2.56 (m, 3H), 2.38 (s, 3H), 2.22 (m, 1H), 2.03 (m, 6H), 1.80 (m, 1H).

[0992] LCMS: m/z 379 (M+H).sup.+ (ES.sup.+); 377 (M−H).sup.− (ES.sup.−).

Example 45: 3-(N-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl))sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[0993] ##STR00171##

[0994] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethan-1-amine (116 mg, 0.85 mmol) with triethylamine (86 mg, 0.85 mmol) to afford the title compound (22 mg, 17%) as a white solid.

[0995] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 2.82 (m, 8H), 2.62 (t, 2H), 2.24 (dt, 1H), 2.03 (m, 6H), 1.62 (m, 4H).

[0996] LCMS: m/z 416 (M+H).sup.+ (ES.sup.+); 414 (M−H).sup.− (ES.sup.−).

Example 46: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-[1,3′-biazetidine]-1′-sulfonamide, potassium salt

[0997] ##STR00172##

[0998] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 1,3′-biazetidine bis(2,2,2-trifluoroacetate) (100 mg, 0.29 mmol) with DABCO (200 mg, 1.78 mmol) to afford the title compound (9 mg, 8%) as a white solid.

[0999] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.80 (m, 1H), 2.82 (m, 16H), 2.03 (m, 6H).

[1000] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+); 389 (M−H).sup.− (ES.sup.−).

Example 47: 3-(N-((1-Ethylazetidin-2-yl)methyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1001] ##STR00173##

[1002] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (127 mg, 0.263 mmol, purity 80%) and (1-ethylazetidin-2-yl)methanamine (commercial from enamine; 30 mg, 0.26 mmol) except that before removal of the solvent potassium tert-butoxide (1.0 equivalent) was added. This afforded the title compound as the potassium salt (9 mg, 7%) as a white solid.

[1003] .sup.1H NMR (CD.sub.3OD) δ 6.89 (s, 1H), 4.24-4.10 (m, 1H), 3.95-3.77 (m, 1H), 3.63-3.46 (m, 3H), 3.26-3.06 (m, 2H), 2.83 (q, 8H), 2.42-2.28 (m, 1H), 2.21 (d, 1H), 2.02 (p, 4H), 1.13 (t, 3H).

[1004] LCMS: m/z 393 (M+H).sup.+ (ES.sup.+); 391 (M−H).sup.− (ES.sup.−).

Example 48: 3-(N-(4-(Dimethylamino)butyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1005] ##STR00174##

[1006] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N1-dimethylbutane-1,4-diamine (116 mg, 1.0 mmol) to afford the title compound (20 mg, 16%) as a white solid.

[1007] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.07 (t, 2H), 2.82 (m, 8H), 2.62 (m, 2H), 2.42 (s, 6H), 2.03 (m, 4H), 1.60 (m, 4H).

[1008] LCMS: m/z 395 (M+H).sup.+ (ES.sup.+); 393 (M−H).sup.− (ES.sup.−).

Example 49: 3-(3-((Diethylamino)pyrrolidine)-1-sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1009] ##STR00175##

[1010] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N,N-diethylpyrrolidin-3-amine (142 mg, 1.0 mmol) to afford the title compound (21 mg, 16%) as a white solid.

[1011] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.66 (m, 1H), 3.40 (m, 3H), 3.17 (m, 1H), 2.82 (m, 8H), 2.67 (q, 4H), 2.13 (m, 1H), 2.03 (m, 4H), 1.80 (m, 1H), 1.80 (t, 6H).

[1012] LCMS: m/z 421 (M+H).sup.+ (ES.sup.+); 419 (M−H).sup.− (ES.sup.−).

Example 50: 3-(N-((1-Isopropylazetidin-2-yl)methyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1013] ##STR00176##

[1014] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (170 mg, 0.54 mmol) and (1-isopropylazetidin-2-yl)methanamine dihydrochloride (Intermediate P2) (72 mg, 0.36 mmol) except that triethylamine (3.0 equivalent) was added to the reaction mixture and except that before removal of the solvent potassium tert-butoxide (3.0 equivalent) was added. This afforded the title compound as the potassium salt (34 mg, 21%) as a white solid.

[1015] .sup.1H NMR (CD.sub.3OD) δ 6.89 (s, 1H), 4.32-4.15 (m, 1H), 3.82 (m, 1H), 3.57 (q, 1H), 3.47 (dd, 1H), 3.24-3.15 (m, 2H), 2.83 (q, 8H), 2.43-2.16 (m, 2H), 2.02 (p, 4H), 1.22 (d, 3H), 1.12 (d, 3H).

[1016] LCMS: m/z 407 (M+H).sup.+ (ES.sup.+); 405 (M−H).sup.− (ES.sup.−).

Example 51: 3-(N,N-Bis(2-(dimethylamino)ethyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1017] ##STR00177##

[1018] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1-(2-(dimethylamino)ethyl)-N2,N2-dimethylethane-1,2-diamine (100 mg, 0.7 mmol) to afford the title compound (14 mg, 11%) as a white solid.

[1019] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.55 (t, 4H), 3.10 (t, 4H), 2.82 (m, 8H), 2.71 (s, 12H), 2.03 (m, 4H).

[1020] LCMS: m/z 438 (M+H).sup.+ (ES.sup.+); 436 (M−H).sup.− (ES.sup.−).

Example 52: 3-(N-(1-Methylpiperidin-3-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1021] ##STR00178##

[1022] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 1-methylpiperidin-3-amine (114 mg, 1.0 mmol) to afford the title compound (16 mg, 13%) as a white solid.

[1023] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.50 (t, 2H), 3.40 (m, 1H), 3.05 (d, 1H), 2.82 (m, 8H), 2.63 (d, 1H), 2.23 (s, 3H), 2.03 (m, 5H), 1.75 (m, 1H), 1.60 (m, 1H), 1.20 (m, 1H).

[1024] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+); 393 (M−H).sup.− (ES.sup.−).

Example 53: 3-(N-(2-(Diethylamino)ethyl)-N-methyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1025] ##STR00179##

[1026] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N1-diethyl-N2-methylethane-1,2-diamine (130 mg, 1.0 mmol) to afford the title compound (3 mg, 3%) as a white solid.

[1027] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.50 (t, 2H), 3.20 (q, 2H), 3.19 (q, 4H), 2.82 (m, 11H), 2.03 (m, 4H), 1.23 (t, 6H).

[1028] LCMS: m/z 409 (M+H).sup.+ (ES.sup.+); 407 (M−H).sup.− (ES.sup.−).

Example 54: 3-((N-(4-Hydroxybutyl))sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1029] ##STR00180##

[1030] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 4-aminobutan-1-ol (116 mg, 1.0 mmol) with triethylamine (0.15 g, 0.2 mL, 0.14 mmol) to afford the title compound (33 mg, 26%) as a white solid.

[1031] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.58 (m, 2H), 3.0 (t, 1H), 2.82 (m, 10H), 2.03 (m, 4H), 1.60 (m, 4H).

[1032] LCMS: m/z 368 (M+H).sup.+ (ES.sup.+); 366 (M−H).sup.− (ES.sup.−).

Example 55: 3-((N-(1-Methyl-1H-pyrazol-3-yl))sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1033] ##STR00181##

[1034] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol), 1-methyl-1H-pyrazol-3-amine (97 mg, 1.0 mmol) and triethylamine (0.15 g, 0.2 mL, 0.14 mmol) to afford the title compound (19 mg, 16%) as a white solid.

[1035] .sup.1H NMR (CD.sub.3OD) δ 7.38 (s, 1H), 6.91 (s, 1H), 6.17 (s, 1H), 3.75 (s, 3H), 2.82 (m, 8H), 2.03 (m, 4H).

[1036] LCMS: m/z 376 (M+H).sup.+ (ES.sup.+); 374 (M−H).sup.− (ES.sup.−).

Example 56: (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-sulfonamide)

[1037] ##STR00182##

[1038] (1R,3s,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride (Intermediate P9) (74 mg, 0.42 mmol) was dissolved in dry THF (10 mL) at 0° C. under a nitrogen atmosphere. Et.sub.3N (0.31 mL) was added, followed by ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (0.13 g, 0.42 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen atmosphere. The solvent was evaporated in vacuo. Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (14 mg, 5%) as a white solid.

[1039] .sup.1H NMR (CD.sub.3OD) δ 6.99 (s, 1H), 4.26-4.02 (m, 1H), 3.79-3.59 (m, 3H), 2.91-2.73 (m, 9H), 2.68 (s, 3H), 2.31-2.16 (m, 2H), 2.13-1.88 (m, 11H).

[1040] LCMS: m/z 419 (M+H).sup.+ (ES.sup.+).

Example 57: 3-(N-(2-(Dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1041] ##STR00183##

[1042] To a solution of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) in THF (10 mL) under N.sub.2 atmosphere was added N2,N2,2-trimethylpropane-1,2-diamine (116 mg, 1.0 mmol). The mixture was stirred for 4 hours at room temperature. Potassium tert-butoxide (100 mg, 0.89 mmol) was added and the reaction mixture was stirred for 5 minutes. The solvent was removed 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 (11 mg, 9%) as a white solid.

[1043] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.75 (t, 1H), 2.82 (m, 8H), 2.55 (s, 6H), 2.20 (s, 2H), 2.03 (m, 4H), 1.55 (m, 1H), 1.20 (s, 6H).

[1044] LCMS: m/z 395 (M+H).sup.+ (ES.sup.+); 393 (M−H).sup.− (ES.sup.−).

Example 58: 3-(N-(2-(Dimethylamino)ethyl)-N-(3-phenylpropyl) sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1045] ##STR00184##

[1046] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N1-dimethyl-N2-(3-phenylpropyl)ethane-1,2-diamine (206 mg, 1.00 mmol) to afford the title compound (16 mg, 10%) as a white solid.

[1047] .sup.1H NMR (CD.sub.3OD) δ 7.20 (m, 5H), 6.91 (s, 1H), 3.59 (t, 2H), 3.23 (m, 2H), 3.18 (t, 2H), 2.82 (m, 14H), 2.63 (t, 2H), 2.03 (m, 6H).

[1048] LCMS: m/z 485 (M+H).sup.+ (ES.sup.+); 483 (M−H).sup.− (ES.sup.−).

Example 59: 3-(N-(1-(Dimethylamino)-2-methylpropan-2-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1049] ##STR00185##

[1050] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N1,2-trimethylpropane-1,2-diamine (116 mg, 1.00 mmol) to afford the title compound (14 mg, 11%) as a white solid.

[1051] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 2.98 (s, 6H), 2.82 (m, 8H), 2.40 (m, 2H), 2.03 (m, 4H), 1.47 (s, 6H).

[1052] LCMS: m/z 395 (M+H).sup.+ (ES.sup.+); 393 (M−H).sup.− (ES.sup.−).

Example 60: 3-(N-(1-(Dimethylamino)-2-methylpropan-2-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1053] ##STR00186##

[1054] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 1,4-diazabicyclo[3.2.1]octane dihydrochloride (110 mg, 0.60 mmol) with DABCO (107 mg, 0.95 mmol) to afford the title compound (6 mg, 5%) as a white solid.

[1055] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.34 (m, 1H), 3.40 (m, 1H), 3.22 (m, 1H), 3.04 (m, 4H), 2.82 (m, 8H), 2.73 (m, 1H), 2.60 (m, 1H), 2.31 (m, 1H), 2.03 (m, 4H), 1.95 (m, 1H).

[1056] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+); 389 (M−H).sup.− (ES.sup.−).

Example 61: 8-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-3-sulfonamide, potassium salt

[1057] ##STR00187##

[1058] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (107 mg, 0.34 mmol) and 8-ethyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P6) (72 mg, 0.34 mmol) to afford the title compound (0.9 mg, 0.5%) as a white solid.

[1059] LCMS: m/z 419 (M+H).sup.+ (ES.sup.+); 417 (M−H).sup.− (ES.sup.−).

Example 62: 3-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-sulfonamide, potassium salt

[1060] ##STR00188##

[1061] To a suspension of 3-ethyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P4) (60 mg, 0.28 mmol) in anhydrous tetrahydrofuran (10 mL) cooled at 0° C. was added sodium hydride (24 mg, 0.59 mmol). The suspension was then heated to 50° C. After heating for 1.5 hours, 1,4-diazabicyclo[2.2.2]octane (94 mg, 0.84 mmol) was added. After heating for 0.5 hour, the reaction mixture was cooled to 0° C. and then ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (176 mg, 0.56 mmol) was added. The reaction mixture was stirred overnight at room temperature and then potassium tert-butoxide (189 mg, 1.68 mmol) was added. After stirring for 15 minutes, the solvent was removed 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 (0.5 mg, 0.4%) as a white solid.

[1062] LCMS: m/z 419 (M+H).sup.+ (ES.sup.+); 417 (M−H).sup.− (ES.sup.−).

Example 63: (1R,3s,5S)-8-isopropyl-8-azabicyclo[3.2.1]octan-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-sulfonamide)

[1063] ##STR00189##

[1064] (1R,3s,5S)-8-Isopropyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride (Intermediate P17) (0.14 g, 0.71 mmol) was dissolved in dry THF (10 mL) under a nitrogen atmosphere and triethylamine (0.21 g, 0.30 mL, 2.1 mmol) was added, followed by ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (0.22 g, 0.70 mmol). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was evaporated in vacuo. Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (3 mg, 2%) as a white solid.

[1065] .sup.1H NMR (CD.sub.3OD) δ 6.92 (s, 1H), 4.60 (s, 2H), 4.14 (s, 2H), 2.93-2.72 (m, 8H), 2.30-2.09 (m, 4H), 2.09-1.81 (m, 11H), 1.49-1.21 (m, 6H).

[1066] LCMS: m/z 447 (M+H).sup.+ (ES.sup.+); 446 (M−H).sup.− (ES.sup.−).

Example 64: (1R,3r,5S)-3-(Diethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-8-azabicyclo[3.2.1]octane-8-sulfonamide

[1067] ##STR00190##

[1068] (1R,3r,5S)—N,N-Diethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride (Intermediate P15) (0.13 g, 0.60 mmol) was dissolved in dry THF (10 mL) under a nitrogen atmosphere and triethylamine (0.18 g, 0.25 mL, 1.81 mmol) was added, followed by ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (0.19 g, 0.60 mmol). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was evaporated in vacuo. Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (7 mg, 3%) as a white solid.

[1069] .sup.1H NMR (CD.sub.3OD) δ 6.90 (s, 1H), 4.42-4.26 (m, 2H), 3.60-3.41 (m, 1H), 3.14-2.92 (m, 5H), 2.92-2.77 (m, 9H), 2.73-2.56 (m, 2H), 2.37-2.19 (m, 2H), 2.14-1.94 (m, 4H), 1.75-1.54 (m, 2H), 1.50-1.29 (m, 2H), 1.28-1.15 (m, 6H).

[1070] LCMS: m/z 461 (M+H).sup.+ (ES.sup.+).

Example 65: 3-(N-(1-Isopropyl-1H-pyrazol-4-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1071] ##STR00191##

[1072] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 1-isopropyl-1H-pyrazol-4-amine (97 mg, 1.0 mmol) with triethylamine (0.1 g, 0.14 mL, 1.0 mmol) to afford the title compound (16 mg, 12%) as a white solid.

[1073] .sup.1H NMR (CD.sub.3OD) δ 7.42 (s, 1H), 6.91 (s, 1H), 6.19 (s, 1H), 4.18 (m, 1H), 2.82 (m, 8H), 1.41 (d, 6H).

[1074] LCMS: m/z 404 (M+H).sup.+ (ES.sup.+); 402 (M−H).sup.− (ES.sup.−).

Example 66: 3-((R)—N-Methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1075] ##STR00192##

[1076] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and (R)—N,1-dimethylpyrrolidin-3-amine (116 mg, 1.00 mmol) with triethylamine (100 mg, 100 mmol) to afford the title compound (36 mg, 9%) as a white solid.

[1077] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.60 (m, 1H), 2.82 (m, 11H), 2.74 (m, 2H), 2.61 (m, 1H), 2.50 (m, 1H), 2.38 (s, 3H), 2.03 (m, 6H).

[1078] LCMS: m/z 393 (M+H).sup.+ (ES.sup.+); 391 (M−H).sup.− (ES.sup.−).

Example 67: (1S,4S)—N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamide, potassium salt

[1079] ##STR00193##

[1080] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and (S)—N,1-dimethylpyrrolidin-3-amine (116 mg, 1.00 mmol) with triethylamine (100 mg, 100 mmol) to afford the title compound (20 mg, 16%) as a white solid.

[1081] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.29 (s, 1H), 3.62 (s, 1H), 3.42 (dd, 2H), 3.05 (m, 2H), 2.82 (m, 11H), 2.03 (m, 4H), 1.55 (m, 2H).

[1082] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+); 389 (M−H).sup.− (ES.sup.−).

Example 68: 3-(N-(1-(Dimethylamino)-2-methylpropan-2-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1083] ##STR00194##

[1084] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N,N-dimethyl-1-(pyrrolidin-3-yl)methanamine dihydrochloride (80 mg, 0.40 mmol) with triethylamine (100 mg, 1.0 mmol) to afford the title compound (27 mg, 21%) as a white solid.

[1085] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.58 (m, 1H), 3.42 (m, 1H), 3.37 (m, 1H), 3.03 (m, 1H), 2.82 (m, 10H), 2.42 (m, 1H), 2.23 (s, 6H), 2.03 (m, 5H), 1.61 (m, 1H).

[1086] LCMS: m/z 407 (M+H).sup.+ (ES.sup.+); 405 (M−H).sup.− (ES.sup.−).

Example 6A: 3-(N-((1-Methylazetidin-3-yl)methyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1087] ##STR00195##

[1088] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N-((1-methylazetidin-3-yl)methyl) (100 mg, 0.98 mmol) with triethylamine (100 mg, 1.0 mmol) to afford the title compound (12 mg, 10%) as a white solid.

[1089] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.58 (t, 2H), 3.20 (t, 2H), 3.12 (d, 2H), 2.82 (m, 8H), 2.72 (m, 1H), 2.40 (s, 3H), 2.03 (m, 4H).

[1090] LCMS: m/z 379 (M+H).sup.+ (ES.sup.+); 377 (M−H).sup.− (ES.sup.−).

Example 70: (1R,3r,5S)—N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl)-3-(pyrrolidin-1-yl)-8-azabicyclo[3.2.1]octane-8-sulfonamide

[1091] ##STR00196##

[1092] (1R,3r,5S)-3-(Pyrrolidin-1-yl)-8-azabicyclo[3.2.1]octane hydrochloride (Intermediate P14) (112 mg, 0.517 mmol) was dissolved in dry THF (10 mL) under a nitrogen atmosphere and triethylamine (157 mg, 0.216 mL, 1.55 mmol) was added, followed by ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (163 mg, 0.518 mmol). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was evaporated in vacuo.

[1093] Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (13 mg, 5%) as a white solid.

[1094] .sup.1H NMR (CD.sub.3OD) δ 6.92 (s, 1H), 4.36-4.11 (m, 2H), 3.02-2.91 (m, 5H), 2.90-2.75 (m, 9H), 2.60-2.41 (m, 2H), 2.30-2.13 (m, 2H), 2.11-1.98 (m, 5H), 1.96-1.85 (m, 4H), 1.84-1.69 (m, 2H), 1.67-1.47 (m, 2H).

[1095] LCMS: m/z 459 (M+H).sup.+ (ES.sup.+); 457 (M−H).sup.− (ES.sup.−).

Example 71: 3-(N-(2-(tert-Butylamino)ethyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1096] ##STR00197##

[1097] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1-(tert-butyl)ethane-1,2-diamine (100 mg, 0.86 mmol) with triethylamine (100 mg, 1.0 mmol) to afford the title compound (16 mg, 13%) as a white solid.

[1098] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.27 (t, 2H), 3.05 (t, 2H), 2.82 (m, 8H), 2.03 (m, 4H), 1.25 (s, 9H).

[1099] LCMS: m/z 395 (M+H).sup.+ (ES.sup.+).

Example 72: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-[1,3′-bipyrrolidine]-1′-sulfonamide, potassium salt

[1100] ##STR00198##

[1101] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 1,3′-bipyrrolidine (140 mg, 1.00 mmol) to afford the title compound (39 mg, 29%) as a white solid.

[1102] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.62 (dd, 1H), 3.42 (m, 1H), 3.39 (m, 1H), 3.19 (m, 1H), 2.99 (m, 1H), 2.82 (m, 8H), 2.62 (m, 4H), 2.17 (m, 1H), 2.03 (m, 4H), 1.87 (m, 1H), 1.80 (m, 4H).

[1103] LCMS: m/z 419 (M+H).sup.+ (ES.sup.+).

Example 73: 3-(Azetidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)pyrrolidine-1-sulfonamide, potassium salt

[1104] ##STR00199##

[1105] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 3-(azetidin-1-yl)pyrrolidine (100 mg, 0.79 mmol) with triethylamine (100 mg, 1.0 mmol) to afford the title compound (0.9 mg, 0.7%) as a white solid.

[1106] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.58 (t, 2H), 3.50 (m, 2H), 3.40 (m, 3H), 3.12 (m, 2H), 2.82 (m, 8H), 2.20 (m, 2H), 2.03 (m, 6H).

[1107] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+).

Example 74: (1R,3s,5S)-8-Ethyl-8-azabicyclo[3.2.1]octan-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-sulfonamide)

[1108] ##STR00200##

[1109] (1R,3s,5S)-8-Ethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride (Intermediate P18) (79 mg, 0.42 mmol) was dissolved in dry THF (10 mL) under a nitrogen atmosphere and triethylamine (0.13 g, 0.20 mL, 1.25 mmol) was added, followed by ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (0.13 g, 0.42 mmol). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was evaporated in vacuo.

[1110] Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (2 mg, 1%) as a white solid.

[1111] .sup.1H NMR (CD.sub.3OD) δ 6.92 (s, 1H), 3.94 (s, 2H), 3.12-2.96 (m, 3H), 2.93-2.74 (m, 9H), 2.34-2.15 (m, 5H), 2.13-1.99 (m, 7H), 1.98-1.77 (m, 2H), 1.39-1.24 (m, 3H).

[1112] LCMS: m/z 433 (M+H).sup.+ (ES.sup.+).

Example 75: 8-Cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-3,8-diazabicyclo[3.2.1]octane-3-sulfonamide, potassium salt

[1113] ##STR00201##

[1114] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (222 mg, 0.70 mmol) and 8-cyclopropyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Intermediate P8) (106 mg, 0.47 mmol) to afford the title compound (2.1 mg, 1%) as a white solid.

[1115] .sup.1H NMR (CD.sub.3OD) δ 6.95 (s, 1H), 3.42-3.34 (m, 4H), 3.26-3.17 (m, 2H), 2.82 (dt, 8H), 2.14-1.95 (m, 7H), 1.83 (d, 2H), 0.55-0.37 (m, 4H).

[1116] LCMS: m/z 431 (M+H).sup.+ (ES.sup.+).

Example 76: 3-((S)—N-Methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1117] ##STR00202##

[1118] Prepared as described for (1R,4R)—N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamide, potassium salt (Example 43) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (100 mg, 0.36 mmol) to afford the title compound (12 mg, 3%) as a white solid.

[1119] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.60 (m, 1H), 2.82 (m, 11H), 2.74 (m, 2H), 2.61 (m, 1H), 2.50 (m, 1H), 2.38 (s, 3H), 2.03 (m, 6H).

[1120] LCMS: m/z 393 (M+H).sup.+ (ES.sup.+); 391 (M−H).sup.− (ES.sup.−).

Example 77: (1R,3s,5S)-3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-8-azabicyclo[3.2.1]octane-8-sulfonamide

[1121] ##STR00203##

[1122] tert-Butyl (1R,3s,5S)-3-(dimethylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate P12) (0.23 g, 0.90 mmol) was dissolved in a 4N solution of hydrogen chloride in 1,4-dioxane (8 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo. The crude mixture (0.17 g, 0.90 mmol) was dissolved in dry THF (10 mL) under a nitrogen atmosphere and triethylamine (0.27 g, 0.38 mL, 2.7 mmol) was added, followed by ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (0.28 g, 0.90 mmol). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was evaporated in vacuo. Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (24 mg, 6%) as a white solid.

[1123] .sup.1H NMR (CD.sub.3OD) δ 6.95 (s, 1H), 4.06 (s, 2H), 2.96-2.80 (m, 7H), 2.71 (s, 6H), 2.36 (s, 1H), 2.15-1.99 (m, 6H), 1.96-1.70 (m, 7H), 1.66-1.56 (m, 2H).

[1124] LCMS: m/z 433 (M+H).sup.+ (ES.sup.+).

Example 78: (1R,3s,5S)-3-(Diethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-8-azabicyclo[3.2.1]octane-8-sulfonamide

[1125] ##STR00204##

[1126] (1R,3s,5S)—N,N-Diethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride (Intermediate P11) (0.17 g, 0.78 mmol) was dissolved in dry THF (10 mL) under a nitrogen atmosphere and triethylamine (0.32 g, 0.43 mL, 3.1 mmol) was added, followed by ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (0.25 g, 0.78 mmol). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was evaporated in vacuo. Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (17 mg, 5%) as a white solid.

[1127] .sup.1H NMR (CD.sub.3OD) δ 6.90 (s, 1H), 4.40-4.19 (m, 2H), 3.61-3.42 (m, 1H), 3.18-2.91 (m, 4H), 2.93-2.67 (m, 8H), 2.35-2.10 (m, 2H), 2.10-1.84 (m, 8H), 1.75-1.61 (m, 2H), 1.32-1.12 (m, 6H).

[1128] LCMS: m/z 461 (M+H).sup.+ (ES.sup.+); 459 (M−H).sup.− (ES.sup.−).

Example 7A: (1R,3r,5S)-3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-8-azabicyclo[3.2.1]octane-8-sulfonamide

[1129] ##STR00205##

[1130] (1R,3r,5S)—N,N-Dimethyl-8-azabicyclo[3.2.1]octan-3-amine hydrochloride (Intermediate P16) (0.13 g, 0.51 mmol) was dissolved in dry THF (10 mL) under a nitrogen atmosphere and triethylamine (0.15 g, 0.21 mL, 1.53 mmol) was added, followed by ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (0.16 g, 0.51 mmol). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was evaporated in vacuo. Purification by reversed phase column chromatography (see “Experimental Methods”) gave the title compound (17 mg, 8%) as a white solid.

[1131] .sup.1H NMR (CD.sub.3OD) δ 6.92 (s, 1H), 4.41-4.19 (m, 2H), 2.94-2.76 (m, 11H), 2.56-2.43 (m, 7H), 2.27-2.16 (m, 2H), 2.14-1.96 (m, 5H), 1.81-1.62 (m, 2H), 1.57-1.39 (m, 2H).

[1132] LCMS: m/z 433 (M+H).sup.+ (ES.sup.+); 431 (M−H).sup.− (ES.sup.−).

Example 80: 3-(N-Methyl-N-((1-methylpyrrolidin-2-yl)methyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1133] ##STR00206##

[1134] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N-methyl-1-(1-methylpyrrolidin-2-yl)methanamine (racemic Intermediate P23; 128 mg, 1.00 mmol) to afford the title compound (9 mg, 7%) as a white solid.

[1135] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.58 (m, 2H), 3.22 (m, 2H), 2.82 (m, 15H), 2.03 (m, 8H).

[1136] LCMS: m/z 407 (M+H).sup.+ (ES.sup.+); 405 (M−H).sup.− (ES.sup.−).

Example 81: 3-(N-(3-(Dimethylamino)propyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1137] ##STR00207##

[1138] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1,N1-dimethylpropane-1,3-diamine (102 mg, 1.00 mmol) to afford the title compound (26 mg, 22%) as a white solid.

[1139] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.16 (t, 2H), 2.82 (m, 10H), 2.60 (s, 6H), 2.03 (m, 4H), 1.81 (t, 2H).

[1140] LCMS: m/z 381 (M+H).sup.+ (ES.sup.+); 379 (M−H).sup.− (ES.sup.−).

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

[1141] ##STR00208##

[1142] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N,N-dimethyl-1-(pyrrolidin-2-yl)methanamine (128 mg, 1.00 mmol) to afford the title compound (26 mg, 20%) as a white solid.

[1143] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.36 (m, 1H), 3.51 (m, 1H), 3.21 (m, 1H), 3.05 (m, 2H), 2.82 (m, 14H), 2.60 (s, 6H), 2.03 (m, 9H), 1.54 (m, 1H).

[1144] LCMS: m/z 407 (M+H).sup.+ (ES.sup.+); 405 (M−H).sup.− (ES.sup.−).

Example 83: 3-(N-(2-(Dimethylamino)ethyl)-N-isopropylsulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1145] ##STR00209##

[1146] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N1-isopropyl-N2,N2-dimethylethane-1,2-diamine (130 mg, 1.00 mmol) to afford the title compound (9 mg, 7%) as a white solid.

[1147] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.12 (m, 1H), 3.43 (t, 2H), 3.19 (t, 2H), 2.82 (m, 14H), 2.03 (m, 4H), 1.21 (s, 6H).

[1148] LCMS: m/z 409 (M+H).sup.+ (ES.sup.+); 407 (M−H).sup.− (ES.sup.−).

Example 84: 3-(N-Methyl-N-((1-methylazetidin-3-yl)methyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1149] ##STR00210##

[1150] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and N-methyl-1-(1-methylazetidin-3-yl)methanamine (116 mg, 1.02 mmol) to afford the title compound (15 mg, 12%) as a white solid.

[1151] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.07 (m, 4H), 3.43 (m, 2H), 2.97 (m, 1H), 2.87 (s, 3H), 2.82 (m, 8H), 2.80 (s, 3H), 2.03 (m, 4H).

[1152] LCMS: m/z 393 (M+H).sup.+ (ES.sup.+); 391 (M−H).sup.− (ES.sup.−).

Example 8t: 6-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,6-diazabicyclo[3.2.0]heptane-3-sulfonamide

[1153] ##STR00211##

[1154] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (142 mg, 0.45 mmol), 6-ethyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride (Intermediate P20) (59 mg, 0.30 mmol) and triethylamine (0.12 mL, 0.9 mmol) to afford the title compound (0.9 mg, 0.7%) as a white solid.

[1155] .sup.1H NMR (CD.sub.3OD) δ 6.90 (s, 1H), 3.81 (m, 1H), 3.57-3.50 (m, 2H), 3.28-3.12 (m 4H), 3.10-3.04 (m, 1H), 2.89-2.77 (m, 10H), 2.09-1.98 (m, 4H), 1.14 (t, 3H).

[1156] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (M−H).sup.− (ES.sup.−).

Example 86: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-3,6-diazabicyclo[3.2.0]heptane-3-sulfonamide

[1157] ##STR00212##

[1158] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (151 mg, 0.48 mmol), 6-methyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride (Intermediate P19) (59 mg, 0.32 mmol) and triethylamine (0.13 mL, 0.96 mmol) to afford the title compound (3 mg, 2%) as a white solid.

[1159] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.71-4.59 (m, 1H), 4.05-3.93 (m, 1H), 3.89-3.71 (m, 2H), 3.52 (d, 2H), 3.25-3.00 (m, 2H), 2.92-2.70 (m, 11H), 2.08-1.95 (m, 4H).

[1160] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+); 389 (M−H).sup.− (ES.sup.−).

Example 87: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-isopropyl-3,6-diazabicyclo[3.2.0]heptane-3-sulfonamide, potassium salt

[1161] ##STR00213##

[1162] Prepared as described for (1R,4R)—N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamide, potassium salt (Example 43) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol), 6-isopropyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride (Intermediate P21) (121 mg, 0.57 mmol), triethylamine (96 mg, 0.95 mmol), sodium hydride (60%) (19 mg, 0.32 mmol) and DABCO (100 mg, 0.63 mmol) to afford the title compound (1 mg, 1%) as a white solid.

[1163] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.34 (m, 1H), 3.61 (m, 2H), 3.41 (m, 2H), 3.12 (m, 3H), 3.04 (m, 1H), 2.82 (m, 8H), 2.03 (m, 4H), 1.01 (d, 3H), 0.98 (d, 2H).

[1164] LCMS: m/z 419 (M+H).sup.+ (ES.sup.+); 417 (M−H).sup.− (ES.sup.−).

Example 88: 3-((S)—N-(1-Methylpyrrolidin-3-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1165] ##STR00214##

[1166] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and (S)-1-methylpyrrolidin-3-amine (100 mg, 1.00 mmol) to afford the title compound (4 mg, 3%) as a white solid.

[1167] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.95 (m, 1H), 3.01 (dd, 1H), 2.82 (m, 8H), 2.56 (m, 3H), 2.38 (s, 3H), 2.22 (m, 1H), 2.03 (m, 6H), 1.80 (m, 1H).

[1168] LCMS: m/z 379 (M+H).sup.+ (ES.sup.+); 377 (M−H).sup.− (ES.sup.−).

Example 89: 3-((R)—N-(1-Methylpyrrolidin-3-yl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1169] ##STR00215##

[1170] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and (R)-1-methylpyrrolidin-3-amine (100 mg, 1.00 mmol) to afford the title compound (11 mg, 9%) as a white solid.

[1171] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.95 (m, 1H), 3.01 (dd, 1H), 2.82 (m, 8H), 2.56 (m, 3H), 2.38 (s, 3H), 2.22 (m, 1H), 2.03 (m, 6H), 1.80 (m, 1H).

[1172] LCMS: m/z 379 (M+H).sup.+ (ES.sup.+); 377 (M−H).sup.− (ES.sup.−).

Example 90: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-1,4-diazepane-1-sulfonamide, potassium salt

[1173] ##STR00216##

[1174] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 1-methyl-1,4-diazepane (114 mg, 1.00 mmol) to afford the title compound (13 mg, 10%) as a white solid.

[1175] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.55 (m, 2H), 3.48 (t, 2H), 2.99 (m, 2H), 2.82 (m, 8H), 2.67 (m, 2H), 2.40 (s, 3H), 2.03 (m, 4H), 1.95 (m, 2H).

[1176] LCMS: m/z 393 (M+H).sup.+ (ES.sup.+); 391 (M−H).sup.− (ES.sup.−).

Example 91: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-1,6-diazaspiro[3.3]heptane-1-sulfonamide, potassium salt

[1177] ##STR00217##

[1178] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 6-methyl-1,6-diazaspiro[3.3]heptane (114 mg, 1.00 mmol) to afford the title compound (4 mg, 3%) as a white solid.

[1179] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.50 (d, 2H), 4.05 (d, 2H), 3.73 (t, 2H), 2.82 (m, 8H), 2.78 (s, 3H), 2.42 (t, 2H), 2.03 (m, 4H).

[1180] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+); 389 (M−H).sup.− (ES.sup.−).

Example 92: (1S,5S)—N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-3,6-diazabicyclo[3.2.0]heptane-3-sulfonamide, potassium salt

[1181] ##STR00218##

[1182] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (116 mg, 0.37 mmol) and (1R,5S)-6-methyl-3,6-diazabicyclo[3.2.0]heptane 2,2,2-trifluoroacetate (125 mg, 0.37 mmol) with DABCO (124 mg, 1.10 mmol) to afford the title compound (22 mg, 15%) as a white solid.

[1183] .sup.1H NMR (CD.sub.3OD) δ 6.89 (s, 1H), 4.08 (m, 1H), 3.67 (d, 1H), 3.50 (t, 1H), 3.15 (m, 1 Ho, 2.99 (m, 1H), 2.82 (m, 12H), 2.40 (s, 3H), 2.03 (m, 4H).

[1184] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+); 389 (M−H).sup.− (ES.sup.−).

Example 93: (1R,5R)—N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl)-6-methyl-3,6-diazabicyclo[3.2.0]heptane-3-sulfonamide, potassium salt

[1185] ##STR00219##

[1186] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (116 mg, 0.37 mmol) and (1S,5R)-6-methyl-3,6-diazabicyclo[3.2.0]heptane 2,2,2-trifluoroacetate (125 mg, 0.37 mmol) with DABCO (124 mg, 1.10 mmol) to afford the title compound (1 mg, 1%) as a white solid.

[1187] .sup.1H NMR (CD.sub.3OD) δ 6.85 (s, 1H), 3.98 (m, 1H), 3.60 (d, 1H), 3.40 (t, 1H), 3.20 (m, 1H), 3.05 (m, 2H), 2.95 (m, 1H), 2.82 (m, 9H), 2.30 (s, 3H), 2.03 (m, 4H).

[1188] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+); 389 (M−H).sup.− (ES.sup.−).

Example 94: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-sulfonamide, potassium salt

[1189] ##STR00220##

[1190] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 3-methyl-3,6-diazabicyclo[3.2.0]heptane (100 mg, 0.89 mmol) to afford the title compound (1.3 mg, 1%) as a white solid.

[1191] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.17 (t, 1H), 3.59 (d, 2H), 3.42 (m, 1H), 3.18 (m, 1H), 2.82 (m, 14H), 2.70 (m, 1H), 2.03 (m, 4H).

[1192] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+).

Example 95: 3-((R)—N-Methyl-N-((1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt

[1193] ##STR00221##

[1194] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and (R)—N-methyl-1-(1-methylpyrrolidin-2-yl)methanamine (Intermediate P23; 100 mg, 0.90 mmol) to afford the title compound (6 mg, 5%) as a white solid.

[1195] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.78 (d, 2H), 3.42 (m, 1H), 3.08 (m, 2H), 2.82 (m, 14H), 2.20 (m, 2H), 2.03 (m, 6H).

[1196] LCMS: m/z 408 (M+H).sup.+ (ES.sup.+).

Example 96: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-sulfonamide, potassium salt

[1197] ##STR00222##

[1198] Prepared as described for 3-(N-(2-(dimethylamino)-2-methylpropyl)sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, potassium salt (Example 57) using ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (100 mg, 0.32 mmol) and 1-methyloctahydropyrrolo[3,4-b]pyrrole (80 mg, 0.63 mmol) with triethylamine (73 mg, 0.72 mmol) to afford the title compound (14 mg, 11%) as a white solid.

[1199] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.41 (d, 1H), 3.22 (d, 1H), 3.17 (m, 3H), 3.05 (m, 1H), 2.99 (m, 1H), 2.82 (m, 10H), 2.42 (s, 3H), 2.12 (m, 1H), 2.03 (m, 4H).

[1200] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (M−H).sup.− (ES.sup.−).

Example 97: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridine-6-sulfonamide

[1201] ##STR00223##

[1202] Chlorosulfonyl isocyanate (81.7 mg, 1 eq, 0.58 mmol) was dissolved in DCM (20 mL) under N.sub.2 atmosphere and cooled to 0° C. 1,2,3,5,6,7-Hexahydro-s-indacen-4-amine (100 mg, 1 eq, 0.58 mmol) was added and the mixture was stirred for 10 minutes. 1-Methyloctahydro-1H-pyrrolo[3,4-b]pyridine (100 mg, 1.24 eq, 0.72 mmol) and TEA (0.1 mL, 1 eq, 0.7 mmol) were added and the mixture was allowed to reach room temperature over 1 hour. The suspension was evaporated to near dryness and submitted for reversed phase column chromatography to afford the title compound (32 mg, 13%) as a white solid.

[1203] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.78 (d, 1H), 3.50 (m, 2H), 3.38 (t, 1H), 3.07 (m, 1H), 2.82 (m, 10H), 2.48 (m, 1H), 2.41 (s, 3H), 2.03 (m, 4H), 1.60 (m, 4H).

[1204] LCMS: m/z 419 (M+H).sup.+ (ES.sup.+).

Example 98: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyloctahydro-6H-pyrrolo[2,3-c]pyridine-6-sulfonamide

[1205] ##STR00224##

[1206] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridine-6-sulfonamide (Example 97) using chlorosulfonyl isocyanate (49 mg, 0.35 mmol), 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (60 mg, 0.35 mmol) and 1-methyloctahydro-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.73 mmol) with triethylamine (73 mg, 0.72 mmol) to afford the title compound (8 mg, 6%) as a white solid.

[1207] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 4.09 (d, 1H), 3.58 (m, 1H), 3.43 (m, 1H), 2.99 (m, 2H), 2.82 (m, 10H), 2.79 (s, 3H), 2.42 (m, 1H), 2.12 (m, 1H), 2.03 (m, 4H), 1.63 (m, 3H).

[1208] LCMS: m/z 419 (M+H).sup.+ (ES.sup.+); 417 (M−H).sup.− (ES.sup.−).

Example 99: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-sulfonamide

[1209] ##STR00225##

[1210] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridine-6-sulfonamide (Example 97) using chlorosulfonyl isocyanate (82 mg, 0.58 mmol), 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (100 mg, 0.58 mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (146 mg, 1.15 mmol) with triethylamine (73 mg, 0.72 mmol) to afford the title compound (4 mg, 2%) as a white solid.

[1211] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.38 (m, 2H), 3.23 (m, 4H), 3.12 (m, 4H), 2.82 (m, 8H), 2.65 (s, 3H), 2.03 (m, 4H).

[1212] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (M−H).sup.− (ES.sup.−).

Example 100: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-sulfonamide

[1213] ##STR00226##

[1214] Chlorosulfonyl isocyanate (81.7 mg, 1 eq, 0.58 mmol) was dissolved in DCM (20 mL) under N.sub.2 atmosphere and cooled to 0° C. 1,2,3,5,6,7-Hexahydro-s-indacen-4-amine (100 mg, 1 eq, 0.58 mmol) was added and the mixture was stirred for 10 minutes. 6-Methyl-3,6-diazabicyclo[3.1.1]heptane hydrochloride (Intermediate P22) (100 mg, 1.15 eq, 0.67 mmol), pre-treated with NaH (69 mg, 1.73 mmol) and DABCO (129 mg, 1.15 mmol) in DCM (5 mL), was added and the mixture was allowed to reach room temperature over 1 hour. The suspension was evaporated to near dryness and submitted for reversed phase column chromatography to afford the title compound (2 mg, 1%) as a white solid.

[1215] .sup.1H NMR (CD.sub.3OD) δ 6.91 (s, 1H), 3.85 (m, 2H), 3.62 (m, 2H), 2.82 (m, 15H), 2.03 (m, 4H).

[1216] LCMS: m/z 391 (M+H).sup.+ (ES.sup.+).

[1217] The compounds of examples 101-108 were synthesised by methods analogous to those outlined above and below.

TABLE-US-00001 TABLE 1 .sup.1H NMR and MS data Ex Structure and Name 1H NMR spectrum MS MW 101 [00227] .sup.1H NMR (Methanol-d.sub.4) δ 8.71 (dd, 1H), 7.97 (d, 1H), 7.73 (dd, 1H), 7.19 (dd, 1H), 7.02 (dd, 1H), 4.44 (q, 1H), 3.09- 3.00 (m, 2H), 3.00- 2.91 (m, 2H), 2.91-2.71 (m, 1H), 2.64 (s, 3H), 2.59 (s, 3H), 2.05 (dq, 1H), 1.98-1.82 (m, 1H), 1.35-1.16 (m, 6H). m/z 475.2 (M + H).sup.+ (ES.sup.+) 474.56 102 [00228] .sup.1H NMR (Methanol-d.sub.4) δ 8.73 (d, 1H), 8.03 (d, 1H), 7.78 (d, 1H), 7.21 (dd, 1H), 7.07 (dd, 1H), 4.57 (m, 1H), 3.37- 3.07 (m, 3H), 2.91 (m, 2H), 2.79 (s, 3H), 2.65 (s, 3H), 2.22-1.83 (m, 4H), 1.25 (dd, 6H). m/z 489.2 (M + H).sup.+ (ES.sup.+) 488.58 103 [00229] .sup.1H NMR (Methanol-d.sub.4) δ 8.68 (dd, 1H), 7.95 (dd, 1H), 7.73 (dd, 1H), 7.32-7.14 (m, 3H), 4.51 (q, 1H), 3.26-3.13 (m, 1H), 3.11-2.89 (m, 6H), 2.70 (d, 6H), 2.14 (m, 3H), 2.09-1.89 (m, 1H). m/z 455.2 (M + H).sup.+ (ES.sup.+) 454.55 104 [00230] .sup.1H NMR (Methanol-d.sub.4) δ 8.67 (dd, 1H), 7.95 (dd, 1H), 7.73 (dd, 1H), 7.21 (q, 2H), 3.62-3.40 (m, 2H), 3.16-2.88 (m, 9H), 2.81 (dt, 1H), 2.72 (s, 3H), 2.38-2.25 (m, 1H), 2.25-2.04 (m, 2H), 1.57 (dd, 1H). m/z 467.2 (M + H).sup.+ (ES.sup.+) 466.56 105 [00231] .sup.1H NMR (Methanol-d.sub.4) δ 8.71 (dd, 1H), 7.97 (d, 1H), 7.74 (dd, 1H), 7.19 (dd, 1H), 7.02 (dd, 1H), 3.46 (dd, 2H), 3.04- 2.86 (m, 6H), 2.88- 2.73 (m, 1H), 2.68 (s, 3H), 2.32-2.21 (m, 1H), 1.67-1.41 (m, 1H), 1.37-1.13 (m, 6H). m/z 487.2 (M + H).sup.+ (ES.sup.+) 486.57 106 [00232] .sup.1H NMR (Methanol-d.sub.4) δ 8.12 (dd, 1H), 7.27- 7.10 (m, 2H), 7.02 (dd, 1H), 6.85 (d, 1H), 3.93 (s, 3H), 3.55 (dd, 2H), 3.18-3.05 (m, 3H), 2.96 (dt, 6H), 2.80 (dt, 1H), 2.72 (s, 3H), 2.30 (dt, 1H), 2.11 (p, 2H), 1.62 (ddd, 1H). m/z 472.2 (M + H).sup.+ (ES.sup.+) 471.58 107 [00233] .sup.1H NMR (Methanol-d.sub.4) δ 8.68 (dd, 1H), 8.03 (dd, 1H), 7.78 (dd, 1H), 7.23 (d, 2H), 3.72 (dd, 1H), 3.51 (d, 1H), 3.19- 3.09 (m, 1H), 3.09- 2.91 (m, 6H), 2.79 (s, 3H), 2.71 (s, 3H), 2.13 (p, 2H), 1.99 (m, 3H), 1.65 (m, 1H). m/z 469.4 (M + H).sup.+ (ES.sup.+) 468.58 108 [00234] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.57 (d, 2 H), 7.52 (d, 2 H), 7.18 (dd, 1 H), 6.98 (dd, 1 H), 4.43 (m, 1 H), 2.98-2.82 (m, 3 H), 2.80-2.70 (m, 2.62 (s, 3 H), 2.54 (s, 3 H), 2.05-1.80 (m, 2 H), 1.22 (d, 6 H). m/z 450.2 (M + H).sup.+ (ES.sup.+) m/z 448.2 (M − H).sup.− (ES.sup.−) 449.55

Example 109: 1-(5-Isopropyl-2-methyl-3-(4-pyridyl)imidazol-4-yl)-3-(methyl-(1-methylpyrrolidin-3-yl) sulfamoyl)urea

Step A: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)amide

[1218] ##STR00235##

[1219] A solution of N,N-dimethylpyridin-4-amine (366 mg, 3.00 mmol, 2 eq) and 1-methyl-3-[methyl(sulfamoyl)amino]pyrrolidine (Intermediate P26) (0.29 g, 1.50 mmol, 1 eq) in MeCN (8 mL) was stirred at 20° C. for 30 minutes. Then diphenyl carbonate (353 mg, 1.65 mmol, 1.1 eq) was added. The resulting mixture was stirred at 20° C. for 12 hours. The mixture (theoretical amount: 0.53 g, crude) was used directly in the next step.

Step B: 1-(5-Isopropyl-2-methyl-3-(4-pyridyl)imidazol-4-yl)-3-(methyl-(1-methylpyrrolidin-3-yl)sulfamoyl)urea

[1220] ##STR00236##

[1221] To a mixture of 4-isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-amine (Intermediate A8) (0.2 g, 791.32 μmol, 1 eq, HCl salt) in MeCN (1 mL) was added a solution of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)amide (the reaction mixture of step A) in MeCN (8 mL). The resulting mixture was heated to 70° C. and stirred for 30 minutes under N.sub.2. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) and then further purified by prep HPLC (column: Waters XBridge C18, 150 mm×25 mm×5 μm; mobile phase [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 1%-15%, 10 minutes) to give the title compound (25.13 mg, 7% yield over two steps, 100% purity on LCMS) as a white solid.

[1222] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.70 (d, J=6.0 Hz, 2H), 7.50-7.48 (m, 2H), 4.48-4.44 (m, 1H), 3.30-2.92 (m, 5H), 2.74 (s, 3H), 2.63 (s, 3H), 2.29 (s, 3H), 2.15-1.98 (m, 2H), 1.27 (d, J=6.8 Hz, 6H). 2×NH were missing.

[1223] LCMS: m/z 436.1 (M+H).sup.+ (ES.sup.+).

Example 110: (R)-3-(N-Methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea, potassium salt

[1224] ##STR00237##

[1225] Prepared as described for 3-(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea (Example 1), using chlorosulfonyl isocyanate (109 μL, 1.25 mmol), 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A2) (300 mg, 1.25 mmol) and (S)—N,1-dimethylpyrrolidin-3-amine (0.19 mL, 1.50 mmol), except that a solution of (S)—N,1-dimethylpyrrolidin-3-amine and triethylamine (0.21 mL, 1.50 mmol) in DCM (5 mL) was added to the reaction mixture and the reaction was allowed to reach room temperature over one hour. Then the mixture was evaporated to dryness in vacuo. The residue was suspended in tetrahydrofuran, and then potassium tert-butoxide (280 mg, 2.50 mmol) was added. The suspension was sonicated for 15 minutes and then concentrated in vacuo. The crude product was purified by reversed phase chromatography to afford the title compound (24 mg, 4%) as a white solid.

[1226] .sup.1H NMR (CD.sub.3OD) δ 8.11 (dd, 1H), 7.19 (d, 1H), 7.12 (d, 1H), 7.02 (dd, 1H), 6.85 (d, 1H), 4.49 (p, 1H), 3.93 (s, 3H), 2.95 (dt, 5H), 2.87-2.77 (m, 3H), 2.71 (s, 3H), 2.50 (s, 3H), 2.18-2.02 (m, 3H), 1.89 (dq, 1H).

[1227] LCMS: m/z 460 (M+H).sup.+ (ES.sup.+).

Example 11: (S)-3-(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea, potassium salt

[1228] ##STR00238##

[1229] Prepared as described for 3-(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea (Example 1), using chlorosulfonyl isocyanate (109 μL, 1.25 mmol), 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A2) (300 mg, 1.25 mmol) and (R)—N,1-dimethylpyrrolidin-3-amine (0.19 mL, 1.50 mmol), except that a solution of (R)—N,1-dimethylpyrrolidin-3-amine and triethylamine (0.21 mL, 1.50 mmol) in DCM (5 mL) was added to the reaction mixture and the reaction was allowed to reach room temperature over one hour. Then the mixture was evaporated to dryness in vacuo. The residue was suspended in tetrahydrofuran, and then potassium tert-butoxide (280 mg, 2.50 mmol) was added. The suspension was stirred for 10 minutes and then concentrated in vacuo. The crude product was purified by reversed phase chromatography to afford the title compound (55 mg, 9%) as a white solid.

[1230] .sup.1H NMR (CD.sub.3OD) δ 8.11 (d, 1H), 7.20 (d, 1H), 7.12 (d, 1H), 7.01 (dd, 1H), 6.85 (d, 1H), 4.49 (p, 1H), 3.93 (s, 3H), 3.07-2.79 (m, 8H), 2.72 (s, 3H), 2.52 (s, 3H), 2.08 (dp, 3H), 1.91 (dq, 1H).

[1231] LCMS: m/z 460 (M+H).sup.+ (ES.sup.+).

Example 112: (R)—(N-Methyl-N-((1-methylpyrrolidin-2-yl)methyl) sulfamoyl)((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)amide, potassium salt

[1232] ##STR00239##

[1233] 1,2,3,5-Tetrahydro-s-indacen-4-amine (Intermediate A5; 50 mg, 0.29 mmol) was dissolved in anhydrous THF (12.5 mL). The mixture was cooled in a bath of ice with brine. Next, chlorosulfonyl isocyanate (25 μL, 0.29 mmol) was added dropwise. After stirring for 10 minutes on ice, (R)—N-methyl-1-(1-methylpyrrolidin-2-yl)methanamine (Intermediate P23; 169 mg, 0.99 mmol) was added dropwise. After another 15 minutes stirring on ice, potassium tert-butoxide (66 mg, 0.58 mmol) was added. After 5 minutes, the reaction mixture was concentrated in vacuo. The crude was dissolved in methanol and submitted for reversed phase purification using acetonitrile and water as eluent. The fractions containing the product were combined and lyophilized. The yellowish solid that was obtained was submitted for prep LC-MS purification. The product fractions were lyophilized to afford the title compound (33 mg; 26%) as a yellowish solid.

[1234] .sup.1H NMR (CD.sub.3OD) δ 7.21-7.02 (m, 1H), 6.88-6.72 (m, 1H), 6.54-6.37 (m, 1H), 3.88-3.71 (m, 1H), 3.71-3.56 (m, 1H), 3.52-3.40 (m, 1H), 3.32-3.28 (m, 2H), 3.29-3.22 (m, 1H), 3.12-2.97 (m, 1H), 2.98-2.81 (m, 10H), 2.27-2.14 (m, 1H), 2.14-1.96 (m, 5H).

[1235] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+); 403 (M−H).sup.− (ES.sup.−).

Example 113: N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)N,N-dimethylsulfamide

[1236] ##STR00240##

[1237] 6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A6; 58 mg, 0.172 mmol) was added to a suspension of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)(N,N-dimethylsulfamoyl)amide (Intermediate P24; 47 mg, 0.173 mmol) in MeCN (1 mL). The reaction was stirred at 60° C. for 1 hour, then cooled to room temperature and stirred for 72 hours. The reaction mixture was concentrated in vacuo and purified by basic prep HPLC (10-40% MeCN in water) to afford the title compound (17 mg, 19%) as a white solid.

[1238] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J=5.2 Hz, 1H), 7.46 (br s, 1H), 7.10 (s, 1H), 6.72 (dd, J=5.2, 1.4 Hz, 1H), 6.52 (s, 1H), 5.04-4.95 (m, 1H), 2.90 (t, J=7.4 Hz, 2H), 2.77-2.69 (m, 4H), 2.64 (s, 6H), 2.28-2.16 (m, 5H), 2.09-1.94 (m, 7H), 1.73-1.64 (m, 2H). One exchangeable proton not observed.

[1239] LCMS m/z 488.4 (M+H).sup.+ (ES.sup.+); 486.3 (M−H).sup.− (ES.sup.−).

Example 14: N-((5-(2-Methoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)(N,N-dimethylsulfamoyl)amide

[1240] ##STR00241##

[1241] 5-(2-Methoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate A7; 38 mg, 0.149 mmol) was added to a suspension of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)(N,N-dimethylsulfamoyl)amide (Intermediate P24; 41 mg, 0.151 mmol) in MeCN (1 mL) and the reaction mixture was stirred at 60° C. for 1 hour. The volatiles were evaporated, and the crudes dissolved in DMSO (1 mL), filtered and purified by basic prep HPLC (20-50% MeCN in water) to afford the title compound (17 mg, 28%) as a white solid.

[1242] .sup.1H NMR (DMSO-d6) δ 9.66 (br s, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.46 (s, 1H), 7.11 (s, 1H), 6.75 (dd, J=5-3, 1.4 Hz, 1H), 6.59 (s, 1H), 3.89 (s, 3H), 2.90 (t, J=7.4 Hz, 2H), 2.76-2.70 (m, 2H), 2.66 (s, 6H), 2.05-1.96 (m, 5H).

[1243] LCMS m/z 405.2 (M+H).sup.+ (ES.sup.+).

Example 115: 3-((S)—N-Methyl-N-((-1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, sodium salt

Step A: 3-((S)—N-Methyl-N-((-1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea

[1244] ##STR00242##

[1245] To a solution of (S)—N-methyl-1-(1-methylpyrrolidin-2-yl)methanamine (Intermediate P25) (1.02 g, 7.94 mmol, 5 eq) in THF (4 mL) was added ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl chloride (Intermediate A4) (0.5 g, 1.59 mmol, 1 eq) in THF (1 mL). The reaction mixture was stirred at 0° C. for 10 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters XBridge C18, 150 mm×25 mm×5 μm; mobile phase [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 19%-49%, 10 minutes) to give the title compound (33 mg, 5% yield, 98.8% purity on HPLC) as a white solid.

[1246] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 6.92 (s, 1H), 3.80-3.70 (m, 2H), 3.51-3.45 (m, 1H), 3.30-3.24 (m, 1H), 3.10-3.03 (m, 1H), 2.91 (s, 3H), 2.89-2.77 (m, 11H), 2.24-2.18 (m, 1H) and 2.13-1.94 (m, 7H). 2×NHs were missing.

[1247] LCMS: m/z 407.2 (M+H).sup.+ (ES.sup.+).

Step B: 3-((S)—N-Methyl-N-((-1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea, sodium salt

[1248] ##STR00243##

[1249] To a solution of 3-((S)—N-methyl-N-((-1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea (30 mg, 73.79 μmol, 1 eq) in THF (10 mL) was added t-BuONa (7 mg, 73.79 μmol, 1 eq) at 0° C. The reaction mixture was stirred at 5° C. for 30 minutes. Then the reaction mixture was concentrated in vacuo and lyophilized to give the title compound (20.92 mg, 65% yield, 98.1% purity on HPLC) as a white solid.

[1250] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 6.87 (s, 1H), 3.32-3.31 (m, 1H), 3.12-3.03 (m, 2H), 2.86-2.80 (m, 11H), 2.58-2.55 (m, 1H), 2.42 (s, 3H), 2.31-2.26 (m, 1H), 2.07-1.99 (m, 5H) and 1.77-1.67 (m, 3H). 1×NH was missing.

[1251] LCMS: m/z 407.4 (M−Na+2H).sup.+ (ES.sup.+).

Examples—Biological Studies

[1252] NLRP and Pyroptosis

[1253] 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-1β) from the cell.

[1254] THP-1 Cells: Culture and Preparation

[1255] 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 μg/ml Final Assay Concentration (FAC). 40 μl of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

[1256] THP-1 Cells Pyroptosis Assay

[1257] The following method step-by-step assay was followed for compound screening. [1258] 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 μg/ml LPS in 40 μl of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) [1259] 2. Add 5 μl compound (8 points half-log dilution, with 10 μM top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1260] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1261] 4. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells [1262] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1263] 6. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant [1264] 7. Then add 50 μl of resazurin (Sigma #R7017) (FAC 100 μM resazurin in RPMI medium without FBS) and incubate plates for a further 1-2 hrs at 37° C. and 5% CO.sub.2 [1265] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [1266] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

TABLE-US-00002 96-well Plate Man 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 Low Drug free control half-log dilution

[1267] The results of the pyroptosis assay performed are summarised in Table 2 below as THP IC.sub.50.

[1268] Human Whole Blood IL-1β Release Assay

[1269] 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.

[1270] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [1271] 1. Plate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [1272] 2. Add 10 μl compound (8 points half-log dilution with 10 μM top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1273] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1274] 4. Add 10 μl nigericin (Sigma #N7143) (10 μM FAC) to all wells [1275] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1276] 6. At the end of the incubation period, spin plates at 300×g for 5 mins to pellet cells and remove 20 μl of supernatant and add to 96-well v-bottom plates for IL-1β analysis (note: these plates containing the supernatants can be stored at −80° C. to be analysed at a later date) [1277] 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [1278] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[1279] The results of the human whole blood assay are summarised in Table 2 below as HWB IC.sub.50.

TABLE-US-00003 TABLE 2 NLRP.sub.3 inhibitory activity (≤0.5uM = ‘++++’, ≤1 uM = ‘+++‘, ≤5 uM = ≤10 uM = not determined = ‘ND’). Example THP HWB No IC.sub.50 IC.sub.50 1 ++++ ++++ 2 ++++ ++++ 3 ++++ ++++ 4 ++++ ++++ 5 ++++ ++++ 6 ++++ ++++ 7 +++ ND 8 +++ ++++ 9 ++++ ++++ 10 ++ ++ 11 ++++ ++++ 12 ++ ND 13 +++ ND 14 ++++ ++++ 15 ++++ ++++ 16 ++ ND 17 +++ ND 18 ++ ND 19 +++ ND 20 ++++ ++++ 21 ++ ND 22 ++++ ND 23 ++ ND 24 + ND 25 +++ ++++ 26 ++++ +++ 27 +++ ND 28 ++++ ++++ 29 ++++ ++++ 30 +++ ++++ 31 ++++ ++++ 32 ++ ND 33 ++ ND 34 ++++ ++++ 35 ++ +++ 36 ++++ +++ 37 ++++ +++ 38 ++++ +++ 39 ++++ +++ 40 +++ ++++ 41 ++ ND 42 ++ ND 43 ++++ ++++ 44 +++ ++++ 45 ++++ + 46 +++ ++ 47 +++ +++ 48 +++ ND 49 ++++ ++++ 50 ++++ ++++ 51 + ND 52 ++++ ++++ 53 ++ ND 54 ++ ND 55 +++ ND 57 ++ ND 58 ++++ ++ 59 ++ ND 60 +++ ND 61 ++++ ++++ 62 ++++ +++ 63 +++ ND 64 ++++ ND 65 ++++ ++ 66 ++++ ++++ 67 +++ ND 68 ++++ +++ 69 +++ ND 70 +++ ND 71 ++++ +++ 72 ++++ ++++ 73 +++ ++ 74 ++ ND 75 ++++ ++ 76 ++++ ++++ 77 + ND 78 ++ ND 79 ++++ ++++ 80 ++++ ++++ 81 ++++ ++++ 82 ++ ND 83 +++ ++ 84 ++++ +++ 85 ++++ ++++ 86 ++++ ++++ 87 ++++ ++ 88 +++ ++++ 89 ++++ ++++ 90 +++ ++++ 91 +++ ++ 92 ++++ ++++ 93 ++++ ++++ 94 ++++ +++ 95 ++++ ++++ 96 ++++ ++++ 97 ++++ ++++ 98 ++ ++ 99 ++ ND 100 ++++ ND 101 ++ ND 102 ++ ND 103 ++++ ++++ 104 +++ ++++ 105 + ND 106 ++++ ++++ 107 +++ ++++ 108 ++++ ++++ 109 + ND 110 ++++ ++++ 111 ++++ ++++ 112 +++ ++ 113 ++++ ++++ 114 ++++ +++ 115 ++++ +++

[1280] PK Protocol

[1281] 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.

[1282] 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 or jugular vein. For oral administration, compounds were formulated as a solution in 0.5% w/v methyl cellulose in water in 5 mL/kg dosing volume and administered orally.

[1283] Serial blood samples (about 120-300 μL) 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-00004 TABLE 3 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) 1 0.96 1318.7 11.1 8.69 12.6 3 1.27 1024 2.55 1.89 20.7 6 0.08 7271.1 2.7 0.35 2.3 8 1.3 2291.0 4.0 0.61 7.3 11 0.4 5661.0 2.7 0.59 2.9 20 1.32 2355.0 1.2 0.4 7.1 36 0.94 5909.7 1.1 0.23 2.8 66 1.48 6762 3.44 0.43 3.7 96 1.75 5149 1.14 0.45 5.7 106 1.86 5154 5.61 0.84 6.0 110 1 835 3.9 1.6 20 111 1 979 4.8 1.3 17

TABLE-US-00005 TABLE 4 PK data (oral administration) AUC Cl/F Bioavail- Example Dose C.sub.max (ng .Math. T.sub.max T.sub.1/2 (mL/ ability No (mg/kg) (ng/mL) hr/mL) (hr) (hr) min/kg) (%) 110 3 277 1020 0.67 3-4 50 41 111 3 318 1376 0.67 4-0 38 47

[1284] As is evident from the results presented in Table 2, 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 the human whole blood assay.

[1285] As is evident from the results presented in Tables 3 and 4, 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.

[1286] 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.