NLRP3 INHIBITORS

Abstract

The present application relates to compounds with NLRP.sub.3inhibitory activity and to associated salts, solvates, prodrugs and pharmaceutical compositions. The present application further relates to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by NLRP.sub.3inhibition.

Claims

1. A compound of formula (I): ##STR00298## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R.sup.1 is a C.sub.1-C.sub.3 alkyl group; R.sup.11 is a C.sub.1-C.sub.3 alkyl group; R.sup.12 is hydrogen or a C.sub.1-C.sub.3 alkyl group; and R.sup.13 is hydrogen or a C.sub.1-C.sub.3 alkyl group; or R.sup.12 and R.sup.13 together with the carbon atom to which they are attached form a C.sub.3-C.sub.6 cycloalkyl group; or a compound of formula (II): ##STR00299## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R.sup.2 is a C.sub.1-C.sub.3 haloalkyl group; or a compound of formula (III): ##STR00300## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R.sup.3 is a C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, (C.sub.3-C.sub.6 cycloalkylene)(C.sub.1-C.sub.2 alkyl) or (C.sub.1-C.sub.2 alkylene)(C.sub.3-C.sub.6 cycloalkyl) group, each of which is substituted with —NR.sup.aR.sup.b; R.sup.a is a C.sub.1-C.sub.3 alkyl group; and R.sup.b is a C.sub.1-C.sub.3 alkyl group; or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; provided that R.sup.3 comprises 8 or more atoms other than hydrogen or halogen; or a compound of formula (IV): ##STR00301## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R.sup.4 is a C.sub.1-C.sub.3 haloalkyl group; R.sup.5 is selected from: ##STR00302## X.sup.1 is H, F, Cl, Br or CN; and X.sup.2 is F, Cl, Br or CN; or a compound of formula (V): ##STR00303## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R.sup.6 is a C.sub.2-C.sub.4 alkyl group; R.sup.7 is a C.sub.1-C.sub.3 alkyl group; q is 0 or 1; and X.sup.3 is H, F, Cl, Br or CN; or a compound of formula (VI): ##STR00304## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R.sup.8 is selected from: ##STR00305## and X.sup.4 is F, Cl, Br or CN; or a compound of formula (VII): ##STR00306## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R.sup.9 is halo or a group —CR.sup.91R.sup.92(OH); R.sup.91 is hydrogen or a C.sub.1-C.sub.3 alkyl group; R.sup.92 is hydrogen or a C.sub.1-C.sub.3 alkyl group; R.sup.10 is selected from: ##STR00307## X.sup.5 is H, F, Cl, Br or CN; and X.sup.6 is F, Cl, Br or CN; or a compound of formula (VIII): ##STR00308## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R.sup.14 is a C.sub.1-C.sub.3 alkyl group substituted with —NR.sup.cR.sup.d; R.sup.c is a C.sub.1-C.sub.3 alkyl group; R.sup.d is a C.sub.1-C.sub.3 alkyl group; or R.sup.c and R.sup.d together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocycle; R.sup.15 is a C.sub.1-C.sub.3 alkyl group; and r is 0, or 2; or a compound of formula (IX): ##STR00309## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R.sup.16 is 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; and R.sup.17 is a cyclic group substituted at the α-position, wherein R.sup.17 may optionally be further substituted; or a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, selected from the group consisting of: ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317## ##STR00318## or a pharmaceutically acceptable salt, solvate or prodrug thereof.

2.-11. (canceled)

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

13. (canceled)

14. 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, pharmaceutically acceptable salt, solvate or prodrug 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.

15. The method as claimed in claim 14, 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; (xvii) a condition associated with diabetes; and (xviii) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

16. The method as claimed in claim 14 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).

17. (canceled)

18. The method as claimed in claim 14, wherein the compound, pharmaceutically acceptable salt, solvate or prodrug is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

19. 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.

20. 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

[0348] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0349] 2-MeTHF 2-methyltetrahydrofuran [0350] Ac.sub.2O acetic anhydride [0351] AcOH acetic acid [0352] AIBN azobisisobutyronitrile [0353] aq aqueous [0354] Boc tert-butyloxycarbonyl [0355] br broad [0356] Cbz carboxybenzyl [0357] CDI 1,1-carbonyl-diimidazole [0358] conc concentrated [0359] d doublet [0360] DABCO 1,4-diazabicyclo[2.2.2]octane [0361] DCE 1,2-dichloroethane, also called ethylene dichloride [0362] DCM dichloromethane [0363] DIPEA N,N-diisopropylethylamine, also called Hünig's base [0364] DMA dimethylacetamide [0365] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0366] DME dimethoxyethane [0367] DMF N,N-dimethylformamide [0368] DMSO dimethyl sulfoxide [0369] EDC or EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, also called 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0370] eq or equiv equivalent [0371] (ES.sup.+) electrospray ionization, positive mode [0372] Et ethyl [0373] EtOAc ethyl acetate [0374] EtOH ethanol [0375] h hour(s) [0376] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]Pyridinium 3-oxid hexafluorophosphate [0377] HPLC high performance liquid chromatography [0378] KO.sup.tBu potassium tert-butoxide [0379] LC liquid chromatography [0380] m multiplet [0381] m-CPBA 3-chloroperoxybenzoic acid [0382] Me methyl [0383] MeCN acetonitrile [0384] MeOH methanol [0385] (M+H).sup.+ protonated molecular ion [0386] MHz megahertz [0387] min minute(s) [0388] MS mass spectrometry [0389] Ms mesyl, also called methanesulfonyl [0390] MsCl mesyl chloride, also called methanesulfonyl chloride [0391] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0392] m/z mass-to-charge ratio [0393] NaO.sup.tBu sodium tert-butoxide [0394] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0395] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0396] NMP N-methylpyrrolidine [0397] NMR nuclear magnetic resonance (spectroscopy) [0398] Pd(crotyl)(XPhos)Cl chloro(crotyl)(2-dicyclohexylphosphino-2′,4′,6′-triisopropybiphenyl)palladium(II) [0399] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone) dipalladium(0) [0400] Pd(dba).sub.2 bis(dibenzylideneacetone) palladium(0) [0401] Pd(dba).sub.3 tris(dibenzylideneacetone) dipalladium(0) [0402] Pd(dppf)Cl.sub.2 [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [0403] PE petroleum ether [0404] Ph phenyl [0405] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0406] prep-HPLC preparative high performance liquid chromatography [0407] prep-TLC preparative thin layer chromatography [0408] PTSA p-toluenesulfonic acid [0409] q quartet [0410] RP reversed phase [0411] RT room temperature [0412] s singlet [0413] sat saturated [0414] SCX solid supported cation exchange (resin) [0415] Selectfluor® 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), also called N-chloromethyl-N′-fluorotriethylenediammonium bis(tetrafluoroborate) [0416] sept septuplet [0417] t triplet [0418] T3P propylphosphonic anhydride [0419] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0420] TEA triethylamine [0421] TFA 2,2,2-trifluoroacetic acid [0422] THF tetrahydrofuran [0423] TLC thin layer chromatography [0424] TMSCl trimethylsilyl chloride [0425] wt % weight percent or percent by weight [0426] Xantphos® 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [0427] Xphos® 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0428] Experimental Methods

[0429] Nuclear Magnetic Resonance

[0430] 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: [0431] a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe, [0432] a Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control, [0433] a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™, [0434] 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 [0435] an Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

[0436] LC-MS

[0437] 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.

[0438] Reversed Phase HPLC Conditions for the LCMS Analytical Methods

[0439] 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.

[0440] Methods 1a′ and 1b′: UPLC/MS analysis was carried out using either a Waters Acquity CSH C18 or BEH C18 column (2.1×30 mm) maintained at a temperature of 40° C. and eluted with a linear acetonitrile gradient appropriate for the lipophilicity of the compound over 3 or 10 minutes at a constant flow rate of 0.77 ml/min. The aqueous portion of the mobile phase was either 0.1% v/v formic acid (CSH C18 column) (Method 1a′) or 10 mM ammonium bicarbonate (BEH C18 column) (Method 1b′). LC-LTV chromatograms were recorded using a Waters Acquity PDA detector between 210 and 400 nm. Mass spectra were recorded using a Waters Acquity QDa detector with electrospray ionisation switching between positive and negative ion mode. Sample concentration was adjusted to give adequate UV response.

[0441] 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.

[0442] Preparative Reversed Phase HPLC General Methods

[0443] Method 1 (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.

[0444] Method 2: 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 min using UV detection at 215, 235, 254 and 280 nm. Gradient information: 0-5 min, held at 0% methanol; 5-30 min, ramped from 0% to 70% methanol; 30-30.1 min, ramped from 70% to 100% methanol; 30.1-35 min, held at 100% methanol.

[0445] Method 3: XSelect CSH Prep C18 OBD, 5 μm (100×30 mm), eluting with a 10 mM ammonium acetate/MeCN gradient over 12 min. Gradient information: 0-2.5 min, 15% MeCN; 2.5-10 min, ramped from 15% to 35% MeCN; 10-10.1 min, ramped from 35% to 95% MeCN; 10.1-12 min, held at 95% MeCN.

[0446] Method 4 (acidic preparation): Waters X-Select CSH column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with 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, 25% MeCN; 0.2-5.5 min, ramped from 25% MeCN to 55% MeCN; 5.5-5.6 min, ramped from 55% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0447] Synthesis of Intermediates

Intermediate L1: 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide

[0448] ##STR00035##

[0449] Methyl 3-methyl-4-sulfamoylbenzoate (486 mg, 2.12 mmol) was stirred in THF (20 mL) and a solution of methyl magnesium bromide in Et.sub.2O (3M, 4 mL, 12 mmol) was added dropwise. The mixture was stirred at room temperature for 2 days and poured into sat aq NaHCO.sub.3 (aqueous, 20 mL), and concentrated partially (THF removal) and filtered. EtOAc (20 mL) was used to wash the residual solid and extract the filtrate. The organic phase was separated, dried (Na.sub.2SO.sub.4), filtered and concentrated to afford the title compound (0.48 g, 99%) as a yellow solid.

[0450] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.89 (d, 1H), 7.47 (s, 1H), 7.45-7.39 (d, 1H), 2.66 (s, 3H), 1.52 (s, 6H).

Intermediate L2: 1-(Propan-2-yl-d7)-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-(propan-2-yl-d7)-1H-pyrazole-3-sulfonamide

[0451] ##STR00036##

[0452] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L19, Step C) (200 mg, 0.52 mmol) in dimethylformamide (2 mL), was added K.sub.2CO.sub.3(100 mg, 0.72 mmol) and 2-iodopropane-d7 (110 mg, (0.62 mmol). The mixture was stirred for 7 days at room temperature in the dark. The reaction mixture was poured into water (10 mL) and the water layer was extracted with ethyl acetate. The organic layer was washed with water (4 times) and brine. The organic layer was dried (sodium sulfate), filtered and evaporated. The residue was purified over silica, using ethyl acetate/heptane (1:1) as the eluent, to afford the title compound as a colourless oil (140 mg, 62%).

[0453] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.46 (s, 1H), 7.08 (d, 4H), 6.78 (d, 4H), 6.68 (d, 1H), 4.33 (s, 4H), 3.80 (s, 6H).

Step B: 1-(Propan-2-yl-d7)-1H-pyrazole-3-sulfonamide

[0454] ##STR00037##

[0455] N,N-Bis(4-methoxybenzyl)-1-(propan-2-yl-d7)-1H-pyrazole-3-sulfonamide (140 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added and the reaction was stirred for 3 days at room temperature. The solvents were evaporated and the residue was triturated with water. The water layer was filtered and lyophilized to afford the title compound as a white solid (67 mg, 100%).

[0456] .sup.1H NMR (300 MHz, D.sub.2O) δ 7.73 (d, 1H), 7.67 (d, 1H).

Intermediate L3: tert-Butyl 3-sulfamoyl-1H-pyrazole-1-carboxylate

[0457] ##STR00038##

[0458] To a suspension of 1H-pyrazole-3-sulfonamide (103 mg, 0.69 mmol) and Et.sub.3N (0.14 mL, 1.05 mmol) in anhydrous DCM (2 mL) was added di-tert-butyl dicarbonate (188 mg, 0.83 mmol) and the reaction mixture was stirred at room temperature overnight. A sat aq solution of NaHCO.sub.3 was added to the mixture and the aqueous phase extracted with DCM. The organic layer was washed with water and dried over Na.sub.2SO.sub.4. Concentration under reduced pressure gave the title compound as a yellow oil (170 mg, 98%) that was used without further purification.

[0459] .sup.1H NMR (CD.sub.3OD) δ 7.74 (d, 1H), 6.70 (d, 1H), 1.51 (s, 9H).

Intermediate L4: 1-(2-(3-(But-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)-1H-pyrazole-3-sulfonamide, 2,2,2-trifluoroacetate salt

Step A: 1-(2-(3-(But-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0460] ##STR00039##

[0461] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L19, Step C) (58 mg, 0.15 mmol, 1.25 eq) in acetonitrile (3 mL) was added 3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-diazirine (30 mg, 0.12 mol, 1 eq) and potassium carbonate (62 mg, 0.45 mmol, 3.75 eq). The reaction mixture was covered in aluminium foil and then stirred at room temperature. After stirring overnight, extra N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L19, Step C) (23 mg, 0.06 mmol, 0.5 eq) in acetonitrile (0.5 mL) was added to the reaction mixture. After stirring for 3 hours, the reaction mixture was diluted with water, and then extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was submitted to normal phase purification on silica using heptane and ethyl acetate as eluent to afford the title compound (24 mg, 47 μmol, 39%).

[0462] .sup.1H NMR (CDCl.sub.3) δ 7.49 (d, 1H), 7.07 (d, 4H), 6.77 (d, 4H), 6.65 (d, 1H), 4.30 (s, 4H), 4.02 (t, 2H), 3.78 (s, 6H), 2.04 (t, 2H), 2.01-1.96 (m, 1H), 1.93 (dd, 2H), 1.57-1.47 (m, 2H).

Step B: 1-(2-(3-(But-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)-1H-pyrazole-3-sulfonamide, 2,2,2-trifluoroacetate salt

[0463] ##STR00040##

[0464] A solution of 1-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (24 mg, 47 μmol, 1 eq) in trifluoroacetic acid (1.0 mL, 13.05 mmol, 277 eq) was stirred at room temperature. After four hours, toluene was added to the reaction mixture and then the mixture was concentrated in vacuo to afford the title compound (17 mg, 47 μmol, quantitative yield), which was used as such for the following reaction.

[0465] .sup.1H NMR (CD.sub.3OD) δ 7.78 (d, 1H), 6.66 (d, 1H), 4.13 (t, 2H), 2.32-2.22 (m, 1H), 2.05-1.90 (m, 4H), 1.52 (t, 2H).

Intermediate L5: 1-(2-(Bis(methyl-d3)amino)ethyl)-1H-pyrazole-3-sulfonamide, 2,2,2-trifluoroacetate salt

Step A: 1-(2-Hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0466] ##STR00041##

[0467] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L19, Step C) (1.5 g, 3.9 mmol, 1 eq) in acetonitrile (20 mL) was added 2-bromoethan-1-ol (0.57 mL, 7.7 mmol, 2 eq), potassium iodide (64 mg, 0.39 mmol, 0.1 eq) and potassium carbonate (1.6 g, 12.0 mmol, 3 eq). The reaction mixture was heated to 60° C. After stirring overnight, extra 2-bromoethan-1-ol (0.14 mL, 1.95 mmol, 0.5 eq) was added. After stirring for a further 4 hours, the reaction mixture was cooled to room temperature and then diluted with water. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude material was submitted to normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (1.08 g, 2.50 mmol, 65%).

[0468] .sup.1H NMR (CDCl.sub.3) δ 7.56-7.44 (m, 1H), 7.07 (dd, 4H), 6.85-6.73 (m, 4H), 6.70-6.54 (m, 1H), 4.36-4.20 (m, 6H), 4.02-3.88 (m, 2H), 3.78 (s, 6H), 2.21 (s, 1H).

Step B: 2-(3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)ethyl methanesulfonate

[0469] ##STR00042##

[0470] To a solution of 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (780 mg, 1.81 mmol, 1 eq) and N,N-diisopropylethylamine (0.44 mL, 2.53 mmol, 1.4 eq) in dichloromethane (25 mL) was added dropwise methanesulfonyl chloride (0.16 mL, 2.17 mmol, 1.2 eq) at room temperature. After stirring for 40 minutes, the reaction mixture was diluted with dichloromethane (50 mL), then washed twice with sat aq sodium bicarbonate, once with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (921 mg, 1.81 mmol, quantitative yield), which was used as such in the following reaction.

[0471] .sup.1H NMR (CDCl.sub.3) δ 7.54 (q, 1H), 7.12-7.00 (m, 4H), 6.84-6.69 (m, 4H), 6.65 (q, 1H), 4.65-4.46 (m, 4H), 4.31 (s, 4H), 3.78 (s, 6H), 2.92 (s, 3H).

Step C: 1-(2-(Bis(methyl-d3)amino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0472] ##STR00043##

[0473] A microwave vial was charged with 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)ethyl methanesulfonate (922 mg, 1.81 mmol, 1 eq), bis(methyl-d3)amine hydrochloride (634 mg, 7.24 mmol, 4 eq), potassium iodide (601 mg, 3.62 mmol, 2 eq), N,N-diisopropylethylamine (3.2 mL, 18.1 mmol, 10 eq) and acetonitrile (15 mL). The microwave vial was capped and then heated in a sand bath set to 100° C. After 1 hour, the reaction mixture was cooled to room temperature and then water was added. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was submitted to normal phase flash chromatography using dichloromethane and methanol as eluent to afford the title compound (541 mg, 1.16 mmol, 64%).

[0474] .sup.1H NMR (CDCl.sub.3) δ 7.53 (d, 1H), 7.11-7.00 (m, 4H), 6.82-6.70 (m, 4H), 6.62 (d, 1H), 4.30 (s, 4H), 4.26 (t, 2H), 3.78 (s, 6H), 2.74 (t, 2H).

Step D: 1-(2-(Bis(methyl-d3)amino)ethyl)-1H-pyrazole-3-sulfonamide, 2,2,2-trifluoroacetate salt

[0475] ##STR00044##

[0476] To a solution of 1-(2-(bis(methyl-d3)amino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (541 mg, 1.16 mmol, 1 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (5.0 mL, 64.9 mmol, 56 eq). The reaction mixture was stirred at room temperature. After stirring overnight, the mixture was concentrated in vacuo. The crude product was suspended in methanol, filtered and the residue was washed with methanol. The filtrates were combined and concentrated in vacuo to afford the title compound as a trifluoroacetate salt (394 mg, 1.16 mmol, quantitative yield), which was used as such in the following reaction.

[0477] .sup.1H NMR (CD.sub.3OD) δ 7.85 (d, 1H), 6.75 (d, 1H), 4.72-4.61 (m, 2H), 3.76-3.61 (m, 2H).

Intermediate L6: 1-Isopropyl-1H-pyrazole-3-sulfinamide

Step A: 1-Isopropyl-3-nitro-1H-pyrazole

[0478] ##STR00045##

[0479] To a solution of 3-nitro-1H-pyrazole (75 g, 663.3 mmol, 1 eq) in anhydrous DMF (500 mL) was added NaH (29 g, 729.6 mmol, 60% purity in mineral oil, 1.1 eq) under nitrogen at 0° C. The reaction mixture was stirred for 30 minutes. 2-Bromopropane (98 g, 795.9 mmol, 1.2 eq) was added. Stirring was continued at 0° C. for 30 minutes under nitrogen. The ice bath was removed and the reaction mixture was stirred at 20° C. for 15 hours. The resulting mixture was quenched with water (500 mL) and extracted with ethyl acetate (2 L). The organic layer was washed with water (2×500 mL) and brine (2×500 mL), 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, 50:1 to 5:1) to give the title compound (60 g, 58%) as a white solid.

[0480] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.49 (d, 1H), 6.82 (d, 1H), 4.59-4.46 (m, 1H) and 1.51 (d, 6H).

Step B: 1-Isopropyl-1H-pyrazol-3-amine

[0481] ##STR00046##

[0482] To a solution of 1-isopropyl-3-nitro-1H-pyrazole (50 g, 322.26 mmol, 1 eq) and NH.sub.4Cl (86 g, 1.61 mol, 5 eq) in EtOH (500 mL) and H.sub.2O (300 mL) was added Fe (36 g, 644.52 mmol, 2 eq) as powder in portions at 60° C. The reaction mixture was stirred at 60° C. for 16 hours, and then concentrated under reduced pressure to remove EtOH. The residue was diluted with H.sub.2O (1 L) and extracted with EtOAc (3×1 L). The combined organic layers were washed with brine (2×500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (39 g, crude) as a blue oil, which was used directly into the next step.

[0483] .sup.1H NMR (CDCl.sub.3) δ 7.15 (d, 1H), 5.55 (d, 1H), 4.31-4.20 (m, 1H), 3.60 (br s, 2H) and 1.43 (d, 6H).

[0484] LCMS: m/z 126.2 (M+H).sup.+ (ES.sup.+).

Step C: 1-Isopropyl-1H-pyrazole-3-sulfonyl chloride

[0485] ##STR00047##

[0486] A solution of 1-isopropyl-1H-pyrazol-3-amine (23 g, 183.75 mmol, 1 eq) in MeCN (500 mL) at 0° C. was treated with a solution of concentrated HCl (50 mL, 36 wt % in H.sub.2O) in H.sub.2O (50 mL), followed slowly by an aqueous solution of NaNO.sub.2 (15.2 g, 220.50 mmol, 1.2 eq) in H.sub.2O (50 mL). The resulting mixture was stirred at 0° C. for 40 minutes. AcOH (50 mL), CuCl.sub.2 (12.4 g, 91.87 mmol, 0.5 eq), and CuCl (909 mg, 9.19 mmol, 0.05 eq) were added. Then SO.sub.2 gas (15 psi) was bubbled into the mixture at 0° C. for 20 minutes. The reaction mixture was stirred at 0° C. for 1 hour, and then concentrated under reduced pressure to remove most of MeCN and AcOH. The residue was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 30:1 to 10:1) to give the title compound (16.5 g, 43%) as a yellow oil.

[0487] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.59-7.57 (m, 1H), 6.87-6.85 (m, 1H), 4.70-4.59 (m, 1H) and 1.57 (dd, 6H).

Step D: Sodium 1-isopropyl-1H-pyrazole-3-sulfinate

[0488] ##STR00048##

[0489] A solution of Na.sub.2SO.sub.3 (4.35 g, 34.50 mmol, 2 eq) in H.sub.2O (12 mL) was stirred at 20° C. for 10 minutes. Then Na.sub.2CO.sub.3 (3.66 g, 34.50 mmol, 2 eq) was added. The resulting mixture was stirred at 50° C. for 10 minutes. 1-Isopropyl-1H-pyrazole-3-sulfonyl chloride (3.6 g, 17.25 mmol, 1 eq) was added dropwise. The resulting mixture was stirred at 50° C. for 2 hours, and then evaporated in vacuo. The residue was treated with EtOH (24 mL). The suspension was allowed to stir at 20° C. for 10 minutes. The suspension was filtered and the filtrate was evaporated to afford a white solid. The white solid was treated with ethyl acetate (20 mL) for 10 minutes and then the mixture was filtered. The filter cake was collected and dried to afford the title compound (2.4 g, 67% yield, 95% purity on LCMS) as a white solid.

[0490] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ7.58 (s, 1H), 6.17 (s, 1H), 4.46-4.43 (m, 1H) and 1.37 (d, 6H).

[0491] LCMS: m/z 197 (M+H).sup.+(ES.sup.+).

Step E: 1-Isopropyl-1H-pyrazole-3-sulfinamide

[0492] ##STR00049##

[0493] To a solution of sodium 1-isopropyl-1H-pyrazole-3-sulfinate (2.4 g, 12.23 mmol, 1 eq) in THF (15 mL) was added dropwise oxalyl dichloride (3.11 g, 24.46 mmol, 2 eq) at 0° C. After being stirred at 20° C. for 1 hour, the reaction mixture was added to NH.sub.3.H.sub.2O (15 mL, 25 wt % in H.sub.2O) at 0° C. and then stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was treated with DCM (20 mL). The mixture was stirred at 20° C. for 20 minutes, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.2 g, 51% yield, 90% purity on LCMS) as a yellow oil.

[0494] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.87 (d, 1H), 6.55 (d, 1H), 6.26 (s, 2H), 4.58-4.51 (m, 1H) and 1.42 (d, 6H).

[0495] LCMS: m/z 196 (M+Na).sup.+(ES.sup.+).

Intermediate L7: tert-Butyl 3-sulfinamoylazetidine-1-carboxylate

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

[0496] ##STR00050##

[0497] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (50 g, 288.67 mmol, 1 eq) and TEA (87.63 g, 866.01 mmol, 3 eq) in THF (500 mL) was added methanesulfonyl chloride (40 g, 346.40 mmol, 1.2 eq) at 0° C. The reaction mixture was stirred at 25° C. for 12 hours, and then diluted with ethyl acetate (2 L). The organic layer was washed with water (3×1.5 L), brine (3×1.5 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (70 g, 97%) as a yellow oil.

[0498] .sup.1H NMR (400 MHz, CDCl.sub.3) δ5.23-5.19 (m, 1H), 4.30-4.26 (m, 2H), 4.13-4.11 (m, .sub.2H), 3.08 (s, 3H) and 1.45 (s, 9H).

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

[0499] ##STR00051##

[0500] To a solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (35 g, 139.28 mmol, 1 eq) in DMF (360 mL) was added potassium ethanethioate (19 g, 167.13 mmol, 1.2 eq). The reaction mixture was stirred at 80° C. for 12 hours, and then diluted with ethyl acetate (1.5 L). The organic layer was washed with saturated aqueous NH.sub.4Cl solution (3×1 L), brine (3×1 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give crude product. The crude product was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 100:1 to 20:1) to give the title compound (26 g, 81%) as a yellow oil.

[0501] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.30 (t, 2H), 4.11-4.07 (m, 1H), 3.76-3.72 (m, 2H), 2.27 (s, 3H) and 1.36 (s, 9H).

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

[0502] ##STR00052##

[0503] To a solution of tert-butyl 3-(acetylthio)azetidine-1-carboxylate (20 g, 86.46 mmol, 1 eq) in MeOH (80 mL), THF (80 mL) and H.sub.2O (40 mL) was added LiOH.H.sub.2O (3.63 g, 86.46 mmol, 1 eq). The reaction mixture was stirred at 70° C. for 2 hours, poured into water (200 mL), and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (14 g, 86%) as a yellow oil.

[0504] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.37-4.32 (m, 2H), 3.82-3.77 (m, 2H), 3.70-3.59 (m, 1H) and 1.44 (s, 9H).

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

[0505] ##STR00053##

[0506] To a solution of tert-butyl 3-mercaptoazetidine-1-carboxylate (6.5 g, 34.34 mmol, 1 eq) in MeOH (130 mL) was added NBS (12.2 g, 68.68 mmol, 2 eq). The reaction mixture was stirred at 25° C. for 10 minutes, quenched with saturated aqueous Na.sub.2SO.sub.3 solution (200 mL), and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give crude product. The crude product was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 5:1) to give the title compound (5 g, 62%) as a yellow oil.

[0507] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.33-4.29 (m, 1H), 4.14-4.08 (m, 3H), 3.83 (s, 3H), 3.66-3.62 (m, 1H) and 1.45 (s, 9H).

[0508] LCMS: m/z 258.1 (M+Na).sup.+ (ES.sup.+).

Step E: Sodium 1-(tert-butoxycarbonyl)azetidine-3-sulfinate

[0509] ##STR00054##

[0510] To a solution of tert-butyl 3-(methoxysulfinyl)azetidine-1-carboxylate (5 g, 21.25 mmol, 1 eq) in MeOH (50 mL) was added NaOH (1 M, 31.87 mL, 1.5 eq). The reaction mixture was stirred at 25° C. for 1 hour, adjusted to pH=7 with 1 N aqueous HCl solution, and concentrated in vacuo to remove MeOH. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:1 to 0:1) to give the title compound (5 g, 97%) as a white solid.

[0511] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 3.82-3.80 (m, 2H), 3.66-3.64 (m, 2H), 2.72-2.65 (m, 1H) and 1.36 (s, 9H).

Step F: tert-Butyl 3-sulfinamoylazetidine-1-carboxylate

[0512] ##STR00055##

[0513] To a solution of sodium 1-(tert-butoxycarbonyl)azetidine-3-sulfinate (5 g, 20.55 mmol, 1 eq) in THF (350 mL) was added (COCl).sub.2 (5.2 g, 41.11 mmol, 2 eq). The reaction mixture was stirred at 25° C. for 2 hours. In a different vessel, NH.sub.3 (15 psi) was bubbled into THF (20 mL) at −78° C. for 10 minutes. Then the above reaction mixture was added into NH.sub.3/THF (200 mL) at −78° C. The resulting reaction mixture was stirred at 25° C. for another 50 minutes. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:1 to 0:1) to give the title compound (2.5 g, 55%) as a colourless oil.

[0514] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 5.84 (s, 2H), 4.08-3.99 (m, 3H), 3.77-3.75 (m, 1H), 3.63-3.58 (m, 1H) and 1.38 (s, 9H).

Intermediate L8: 1-Isopropyl-1H-pyrazole-3-sulfonamide

[0515] ##STR00056##

[0516] NH.sub.3 gas (15 psi) was bubbled into a solution of 1-isopropyl-1H-pyrazole-3-sulfonyl chloride (Intermediate L6, Step C) (20 g, 47.9 mmol, 1 eq) in THF (300 mL) at 0° C. for 15 minutes. The reaction mixture was stirred at 0° C. for 30 minutes, and then allowed to warm to 20° C. and stirred for another 2 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 5:1 to 1:1) to give the title compound (6.7 g, 74%) as a yellow solid.

[0517] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.91 (d, 1H), 7.35 (s, 2H), 6.57 (d, 1H), 4.63-4.52 (m, 1H) and 1.43 (d, 6H).

[0518] LCMS: m/z 190 (M+H).sup.+(ES.sup.+).

Intermediate L9: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonamide

Step A: 2-(1,1-Dimethoxyethyl)thiazole

[0519] ##STR00057##

[0520] To a solution of 1-(thiazol-2-yl)ethanone (25 g, 196.60 mmol, 1 eq) in MeOH (350 mL) was added trimethoxymethane (121 g, 1.14 mol, 5.80 eq) and 4-methylbenzenesulfonic acid (35.55 g, 206.43 mmol, 1.05 eq) at 25° C. Then the reaction mixture was stirred at 50° C. for 12 hours, poured into H.sub.2O (400 mL), and concentrated in vacuo to remove MeOH. The residue was quenched with saturated aqueous Na.sub.2CO.sub.3 solution (200 mL) and the mixture was extracted with EtOAc (3×100 mL). The organic combined layers were washed with brine (2×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (27 g, crude) as a red oil.

[0521] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.84 (d, 1H), 7.33 (d, 1H), 3.27 (s, 6H) and 1.75 (s, 3H).

Step B: 5-Bromo-2-(1,1-dimethoxyethyl)thiazole

[0522] ##STR00058##

[0523] To a solution of 2-(1,1-dimethoxyethyl)thiazole (54 g, 311.72 mmol, 1 eq) in THF (1000 mL) was added dropwise n-BuLi (2.5 M, 137.16 mL, 1.1 eq) at −78° C. under N.sub.2. The mixture was stirred at −78° C. for 0.5 hour. Then a solution of CBr.sub.4 (113.71 g, 342.89 mmol, 1.1 eq) in THF (250 mL) was added dropwise over 10 minutes. The reaction mixture was filtered and the filtrate was poured into saturated aqueous NH.sub.4Cl solution (200 mL) and water (200 mL). The aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine (2×500 mL), 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, 1:0 to 10:1) to afford the title compound (70 g, 83% yield, 90% purity on .sup.1H NMR) as a yellow oil.

[0524] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.70 (s, 1H), 3.25 (s, 6H) and 1.70 (s, 3H).

Step C: 1-(5-Bromothiazol-2-yl)ethanone

[0525] ##STR00059##

[0526] To a solution of 5-bromo-2-(1,1-dimethoxyethyl)thiazole (70 g, 277.64 mmol, 1 eq) in DCM (500 mL) was added TFA (462 g, 4.05 mol, 14.59 eq) and H.sub.2O (10 g, 555.08 mmol, 2.0 eq) at 25° C. Then the reaction mixture was stirred at 25° C. for 12 hours, and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 15:1) to give the title compound (51 g, 89%) as a red solid.

[0527] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23 (s, 1H) and 2.60 (s, 3H).

Step D: 1-(5-Benzylsulfanylthiazol-2-yl)ethanone

[0528] ##STR00060##

[0529] To a solution of 1-(5-bromothiazol-2-yl)ethanone (20 g, 97.06 mmol, 1 eq), phenylmethanethiol (13.26 g, 106.76 mmol, 1.1 eq), DIPEA (25.09 g, 194.12 mmol, 2 eq) and XantPhos® (2.81 g, 4.85 mmol, 0.05 eq) in dioxane (200 mL) was added Pd(dba).sub.2 (2.79 g, 4.85 mmol, 0.05 eq) at 25° C. The reaction mixture was stirred at 100° C. for 12 hours under N.sub.2, and then at 25° C. for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 30:1) to afford the title compound (20 g, 67% yield, 81.5% purity on LCMS) as a yellow solid.

[0530] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.95 (s, 1H), 7.46-7.27 (m, 5H), 4.30 (s, 2H) and 2.56 (s, 3H).

[0531] LCMS: m/z 250.0 (M+H).sup.+(ES.sup.+).

Step E: 2-Acetylthiazole-5-sulfonyl chloride

[0532] ##STR00061##

[0533] Cl.sub.2 gas (15 psi) was bubbled into a solution of 1-(5-benzylsulfanylthiazol-2-yl)ethanone (20 g, 80.21 mmol, 1 eq) in AcOH (360 mL) and H.sub.2O (40 mL) at 0° C. for 45 minutes. The reaction mixture was stirred at 0° C. for 1 hour, and then poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine (2×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (18 g, crude) as a yellow oil, which was used directly in the next step.

Step F: 2-Acetylthiazole-5-sulfonamide

[0534] ##STR00062##

[0535] NH.sub.3 gas (15 psi) was bubbled into THF (300 mL) at −78° C. for 15 minutes. Then a solution of 2-acetylthiazole-5-sulfonyl chloride (18 g, 79.76 mmol, 1 eq) in THF (50 mL) was added dropwise into the NH.sub.3/THF solution at −78° C. The reaction mixture was stirred at 25° C. for 30 minutes, and then concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 1:1) to afford the title compound (6.8 g, 41%) as a yellow solid.

[0536] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.41 (s, 1H), 8.17 (br s, 2H) and 2.65 (s, 3H).

[0537] LCMS: m/z 206.9 (M+H).sup.+ (ES.sup.+).

Step G: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonamide

[0538] ##STR00063##

[0539] To the solution of 2-acetylthiazole-5-sulfonamide (8.6 g, 41.70 mmol, 1 eq) in THF (200 mL) was added MeMgBr (3 M, 55.60 mL, 4 eq) at −10° C. under N.sub.2. The reaction mixture was stirred at 0° C. for 30 minutes, and then stirred at 20° C. for 2 hours. The reaction mixture was poured into aqueous NH.sub.4Cl solution (500 mL). The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic phases 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, petroleum ether:ethyl acetate, 10:1 to 1:1) to give the title compound (3.5 g, 38%) as a yellow solid.

[0540] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 (s, 1H), 7.81 (br s, 2H), 6.29 (br s, 1H) and 1.51 (s, 6H).

[0541] LCMS: m/z 223.0 (M+H).sup.+ (ES.sup.+).

Intermediate L10: 5-(2-Hydroxypropan-2-yl)thiazole-2-sulfonamide

Step A: Methyl 2-mercaptothiazole-5-carboxylate

[0542] ##STR00064##

[0543] A solution of methyl 2-bromothiazole-5-carboxylate (10 g, 45.03 mmol, 1 eq) and NaHS (7.21 g, 90.07 mmol, 70 wt % purity (contained 30% H.sub.2O), 2 eq) in EtOH (100 mL) was stirred at 80° C. for 2 hours. The mixture was poured into ice-water (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with brine (2×500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (7.82 g, 90% yield, 91% purity on LCMS) as a light yellow solid, which was used in the next step without further purification.

[0544] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.83 (br s, 1H), 8.12 (s, 1H) and 3.77 (s, 3H).

[0545] LCMS: m/z 176.6 (M+H).sup.+ (ES.sup.+).

Step B: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

[0546] ##STR00065##

[0547] To a solution of methyl 2-mercaptothiazole-5-carboxylate (5.5 g, 28.56 mmol, 1 eq) in DCM (60 mL) was added NCS (11.44 g, 85.69 mmol, 3 eq) at 0° C. The reaction mixture was stirred at 25° C. for 1 hour, and then poured into ice-water (100 mL) and extracted with DCM (2×70 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (6.90 g, crude) as a light yellow oil, which was used in the next step without further purification.

Step C: Methyl 2-sulfamoylthiazole-5-carboxylate

[0548] ##STR00066##

[0549] To a stirred solution of methyl 2-(chlorosulfonyl)thiazole-5-carboxylate (6.90 g, 28.55 mmol, 1 eq) in THF (80 mL) was bubbled NH.sub.3 gas (15 psi) at 0° C. for 0.25 hour. The reaction mixture was stirred at 25° C. for 0.5 hour, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 5:1 to 3:1) to give the title compound (1.1 g, 16% yield, 92% purity on LCMS) as a light yellow solid.

[0550] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.62 (s, 1H), 8.38 (s, 2H) and 3.89 (s, 3H).

[0551] LCMS: m/z 223.5 (M+H).sup.+ (ES.sup.+).

Step D: 5(2-Hydroxypropan-2-yl)thiazole-2-sulfonamide

[0552] ##STR00067##

[0553] To a solution of methyl 2-sulfamoylthiazole-5-carboxylate (1 g, 4.50 mmol, 1 eq) in THF (20 mL) was added dropwise MeMgBr (3 M, 6.75 mL, 4.5 eq) at −10° C. under N.sub.2. The reaction mixture was stirred at 0° C. for 0.5 hour, and then warmed to 25° C. and stirred for 15 hours. The reaction mixture was quenched slowly with a saturated aqueous NH.sub.4Cl solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×70 mL), 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 3:1) to give the title compound (0.37 g, 35% yield, 95% purity on LCMS) as a light yellow solid.

[0554] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.99 (s, 2H), 7.81 (s, 1H), 5.92 (s, 1H) and 1.55 (s, 6H).

[0555] LCMS: m/z 223.5 (M+H).sup.+ (ES.sup.+ ).

Intermediate L11: 1-Cyclopropyl-1H-pyrazole-3-sulfonyl chloride

Step A: 1-Cyclopropyl-3-nitro-1H-pyrazole

[0556] ##STR00068##

[0557] To a solution of cyclopropylboronic acid (36.77 g, 428.04 mmol, 1.1 eq) in DCE (500 mL) was added 3-nitro-1H-pyrazole (44 g, 389.12 mmol, 1 eq), 2,2-bipyridine (60.77 g, 389.12 mmol, 1 eq) and Na.sub.2CO.sub.3 (64.59 g, 609.44 mmol, 1.57 eq) at 25° C. The reaction mixture was stirred at 25° C. for 30 minutes. Then Cu(OAc).sub.2 (70.68 g, 389.12 mmol, 1 eq) was added. The resulting reaction mixture was heated to 70° C., stirred for 15.5 hours, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 30:1 to 3:1) to give impure product (26.7 g). The impure product was dissolved in pyrrolidine (10 mL). The resulting mixture was stirred at 70° C. for 2 hours, and then concentrated under reduced pressure to remove pyrrolidine. The residue was diluted with H.sub.2O (33 mL) and adjusted to pH=5-6 with 1M aqueous HCl solution. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×33 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (17.7 g, 30%) as a yellow oil.

[0558] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.54 (d, 1H), 6.84 (d, 1H), 3.73-3.67 (m, 1H), 1.24-1.22 (m, 2H) and 1.13-1.07 (m, 2H).

Step B: 1-Cyclopropyl-1H-pyrazol-3-amine

[0559] ##STR00069##

[0560] To a solution of 1-cyclopropyl-3-nitro-1H-pyrazole (36 g, 235.08 mmol, 1 eq) in EtOH (400 mL) was added a solution of NH.sub.4Cl (62.87 g, 1.18 mol, 5 eq) in H.sub.2O (150 mL). Then the reaction mixture was heated to 60° C. and iron powder (39.38 g, 705.24 mmol, 3 eq) was added in portions. The reaction mixture was stirred at 60° C. for 16 hours, and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (500 mL) and the mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 30:1 to 1:1) to give the title compound (20 g, 69%) as a yellow oil.

[0561] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.14 (d, 1H), 5.11 (d, 1H), 3.57 (br s, 2H), 3.38-3.32 (m, 1H), 0.99-0.95 (m, 2H) and 0.90-0.87 (m, 2H).

[0562] LCMS: m/z 124.2 (M+H).sup.+ (ES.sup.+).

Step C: 1-Cyclopropyl-1H-pyrazole-3-sulfonyl chloride

[0563] ##STR00070##

[0564] To a solution of 1-cyclopropyl-1H-pyrazol-3-amine (19 g, 154.28 mmol, 1 eq) in MeCN (500 mL) and H.sub.2O (50 mL) at 0° C. was added a solution of concentrated HCl (50 mL, 36 wt % in H.sub.2O). Then an aqueous solution of NaNO.sub.2 (12.77 g, 185.13 mmol, 1.2 eq) in H.sub.2O (50 mL) was added slowly. The resulting mixture was stirred at 0° C. for 40 minutes. AcOH (50 mL), CuCl.sub.2 (10.37 g, 77.14 mmol, 0.5 eq) and CuCl (763 mg, 7.71 mmol, 0.05 eq) were added. Then SO.sub.2 gas (15 psi) was bubbled into the resulting mixture at 0° C. for 20 minutes. The reaction mixture was stirred at 0° C. for 1 hour, and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (250 mL) and extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (2×150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 100:0 to 1:1) to give the title compound (14 g, 44%) as a yellow oil.

[0565] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.62 (d, 1H), 6.83 (d, 1H), 3.78-3.72 (m, 1H), 1.28-1.24 (m, 2H) and 1.16-1.12 (m, 2H).

[0566] Intermediate L12: 5-(2-Hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[0567] Step A: 1-Methyl-1H-pyrazole-3-sulfonyl chloride

##STR00071##

[0568] A solution of 1-methyl-1H-pyrazol-3-amine (20 g, 205.93 mmol, 1 eq) in MeCN (500 mL) at 0° C. was treated with aqueous HCl solution (1 N, 50 mL), followed slowly by an aqueous solution of NaNO.sub.2 (17.05 g, 247.12 mmol, 1.2 eq) in H.sub.2O (50 mL). The resulting solution was stirred at 0° C. for 40 minutes. Then AcOH (50 mL), CuCl.sub.2 (13.84 g, 102.97 mmol, 0.5 eq) and CuCl (1.02 g, 10.30 mmol, 0.05 eq) were added. SO.sub.2 gas (15 psi) was bubbled into the mixture at 0° C. for 20 minutes. The reaction mixture was stirred at 0° C. for 1 hour, and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (400 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine (2×200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 30:1 to 1:1) to give the title compound (12 g, 32%) as a yellow oil.

[0569] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.53 (d, 1H), 6.86 (d, 1H) and 4.05 (s, 3H).

Step B: N,N-Bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0570] ##STR00072##

[0571] To a solution of bis(4-methoxybenzyl)amine (60 g, 233.17 mmol, 0.7 eq) in THF (600 mL) were added TEA (67.23 g, 664.41 mmol, 2 eq) and 1-methyl-1H-pyrazole-3-sulfonyl chloride (60 g, 332.20 mmol, 1 eq). The reaction mixture was stirred at 25° C. for 1 hour, and then diluted with H.sub.2O (1 L). The pH was adjusted to pH=5-6 with aqueous HCl solution (1 N). The mixture was extracted with EtOAc (3×1 L). The combined organic layers were washed with brine (2×300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with EtOAc (200 mL) to give the title compound (50 g, 34% yield, 90% purity on LCMS) as a white solid.

[0572] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.41 (d, 1H), 7.07-7.04 (m, 4H), 6.78-6.75 (m, 4H), 6.62 (d, 1H), 4.31 (s, 4H), 3.96 (s, 3H) and 3.78 (s, 6H).

[0573] LCMS: m/z 402.2 (M+H).sup.+ (ES.sup.+).

Step C: 3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid

[0574] ##STR00073##

[0575] To a solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (100 g, 249.08 mmol, 1 eq) in THF (1.35 L) was added dropwise n-BuLi (2.5 M, 104.61 mL, 1.05 eq) at −70° C. The reaction mixture was stirred at −70° C. for 1 hour. Then CO.sub.2 gas (15 psi) was bubbled into the reaction mixture for 15 minutes. The resulting mixture was stirred at −70° C. for another 1 hour, quenched with H.sub.2O (1.2 L), adjusted to pH=3 with aqueous HCl solution (1 N), and extracted with EtOAc (2×1 L). The combined organic phases were washed with brine (2×1 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (300 mL, petroleum ether:ethyl acetate, 1:1) to give the title compound (94 g, 84% yield, 99% purity on LCMS) as a white solid.

[0576] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.98-7.16 (m, 5H), 6.82 (d, 4H), 4.25 (s, 4H), 4.15 (s, 3H) and 3.72 (s, 6H).

[0577] LCMS: m/z 468.2 (M+Na).sup.+ (ES.sup.+).

Step D: Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate

[0578] ##STR00074##

[0579] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (42.75 g, 95.96 mmol, 1 eq) and DMF (701 mg, 9.60 mmol, 0.1 eq) in DCM (500 mL) was added (COCl).sub.2 (37 g, 287.89 mmol, 3 eq) at 0° C. under N.sub.2. The reaction mixture was stirred at 25° C. for 0.5 hour, and then added dropwise into EtOH (100 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1.5 hours, and then concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 15:1 to 10:1) to give the title compound (37.5 g, 80% yield, 97.4% purity on LCMS) as a white solid.

[0580] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.08 (s, 1H), 7.06 (d, 4H), 6.80 (d, 4H), 4.35-4.29 (m, 2H), 4.26 (s, 4H), 4.15 (s, 3H), 3.71 (s, 6H) and 1.32 (t, 3H).

[0581] LCMS: m/z 496.1 (M+Na).sup.+ (ES.sup.+).

Step E: Ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate

[0582] ##STR00075##

[0583] A solution of ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate (35.9 g, 75.81 mmol, 1 eq) in DCM (200 mL) and TFA (100 mL) was stirred at 25° C. for 15 hours. The reaction mixture was concentrated in vacuo at 25° C. The residue was treated with MeOH (200 mL), with some solid not dissolving. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate:DCM, 10:1:1 to 1:1:1) to give the title compound (14.5 g, 81% yield, 98.7% purity on LCMS) as a white solid.

[0584] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.58 (s, 2H), 7.09 (s, 1H), 4.32 (q, 2H), 4.14 (s, 3H) and 1.32 (t, 3H).

[0585] LCMS: m/z 233.9 (M+H).sup.+ (ES.sup.+).

Step F: 5-(2-Hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[0586] ##STR00076##

[0587] To a mixture of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (13.5 g, 57.88 mmol, 1 eq) in THF (400 mL) was added dropwise methylmagnesium bromide (3 M, 96.47 mL, 5 eq) at −10° C. over a period of 0.5 hour under N.sub.2. The reaction mixture was stirred at 0° C. for 0.5 hour, then warmed to 25° C. and stirred for 15 hours. The reaction mixture was quenched slowly with a saturated aqueous NH.sub.4Cl solution (300 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were washed with brine (2×500 mL), 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, 2:1 to 0:1) to give the title compound (5.52 g, 43% yield, 98.7% purity on LCMS) as a colourless oil.

[0588] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.32 (s, 2H), 6.40 (s, 1H), 5.47 (s, 1H), 4.01 (s, 3H) and 1.50 (s, 6H).

[0589] LCMS: m/z 220.1 (M+H).sup.+ (ES.sup.+).

Intermediate L13: 4-((Dimethylamino)methyl)benzenesulfonamide

Step A: 4-(Bromomethyl)benzenesulfonamide

[0590] ##STR00077##

[0591] To a solution of 4-methylbenzenesulfonamide (2 g, 11.68 mmol, 1 eq) and NBS (2.2 g, 12.27 mmol, 1.05 eq) in carbon tetrachloride (20 mL) was added AIBN (192 mg, 1.17 mmol, 0.1 eq) at 20° C. The reaction mixture was stirred at 80° C. for 2 hours, cooled to room temperature and poured into ice-water (20 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (3 g, crude) as a yellow solid.

[0592] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.87 (d, 2H), 7.59 (d, 2H) and 4.62 (s, 2H).

Step B: 4-((Dimethylamino)methyl)benzenesulfonamide

[0593] ##STR00078##

[0594] A mixture of 4-(bromomethyl)benzenesulfonamide (1.5 g, 6.00 mmol, 1 eq) and dimethylamine (10 mL, 33 wt % in H.sub.2O, 10 eq) in THF (5 mL) was stirred at 20° C. for 12 hours, and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (0.6 g, 47%) as a yellow solid.

[0595] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.87 (d, 2H), 7.49 (d, 2H), 3.55 (s, 2H) and 2.25 (s, 6H).

[0596] LCMS: m/z 215.1 (M+H).sup.+(ES.sup.+).

Intermediate L14: 5-(2-Methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate

[0597] ##STR00079##

[0598] Ethyl 3-(chlorosulfonyl)-1-methyl-1H-pyrazole-5-carboxylate (9.2 g, 36.4 mmol) was added dropwise to a solution of bis(4-methoxybenzyl)amine (9.4 g, 36.5 mmol) and triethylamine (10 mL, 71.7 mmol) in DCM (200 mL), cooled in an ice bath. The resulting mixture was stirred for 30 minutes, warmed to room temperature and stirred for 90 minutes before being washed with water (200 mL), aqueous hydrochloric acid (1 M, 200 mL), water (200 mL), dried (MgSO.sub.4), filtered and evaporated to give a yellow oil. This was purified by chromatography on silica gel (220 g column, 0-60% ethyl acetate/isohexane) to afford the title compound (15.9 g, 91%) as a white solid.

[0599] .sup.1H NMR (DMSO-d.sub.6) δ 7.19-7.00 (m, 5H), 6.85-6.77 (m, 4H), 4.33 (q, 2H), 4.25 (s, 4H), 4.15 (s, 3H), 3.71 (s, 6H) and 1.33 (t, 3H).

[0600] LCMS m/z 496.4 (M+Na)+(ES.sup.+).

Step B: 5-(2-Hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0601] ##STR00080##

[0602] Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate (1.4 g, 2.96 mmol) was dissolved in dry THF (50 mL) and cooled to −78° C. in a dry ice/acetone bath. Methyl magnesium chloride (3 M in THF, 5 mL, 15.0 mmol) was added slowly via syringe over the course of 15 minutes. The reaction mixture was allowed to reach room temperature and stirred overnight before being cooled in an ice bath and quenched slowly with portions of aqueous ammonium chloride (20 mL). The mixture was extracted into ethyl acetate (3×50 mL) and the combined organic extracts were washed with brine (10 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford a colourless oil. The crude product was purified by chromatography on silica gel (40 g column, 0-50% ethyl acetate/isohexane) to afford the title compound (1.11 g, 67%) as a thick colourless oil.

[0603] .sup.1H NMR (DMSO-d.sub.6) δ 7.09-7.03 (m, 4H), 6.85-6.80 (m, 4H), 6.41 (s, 1H), 4.21 (s, 4H), 4.04 (s, 3H), 3.72 (s, 6H) and 1.50 (s, 6H). One exchangeable proton not observed.

[0604] LCMS m/z 460 (M+H).sup.+(ES.sup.+); 458 (M−H).sup.− (ES.sup.−).

Step C: N,N-bis-(4-Methoxybenzyl)-5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[0605] ##STR00081##

[0606] 5-(2-Hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (2.5 g, 5.33 mmol) was dissolved in dry DMF (50 mL) under a nitrogen atmosphere. After cooling in an ice bath, sodium hydride (60% in mineral oil, 0.25 g, 6.25 mmol) was added in a single portion and the cloudy yellow mixture was stirred for 30 minutes. Iodomethane (1.5 mL, 24.1 mmol) was added in a single portion and the mixture was stirred for a further 2 hours, while warming to room temperature. The reaction mixture was quenched by slow addition of sat aq ammonium chloride (10 mL) and then partitioned between ethyl acetate (100 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (4×50 mL). The combined organic portions were washed with brine (20 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by chromatography on silica (40 g column, 0-100% ethyl acetate/isohexane) to afford, after drying in vacuo, the title compound (2.41 g, 94%) as a colourless solid.

[0607] .sup.1H NMR (DMSO-d.sub.6) δ 7.10-7.04 (m, 4H), 6.85-6.80 (m, 4H), 6.48 (s, 1H), 4.23 (s, 4H), 3.97 (s, 3H), 3.72 (s, 6H), 2.97 (s, 3H) and 1.50 (s, 6H).

[0608] LCMS m/z 474 (M+H).sup.+ (ES.sup.+); 472 (M−H).sup.− (ES.sup.−).

Step D: 5-(2-Methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[0609] ##STR00082##

[0610] N,N-bis-(4-Methoxybenzyl)-5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (2.4 g, 5.02 mmol) was dissolved in acetonitrile (40 mL). A solution of ceric ammonium nitrate (15 g, 27.4 mmol) in water (10 mL) was added in a single portion and the dark red reaction mixture was stirred at room temperature for 4 hours. Water (10 mL) and DCM (250 mL) were added and the organic phase was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to give an orange oil (about 2.5 g). The crude product was purified by chromatography on silica gel (40 g column, 0-20% methanol/dichloromethane) to afford an orange oil. Trituration of this material in TBME (10 mL) and isohexane (5 mL) gave a tan precipitate which was further purified by chromatography on silica gel (24 g, 20-100% ethyl acetate in hexanes) to afford the title compound (383 mg, 31%) as a yellow solid.

[0611] .sup.1H NMR (CDCl.sub.3) δ 6.57 (s, 1H), 5.08 (s, 2H), 4.06 (s, 3H), 3.08 (s, 3H) and 1.57 (s, 6H).

Intermediate L15: 1-(2,2,2-Trifluoroethyl)-1H-pyrazole-4-sulfonamide

Step A: 1-(2,2,2-Trifluoroethyl)-1H-pyrazol-4-amine

[0612] ##STR00083##

[0613] 4-Nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (1 g, 5.13 mmol) and 10% Pd/C (wet) Type 87 L (27 mg, 0.256 mmol) were suspended with MeOH (12.8 mL) and EtOAc (12.8 mL). The vessel was purged with N.sub.2 three times, then filled with H.sub.2 three times. The reaction mixture was stirred at room temperature under 5 bar H.sub.2 for 18 hours. The reaction mixture was filtered through a pad of Celite. The filter cake was washed with EtOAc (2×5 mL) and the combined filtrates were evaporated in vacuo to give the title compound as a red oil (0.85 g, 100%).

[0614] .sup.1H NMR (Chloroform-d) δ 7.25 (d, J=0.9 Hz, 1H), 7.09 (d, J=0.8 Hz, 1H), 4.57 (q, J=8.4 Hz, 2H), 2.43 (br s, 2H).

[0615] .sup.19F NMR (Chloroform-d) δ −71.88 (t, J=8.4 Hz).

[0616] LCMS m/z 166.0 (M+H).sup.+(ES.sup.+).

Step B: 1-(2,2,2-Trifluoroethyl)-1H-pyrazole-4-sulfonyl chloride

[0617] ##STR00084##

[0618] A mixture of conc HCl (1.9 mL) in water (1.3 mL) and acetonitrile (6.5 mL) was cooled to −10° C. (acetone/dry ice bath) and treated with a solution of sodium nitrite (426 mg, 6.18 mmol) in water (0.7 mL) dropwise, maintaining internal temperature below 0° C. A yellow solution formed which was stirred for 10 minutes and then treated at 0° C. over 15 minutes with a solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (850 mg, 5.15 mmol) in MeCN (6.5 mL), which was pre-cooled to 0° C. The resulting reaction mixture was stirred at 0° C. for 45 minutes. Cold acetic acid (2.6 mL), copper(II) chloride (346 mg, 2.57 mmol) and copper(I) chloride (25.5 mg, 0.257 mmol) were sequentially added to the reaction mixture. Then the reaction mixture was purged with sulfur dioxide gas for 70 minutes at 0° C. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×30 mL), then dried (MgSO.sub.4), filtered and concentrated to dryness to give a brown paste. The crude product was purified by chromatography on silica gel (40 g column, 0-50% DCM/isohexane) to afford the title compound (420 mg, 16%) as a clear yellow oil.

[0619] .sup.1H NMR (Chloroform-d) δ 8.20 (s, 1H), 8.06 (s, 1H), 4.81 (q, J=8.1 Hz, 2H).

Step C: 1-(2,2,2-Trifluoroethyl)-1H-pyrazole-4-sulfonamide

[0620] ##STR00085##

[0621] A solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonyl chloride (420 mg, 0.845 mmol) (50 wt % purity) in THF (1.4 mL) was treated with NH.sub.3 (0.5 M in dioxane, 5 mL). The reaction mixture was then stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue partitioned between water (5 mL) and DCM (15 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated in vacuo to give an orange oil, which was co-evaporated twice with 3:1 isohexane/DCM until the dry mixture solidified. The solid product was then dissolved in DCM (3 mL) and isohexane (9 mL) was added. The supernatant liquid was decanted off and the solid washed with 3:1 isohexane/DCM (1×3 mL) and isohexane (2×3 mL). The solid was collected and dried in vacuo to afford the title compound (159 mg, 78%) as an orange powder.

[0622] .sup.1H NMR (DMSO-d.sub.6) δ 8.32 (d, J=0.7 Hz, 1H), 7.87 (d, J=0.7 Hz, 1H), 7.42 (s, 2H), 5.24 (q, J=9.0 Hz, 2H).

[0623] .sup.19F NMR (DMSO-d.sub.6) δ −70.16 (t, J=9.0 Hz).

[0624] LCMS m/z 227.9/228.9 (M−H).sup.− (ES.sup.−).

Intermediate L16: 1-(2,2,2-Trifluoroethyl)-1H-pyrazole-3-sulfonamide

Step A: 1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-amine

[0625] ##STR00086##

[0626] Prepared according to the general procedure of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (Intermediate L15, Step A) from 3-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole to afford the title compound (420 mg, 98%) as a yellow solid.

[0627] .sup.1H NMR (Chloroform-d) δ 7.23 (d, J=2.4 Hz, 1H), 5.72 (d, J=2.4 Hz, 1H), 4.47 (q, J=8.4 Hz, 2H), 2.96-2.27 (br s, 2H).

[0628] LCMS m/z 166.0 (M+H).sup.+ (ES.sup.+).

Step B: 1-(2,2,2-Trifluoroethyl)-1H-pyrazole-3-sulfonyl chloride

[0629] ##STR00087##

[0630] Prepared according to the general procedure of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonyl chloride (Intermediate L15, Step B) from 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine to afford the title compound (756 mg, 50%) as a clear orange oil.

[0631] .sup.1H NMR (Chloroform-d) δ 7.69 (d, J=2.5 Hz, 1H), 7.00 (d, J=2.5 Hz, 1H), 4.86 (q, J=8.1 Hz, 2H).

[0632] .sup.19F NMR (Chloroform-d) δ −71.16 (t, J=8.1 Hz).

[0633] LCMS m/z 246.8 (M−H).sup.− (ES.sup.−).

Step C: 1-(2,2,2-Trifluoroethyl)-1H-pyrazole-3-sulfonamide

[0634] ##STR00088##

[0635] Prepared according to the general procedure of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide (Intermediate L15, Step C) from 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-sulfonyl chloride to afford the title compound (394 mg, 67%) as a white powder.

[0636] .sup.1H NMR (DMSO-d.sub.6) δ 8.00 (d, J=2.4 Hz, 1H), 7.55 (s, 2H), 6.70 (d, J=2.4 Hz, 1H), 5.26 (q, J=9.1 Hz, 2H).

[0637] .sup.19F NMR (DMSO-d.sub.6) δ −70.08 (t, J=9.2 Hz).

[0638] LCMS m/z 229.1 (M+H).sup.− (ES.sup.−); 227.9 (M−H).sup.− (ES.sup.−).

Intermediate L17: 1-Isopropyl-3-methyl-1H-pyrazole-4-sulfonamide

[0639] ##STR00089##

[0640] Prepared according to the general procedure of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide (Intermediate L15, Step C) from 1-isopropyl-3-methyl-1H-pyrazole-4-sulfonyl chloride to afford the title compound (541 mg, 59%) as a white crystalline solid.

[0641] .sup.1H NMR (DMSO-d.sub.6) δ 8.06 (s, 1H), 7.15 (s, 2H), 4.46 (sept, J=6.6 Hz, 1H), 2.29 (s, 3H), 1.38 (d, J=6.7 Hz, 6H).

[0642] LCMS m/z 204.0 (M+H).sup.+ (ES.sup.+).

Intermediate L18: 1-(Cyclopropylmethyl)-1H-pyrazole-4-sulfonamide

[0643] ##STR00090##

[0644] Prepared according to the general procedure of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide (Intermediate L15, Step C) from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonyl chloride to afford the title compound (153 mg, 66%) as a peach-coloured solid.

[0645] .sup.1H NMR (DMSO-d.sub.6) δ 8.21 (d, J=0.7 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.25 (s, 2H), 4.00 (d, J=7.2 Hz, 2H), δ 1.33-1.17 (m, 1H), 0.63-0.49 (m, 2H), 0.41-0.36 (m, 2H).

[0646] LCMS m/z 202.0 (M+H).sup.+ (ES.sup.+).

Intermediate L19: 1-Ethyl-1H-pyrazole-3-sulfonamide

Step A: Lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate

[0647] ##STR00091##

[0648] A solution of BuLi (100 mL, 250 mmol, 2.5 M in hexanes) was added slowly to a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (36.2 g, 238 mmol) in THF (500 mL) keeping the temperature below −65° C. The mixture was stirred for 1.5 hours, then sulfur dioxide was bubbled through for 10 minutes. The mixture was warmed to room temperature, the solvent evaporated and the residue triturated with TBME (300 mL) and filtered. The solid was washed with TBME and isohexanes and dried to afford the crude title compound (54.9 g, 99%).

[0649] .sup.1H NMR (DMSO-d.sub.6) δ 7.26 (d, J=1.6 Hz, 1H), 6.10 (d, J=1.7 Hz, 1H), 5.99 (dd, J=10.0, 2.5 Hz, 1H), 3.92-3.87 (m, 1H), 3.56-3.49 (m, 1H), 2.25-2.15 (m, 1H), 2.00-1.91 (m, 1H), 1.75-1.69 (m, 1H), 1.66-1.46 (m, 3H).

[0650] LCMS m/z 215 (M−H).sup.− (ES.sup.−).

Step B: N,N-bis(4-Methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide

[0651] ##STR00092##

[0652] NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (20 g, 90 mmol) in DCM (250 mL), cooled in an ice bath. The mixture was stirred for 4 hours, quenched with water (100 mL), and then partitioned between DCM (300 mL) and water (200 mL). The organic phase was washed with water (200 mL), dried (MgSO.sub.4) and evaporated to about 50 mL. The solution was added to a mixture of bis(4-methoxybenzyl)amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL), cooled in an ice bath. After stirring for 1 hour, the mixture was warmed to room temperature, and partitioned between DCM (300 mL) and water (250 mL). The organic layer was washed with water (250 mL), aq 1 M HCl (2×250 mL), water (250 mL), dried (MgSO.sub.4) and evaporated to afford the title compound (41.0 g, 97%) as a brown oil.

[0653] LCMS m/z 494.2 (M+Na)+ (ES.sup.+).

Step C: N,N-bis(4-Methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0654] ##STR00093##

[0655] A mixture of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (41 g, 87 mmol) and aq 1 M HCl (30 mL) in THF (300 mL) and MeOH (50 mL) was stirred at room temperature for 18 hours. The solvent was evaporated and the residue partitioned between EtOAc (400 mL) and aq 1 M HCl (200 mL). The organic layer was washed with 10% brine (200 mL), dried (MgSO.sub.4) and evaporated. The residue was triturated with TBME, filtered and dried to afford the title compound (24.9 g, 69%) as an off white solid.

[0656] .sup.1H NMR (CDCl.sub.3) δ 7.88 (d, J=2.4 Hz, 1H), 7.06-7.02 (m, 4H), 6.79-6.75 (m, 4H), 6.63 (d, J=2.4 Hz, 1H), 4.31 (s, 4H), 3.78 (s, 6H). One exchangeable proton not observed.

[0657] LCMS m/z 388 (M+H).sup.+ (ES.sup.+); 386 (M−H).sup.− (ES.sup.−).

Step D: 1-Ethyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0658] ##STR00094##

[0659] Under nitrogen, N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.347 g, 0.896 mmol) was dissolved in dry MeCN (10 mL) and K.sub.2CO.sub.3 (0.619 g, 4.48 mmol) was added. Bromoethane (0.267 mL, 3.58 mmol) was added in a single portion and the cloudy mixture was heated to 60° C. for 30 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (3×25 mL). The organic phase was dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (280 mg, 69%) as a colourless oil.

[0660] LCMS m/z 416 (M+H).sup.+ (ES.sup.+).

Step E: 1-Ethyl-1H-pyrazole-3-sulfonamide

[0661] ##STR00095##

[0662] 1-Ethyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (280 mg, 0.674 mmol) was dissolved in DCM (1 mL), and water (0.5 mL) and TFA (2 mL) were added. The reaction mixture was stirred at room temperature for 15 hours. The solution was concentrated in vacuo and the residue purified by reversed phase chromatography on RP Flash C18 (12 g column, 1-30% MeCN/10 mM ammonium bicarbonate) to afford the title compound (102 mg, 83%) as white solid.

[0663] .sup.1H NMR (DMSO-d.sub.6) δ 7.88 (d, J=2.3 Hz, 1H), 7.36 (br s, 2H), 6.57 (d, J=2.3 Hz, 1H), 4.20 (q, J=7.3 Hz, 2H), 1.40 (t, J=7.3 Hz, 3H).

Intermediate L20: 1-Isopropyl-1H-1,2,4-triazole-3-sulfonamide

Step A: 3-(Benzylthio)-1-isopropyl-1H-1,2,4-triazole

[0664] ##STR00096##

[0665] 2-Iodopropane (3.00 mL, 30.0 mmol) was added to a mixture of 3-(benzylthio)-1H-1,2,4-triazole (8.2 g, 30.0 mmol) and K.sub.2CO.sub.3 (8.30 g, 60.0 mmol) in DMF (100 mL), cooled in an ice bath. The mixture was stirred for 2 hours, then warmed to room temperature and stirred for 20 hours. The mixture was partitioned between EtOAc (200 mL) and water (100 mL), the organic layer washed with water (2×100 mL), dried (MgSO.sub.4) and evaporated. The residue was purified by chromatography on silica gel (80 g column, 0-50% EtOAc/isohexane) to afford the title compound (2.8 g, 40%) as an oil.

[0666] .sup.1H NMR (DMSO-d.sub.6) δ 8.53 (s, 1H), 7.41-7.35 (m, 2H), 7.33-7.19 (m, 3H), 4.54 (sept, J=6.8 Hz, 1H), 4.31 (s, 2H), 1.42 (d, J=6.6 Hz, 6H).

[0667] LCMS m/z 234.4 (M+H).sup.+ (ES.sup.+).

Step B: 1-Isopropyl-1H-1,2,4-triazole-3-sulfonyl chloride

[0668] ##STR00097##

[0669] NCS (5.59 g, 41.8 mmol) was added to a solution of 3-(benzylthio)-1-isopropyl-1H-1,2,4-triazole (2 g, 10.46 mmol) in AcOH (40 mL) and water (20 mL). The mixture was stirred for 2 hours, then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was washed with sat aq NaHCO.sub.3(100 mL), brine (50 mL), dried (MgSO.sub.4), filtered and evaporated. TBME (20 mL) was added to the residue, the solid filtered off and the filtrate evaporated to afford the title compound (1.80 g) as a yellow oil that was used without purification in the next step.

Step C: 1-Isopropyl-1H-1,2,4-triazole-3-sulfonamide

[0670] ##STR00098##

[0671] Prepared according to the general procedure of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide (Intermediate L15, Step C) from 1-isopropyl-1H-1,2,4-triazole-3-sulfonyl chloride to afford the title compound (770 mg, 37% yield over 2 steps) as a colourless solid.

[0672] .sup.1H NMR (DMSO-d.sub.6) δ 8.76 (s, 1H), 7.71 (s, 2H), 4.69 (sept, J=6.7 Hz, 1H), 1.47 (d, J=6.7 Hz, 6H).

Intermediate L21: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide

[0673] ##STR00099##

[0674] A solution of 1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (712 mg, 3.76 mmol) in MeCN (4.4 mL) was treated with N,N-dimethylpyridin-4-amine (919 mg, 7.53 mmol) and the reaction mixture was stirred at room temperature until the sulfonamide had dissolved. Diphenyl carbonate (887 mg, 4.14 mmol) was added and the reaction mixture was left for 16 hours at room temperature. The resulting precipitate was separated by filtration, washed with MTBE and dried to afford the title compound (776 mg, 61%) as a white solid, which was used without further purification.

[0675] .sup.1H NMR (CDCl.sub.3) δ 8.95 (d, J=7.5 Hz, 2H), 7.35 (d, J=2.3 Hz, 1H), 6.83 (d, J=2.3 Hz, 1H), 6.62 (d, J=7.5 Hz, 2H), 4.58-4.43 (m, 1H), 3.24 (s, 6H), 1.42 (d, J=6.7 Hz, 6H).

Intermediate L22: 1-Isopropyl-1H-1,2,3-triazole-5-sulfonamide

Step A: 4-(Benzylthio)-1H-1,2,3-triazole

[0676] ##STR00100##

[0677] Benzyl bromide (24 mL, 202 mmol) was added dropwise to a suspension of sodium 1H-1,2,3-triazole-4-thiolate (25 g, 203 mmol) in EtOH (300 mL), cooled in an ice bath. The mixture was stirred for 48 hours, then the solvent was evaporated. The residue was partitioned between EtOAc (500 mL) and water (300 mL), the organic layer washed with brine (200 mL), dried (MgSO.sub.4) and evaporated. The residue was triturated with TBME/isohexane to afford the title compound (35.1 g, 88%) as a white solid.

[0678] .sup.1H NMR (CDCl.sub.3) δ 7.40-7.24 (m, 7H), 4.16 (s, 2H).

[0679] LCMS m/z 192 (M+H).sup.+ (ES.sup.+); 190 (M−H).sup.− (ES.sup.−).

Step B: 5-(Benzylthio)-1-isopropyl-1H-1,2,3-triazole

[0680] ##STR00101##

[0681] 2-Iodopropane (7 mL, 70.1 mmol) was added to a mixture of 4-(benzylthio)-1H-1,2,3-triazole (12 g, 62.7 mmol) and K.sub.2CO.sub.3 (18 g, 130 mmol) in DMF (150 mL), cooled in an ice bath. The mixture was stirred for 2 hours, then warmed to room temperature and stirred for 20 hours. The mixture was partitioned between EtOAc (400 mL) and water (400 mL). The organic layer was washed with water (2×300 mL), dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by chromatography on silica gel (220 g column, 0-50% EtOAc/isohexane) to afford the title compound (1.95 g, 13%) as an oil.

[0682] .sup.1H NMR (CDCl.sub.3) δ 7.62 (s, 1H), 7.32-7.26 (m, 3H), 7.14-7.10 (m, 2H), 4.64 (sept, J=6.7 Hz, 1H), 3.94 (s, 2H), 1.41 (d, J=6.7 Hz, 6H).

[0683] 4-(Benzylthio)-1-isopropyl-1H-1,2,3-triazole (2.39 g, 16%) and 4-(benzylthio)-2-isopropyl-2H-1,2,3-triazole (9.16 g, 61%) were also isolated from this reaction.

Step C: 1-Isopropyl-1H-1,2,3-triazole-5-sulfonyl chloride

[0684] ##STR00102##

[0685] Prepared according to the general procedure of 1-isopropyl-1H-1,2,4-triazole-3-sulfonyl chloride (Intermediate L20, Step B) from 5-(benzylthio)-1-isopropyl-1H-1,2,3-triazole to afford an oil which was used without purification in the next step.

[0686] Step D: 1-Isopropyl-1H-1,2,3-triazole-5-sulfonamide

##STR00103##

[0687] Prepared according to the general procedure of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide (Intermediate L15, Step C) from 1-isopropyl-1H-1,2,3-triazole-5-sulfonyl chloride to afford the title compound (757 mg, 65%) as an off white solid.

[0688] .sup.1H NMR (DMSO-d.sub.6) δ 8.32 (br s, 2H), 8.04 (s, 1H), 5.15 (sept, J=6.6 Hz, 1H), 1.56 (d, J=6.6 Hz, 6H).

Intermediate L23: 2-Isopropyl-2H-1,2,3-triazole-4-sulfonamide

[0689] ##STR00104##

[0690] Prepared according to the general procedure of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide (Intermediate L15, Step C) from 2-isopropyl-2H-1,2,3-triazole-4-sulfonyl chloride to afford the title compound (1.17 g, 71%) as a white solid.

[0691] .sup.1H NMR (CDCl.sub.3) δ 7.97 (s, 1H), 5.18 (br s, 2H), 4.92 (sept, J=6.7 Hz, 1H), 1.64 (d, J=6.7 Hz, 6H).

Intermediate L24: 5-(2-Hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide

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

[0692] ##STR00105##

[0693] Prepared according to the general procedure of ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate (Intermediate L14, Step A) from 1-isopropyl-1H-pyrazole-3-sulfonyl chloride (Intermediate L6, Step C) to afford the title compound (16.6 g, 80%) as a white solid.

[0694] .sup.1H NMR (DMSO-d.sub.6) δ 8.00 (d, J=2.4 Hz, 1H), 7.07-6.96 (m, 4H), 6.85-6.76 (m, 4H), 6.70 (d, J=2.4 Hz, 1H), 4.61 (sept, J=6.7 Hz, 1H), 4.20 (s, 4H), 3.71 (s, 6H), 1.44 (d, J=6.7 Hz, 6H).

[0695] LCMS m/z 452.2 (M+Na)+ (ES.sup.+).

Step B: 5-(2-Hydroxypropan-2-yl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0696] ##STR00106##

[0697] A solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (2.5 g, 5.82 mmol) in THF (30 mL) was cooled to −78° C. and BuLi (2.5 M in THF, 2.4 mL, 6.00 mmol) was added slowly via syringe. Upon complete addition, the mixture was stirred at −78° C. for 1 hour, before propan-2-one (0.52 mL, 7.08 mmol) was added slowly via syringe. The mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched with sat aq NH.sub.4Cl (25 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with brine (50 mL), dried (phase separator) and evaporated to give a yellow oil. The crude product was purified by chromatography on silica gel (80 g column, 0-100% EtOAc/isohexane) to afford the title compound (2.80 g, 49%) as a clear yellow oil that solidified slowly.

[0698] LCMS m/z 510.5 (M+Na)+ (ES.sup.+).

Step C: 5-(2-Hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[0699] ##STR00107##

[0700] Prepared according to the general procedure of 5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L14, Step D) from 5-(2-hydroxypropan-2-yl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (72.5 mg, 28%) as a pale yellow solid.

[0701] .sup.1H NMR (DMSO-d.sub.6) δ 7.32 (s, 2H), 6.34 (s, 1H), 5.51 (s, 1H), 5.27 (sept, J=6.6 Hz, 1H), 1.51 (s, 6H), 1.39 (d, J=6.6 Hz, 6H).

[0702] LCMS m/z 248.4 (M+H).sup.+ (ES.sup.+).

Intermediate L25: 5-(1-Methoxycyclobutyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: 5-(1-Hydroxycyclobutyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0703] ##STR00108##

[0704] Prepared according to the general procedure of 5-(2-hydroxypropan-2-yl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L24, Step B) from N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L12, Step B) and cyclobutanone to afford a 3:2 mixture of the title compound (1.09 g, 61%) and the starting material.

[0705] LCMS m/z 472.5 (M+H).sup.+ (ES.sup.+).

Step B: N,N-bis(4-Methoxybenzyl)-5-(1-methoxycyclobutyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0706] ##STR00109##

[0707] Prepared according to the general procedure of N,N-bis-(4-methoxybenzyl)-5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L14, Step C) from 5-(1-hydroxycyclobutyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.41 g, 91%) as a colourless oil.

[0708] .sup.1H NMR (DMSO-d.sub.6) δ=7.09-7.04 (m, 4H), 6.85-6.79 (m, 4H), 6.75 (s, 1H), 4.24 (s, 4H), 3.81 (s, 3H), 3.71 (s, 6H), 2.85 (s, 3H), 2.44-2.25 (m, 4H), 1.89-1.76 (m, 1H), 1.62-1.49 (m, 1H).

[0709] LCMS m/z 508.5 (M+Na).sup.+, 486.5 (M+H).sup.+ (ES.sup.+).

Step C: 5-(1-Methoxycyclobutyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0710] ##STR00110##

[0711] Prepared according to the general procedure of 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19, Step E) from N,N-bis(4-methoxybenzyl)-5-(1-methoxycyclobutyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.198 g, 89%) as a pale brown solid.

[0712] LCMS m/z 245.8 (M+H).sup.+ (ES.sup.+).

Intermediate L26: 5-(1-Methoxycyclopentyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: 5-(1-Hydroxycyclopentyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0713] ##STR00111##

[0714] Prepared according to the general procedure of 5-(2-hydroxypropan-2-yl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L24, Step B) from N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L12, Step B) and cyclopentanone to afford a 63:37 mixture (by HPLC) of starting material and title compound (1.96 g, 55%) as a cream coloured solid.

[0715] LCMS m/z 486.2 (M+H).sup.+ (ES.sup.+).

Step B: N,N-bis(4-Methoxybenzyl)-5-(1-methoxycyclopentyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0716] ##STR00112##

[0717] Prepared according to the general method of N,N-bis-(4-methoxybenzyl)-5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L14, Step C) from 5-(1-hydroxycyclopentyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.61 g, 93%) as a colourless oil.

[0718] LCMS m/z 500.2 (M+H).sup.+ (ES.sup.+).

Step C: 5-(1-Methoxycyclopentyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0719] ##STR00113##

[0720] Prepared according to the general method of 5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L14, Step D) from N,N-bis(4-methoxybenzyl)-5-(1-methoxycyclopentyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.22 g, 35%) as an orange solid.

[0721] LCMS m/z 260.3 (M+H).sup.+ (ES.sup.+).

Intermediate L27: 5-(1-Methoxyethyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: 5-(1-Hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0722] ##STR00114##

[0723] Prepared according to the general procedure of 5-(2-hydroxypropan-2-yl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L24, Step B) from N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L12, Step B) and acetaldehyde to afford the title compound (2.12 g, 60%) as a viscous colourless oil.

[0724] .sup.1H NMR (DMSO-d.sub.6) δ 7.09-7.01 (m, 4H), 6.86-6.77 (m, 4H), 6.54 (s, 1H), 5.51 (d, J=5.7 Hz, 1H), 4.86 (p, J=6.4 Hz, 1H), 4.20 (s, 4H), 3.91 (s, 3H), 3.72 (s, 6H), 1.43 (d, J=6.5 Hz, 3H).

[0725] LCMS m/z 446 (M+H).sup.+ (ES.sup.+).

Step B: N,N-bis(4-Methoxybenzyl)-5-(1-methoxyethyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0726] ##STR00115##

[0727] Prepared according to the general procedure of N,N-bis-(4-methoxybenzyl)-5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L14, Step C) from 5-(1-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (858 mg, 99%) as an oil.

[0728] .sup.1H NMR (CDCl.sub.3) δ 7.12-7.08 (m, 4H), 6.81-6.76 (m, 4H), 6.51 (s, 1H), 4.53 (q, J=6.6 Hz, 1H), 4.34 (s, 4H), 3.95 (s, 3H), 3.80 (s, 6H), 3.29 (s, 3H), 1.53 (d, J=6.6 Hz, 3H).

[0729] LCMS m/z 460.1 (M+H).sup.+ (ES.sup.+).

Step C: 5-(1-Methoxyethyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0730] ##STR00116##

[0731] Prepared according to the general procedure of 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19, Step E) from N,N-bis(4-methoxybenzyl)-5-(1-methoxyethyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (395 mg, 93%) as a brown solid.

[0732] .sup.1H NMR (DMSO-d.sub.6) δ 7.37 (s, 2H), 6.53 (s, 1H), 4.64 (q, J=6.5 Hz, 1H), 3.87 (s, 3H), 3.22 (s, 3H), 1.43 (d, J=6.5 Hz, 3H).

[0733] LCMS m/z 220.2 (M+H).sup.+ (ES.sup.+).

Intermediate L28: 5-(1-Hydroxyethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

Step A: 5-(1-Hydroxyethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0734] ##STR00117##

[0735] Prepared according to the general procedure of 5-(2-hydroxypropan-2-yl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L24, Step B) from 1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L24, Step A) and acetaldehyde to afford the title compound (2.14 g, 65%) as a white solid.

[0736] .sup.1H NMR (DMSO-d.sub.6) δ 7.07-6.99 (m, 4H), 6.84-6.78 (m, 4H), 6.51 (s, 1H), 5.49 (d, J=6.0 Hz, 1H), 4.96-4.76 (m, 2H), 4.19 (s, 4H), 3.72 (s, 6H), 1.44 (d, J=6.5 Hz, 3H), 1.39 (app t, J=6.4 Hz, 6H).

[0737] LCMS m/z 496.4 (M+Na).sup.+ (ES.sup.+).

Step B: 5-(1-Hydroxyethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[0738] ##STR00118##

[0739] Prepared according to the general procedure of 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19, Step E) from 5-(1-hydroxyethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (0.09 g, 36%) as a white solid.

[0740] LCMS 234.3 (M+H).sup.− (ES.sup.−).

Intermediate L29: 4-Fluoro-1-isopropyl-1H-pyrazole-3-sulfonamide

[0741] ##STR00119##

[0742] Selectfluor® (2.81 g, 7.93 mmol) was added to a solution of 1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (0.5 g, 2.64 mmol) in dry acetonitrile (8 mL) portionwise at room temperature, then the solution was stirred at 66° C. for 24 hours. A further portion of Selectfluor® (2.81 g, 7.93 mmol) was added and the reaction was stirred at 66° C. for a further 24 hours. The reaction was diluted with MeOH (50 mL), filtered and concentrated under reduced pressure. The residue was taken up in dry MeCN (10 mL), Selectfluor® (4.68 g, 13.2 mmol) was added portionwise and the reaction was stirred at 66° C. for 24 hours, cooled to room temperature, taken up in MeOH (50 mL), filtered and concentrated under reduced pressure. The residue was taken up in dry MeCN (20 mL), further Selectfluoro (3.7 g, 10.6 mmol) was added portionwise and the reaction was stirred at 66° C. for a further 18 hours. The volatiles were removed under reduced pressure and the residue was taken up in DCM/water (1:1, 150 mL). The organic phase separated, the aqueous phase further extracted with EtOAc (70 mL) and the combined organic phases dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by reversed phase prep-HPLC method 1 to afford the title compound (36 mg, 6%) as a white solid.

[0743] LCMS m/z 208.0 (M+H).sup.+ (ES.sup.+).

Intermediate L30: 1-(1-(Azetidin-1-yl)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide

Step A: Methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoate

[0744] ##STR00120##

[0745] Prepared according to the general procedure of 1-ethyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L19, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L19, Step C) and methyl 2-bromo-2-methylpropanoate to afford the title compound (2.45 g, 94%) as a clear colourless oil.

[0746] .sup.1H NMR (DMSO-d.sub.6) δ 8.18 (d, J=2.5 Hz, 1H), 7.05-6.95 (m, 4H), 6.85-6.78 (m, 4H), 6.78 (d, J=2.5 Hz, 1H), 4.18 (s, 4H), 3.72 (s, 6H), 3.65 (s, 3H), 1.81 (s, 6H).

[0747] LCMS m/z 511 (M+Na).sup.+ (ES.sup.+).

Step B: 2-(3-(N,N-bis(4-Methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid

[0748] ##STR00121##

[0749] A mixture of methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoate (2.4 g, 4.92 mmol) and aq 2 M NaOH (5 mL, 10 mmol) in THF (5 mL) and MeOH (3 mL) was stirred at room temperature for 20 hours. The mixture was partitioned between EtOAc (100 mL) and aq 1 M HCl (100 mL), the organic layer washed with brine (50 mL), dried (MgSO.sub.4) and evaporated to afford the title compound (2.38 g, 95%) as a gum that solidified on standing.

[0750] .sup.1H NMR (CDCl.sub.3) δ 7.64 (d, J=2.5 Hz, 1H), 7.09-7.05 (m, 4H), 6.80-6.77 (m, 4H), 6.73 (d, J=2.5 Hz, 1H), 4.32 (s, 4H), 3.80 (s, 6H), 1.91 (s, 6H). One exchangeable proton not observed.

[0751] LCMS m/z 472 (M−H).sup.− (ES.sup.−).

Step C: 1-(1-(Azetidin-1-yl)-2-methyl-1-oxopropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0752] ##STR00122##

[0753] A mixture of 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid (1.15 g, 2.23 mmol), Hunig's Base (1.56 mL, 8.91 mmol) and HATU (0.921 g, 2.42 mmol) in DMF (6.5 mL) was stirred at 0-5° C. for 10 minutes. Then azetidine HCl (0.272 g, 2.90 mmol) was added. The mixture was warmed to room temperature and stirred for 20 hours. Further HATU (0.263 g, 1.12 mmol) was added, followed by further Hunig's Base (0.390 mL, 2.23 mmol). The mixture was cooled to 0-5° C. for 10 minutes, then further azetidine HCl (0.064 g, 1.12 mmol) was added. The mixture was warmed to room temperature, stirred for a further 1 hour, then partitioned between TBME (75 mL) and water (40 mL). The organic layer was washed with aq 1 M HCl (40 mL), water (25 mL), dried (MgSO.sub.4), evaporated and purified by chromatography on silica gel (120 g column, 0-100% TBME/isohexane) to afford the title compound (615 mg, 51%) as a clear gum.

[0754] .sup.1H NMR (CDCl.sub.3) δ 7.56 (d, J=2.4 Hz, 1H), 7.13-7.09 (m, 4H), 6.80-6.76 (m, 5H), 4.32 (s, 4H), 3.99 (t, J=7.8 Hz, 2H), 3.79 (s, 6H), 3.23 (t, J=7.7 Hz, 2H), 2.08-2.01 (m, 2H), 1.78 (s, 6H).

[0755] LCMS m/z 513.1 (M+H).sup.+ (ES.sup.+).

Step D: 1-(1-(Azetidin-1-yl)-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0756] ##STR00123##

[0757] BH.sub.3.THF (1 M in THF, 21.5 mL, 21.5 mmol) was added to a solution of 1-(1-(azetidin-1-yl)-2-methyl-1-oxopropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (3.15 g, 6.15 mmol) in THF (26.3 mL). The mixture was stirred for 3 minutes, then heated to reflux over the weekend. The reaction was cooled to room temperature, before being placed in an ice-bath. MeOH (50 mL) was added dropwise and the mixture was heated at 60° C. for 3 hours, then cooled to room temperature overnight. The mixture was concentrated in vacuo and loaded onto a column of SCX (30 g) in MeOH (50 mL). The column was washed with MeOH (100 mL), 0.7 M ammonia in MeOH (100 mL) and the product was eluted with 7 M ammonia in MeOH (100 mL). The resultant mixture was concentrated in vacuo to afford the title compound (2.89 g, 85%) as a colourless viscous oil.

[0758] .sup.1H NMR (DMSO-d.sub.6) δ 7.98 (d, J=2.5 Hz, 1H), 7.07-7.02 (m, 4H), 6.84-6.79 (m, 4H), 6.69 (d, J=2.4 Hz, 1H), 4.19 (s, 4H), 3.72 (s, 6H), 2.92 (t, J=7.0 Hz, 4H), 2.68 (s, 2H), 1.84 (p, J=7.0 Hz, 2H), 1.48 (s, 6H).

[0759] LCMS m/z 499.2 (M+H).sup.− (ES.sup.−).

Step E: 1-(1-(Azetidin-1-yl)-2-Methylpropan-2-yl)-1H-pyrazole-3-sulfonamide

[0760] ##STR00124##

[0761] Prepared according to the general procedure of 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19, Step E) from 1-(1-(azetidin-1-yl)-2-Methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (1.06 g, 69%) as a white solid.

[0762] .sup.1H NMR (DMSO-d.sub.6) δ 7.89 (d, J=2.5 Hz, 1H), 7.34 (s, 2H), 6.54 (d, J=2.4 Hz, 1H), 2.94 (t, J=7.0 Hz, 4H), 2.68 (s, 2H), 1.84 (p, J=7.0 Hz, 2H), 1.47 (s, 6H).

[0763] LCMS m/z 259.1 (M+H).sup.+ (ES.sup.+).

Intermediate L31: 3-((Dimethylamino)methyl)-5-methylbenzenesulfonamide

Step A: 3-Bromo-N,N-bis(4-methoxybenzyl)-5-methylbenzenesulfonamide

[0764] ##STR00125##

[0765] Prepared according to the general procedure of ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate (Intermediate L14, Step A) from 3-bromo-5-methylbenzene-1-sulfonyl chloride to afford the title compound (1.56 g, 77%) as a pale orange oil which solidified upon standing.

[0766] .sup.1H NMR (Chloroform-d) δ 7.70-7.65 (m, 1H), 7.53-7.49 (m, 1H), 7.49-7.45 (m, 1H), 7.10-7.02 (m, 4H), 6.86-6.78 (m, 4H), 4.29 (s, 4H), 3.81 (s, 6H), 2.38 (s, 3H).

Step B: 3-((Dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-5-methylbenzenesulfonamide

[0767] ##STR00126##

[0768] A solution of 3-bromo-N,N-bis(4-methoxybenzyl)-5-methylbenzenesulfonamide (290 mg, 0.591 mmol), potassium (N,N-dimethylaminomethyl)trifluoroboronate (117 mg, 0.710 mmol) and cesium carbonate (578 mg, 1.77 mmol) in THF (10 mL) and water (1 mL) was degassed with nitrogen for 5 minutes. Pd(crotyl)(XPhos)Cl (20 mg, 0.030 mmol) was added and the reaction mixture was stirred at reflux for 21 hours. The reaction mixture was cooled to room temperature and more potassium (N,N-dimethylaminomethyl)trifluoroboronate (117 mg, 0.710 mmol) and Pd(crotyl)(XPhos)Cl (20 mg, 0.030 mmol) were added. The reaction mixture was again stirred at reflux for 3 hours. After this time, the reaction mixture was partitioned between EtOAc (20 mL) and sat aq NH.sub.4Cl (20 mL). The aqueous layer was separated and extracted with EtOAc (2×20 mL). The combined organics were washed with brine (30 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford an orange oil (322 mg). The crude product was loaded onto a column of SCX (2 g) in MeOH. The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (118 mg, 38%) as a sticky orange oil.

[0769] .sup.1H NMR (Chloroform-d) δ 7.57-7.48 (m, 3H), 7.03-6.97 (m, 4H), 6.81-6.75 (m, 4H), 4.28 (s, 4H), 3.80 (s, 6H), 3.54 (s, 2H), 2.42 (s, 3H), 2.33 (s, 6H).

[0770] LCMS m/z 469.5 (M+H).sup.+ (ES.sup.+).

Step C: 3-((Dimethylamino)methyl)-5-methylbenzenesulfonamide

[0771] ##STR00127##

[0772] Prepared according to the general procedure of 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19, Step E) from 3-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-5-methylbenzenesulfonamide to afford the title compound (45 mg, 64%) as an orange gum.

[0773] .sup.1H NMR (DMSO-d.sub.6) δ 7.60-7.51 (m, 2H), 7.32 (s, 1H), 7.28 (s, 2H), 3.43 (s, 2H), 2.38 (s, 3H), 2.17 (s, 6H).

[0774] LCMS m/z 229.1 (M+H).sup.+ (ES.sup.+).

Intermediate L32: 1-(2,2-Difluoroethyl)-1H-pyrazole-4-sulfonamide

[0775] ##STR00128##

[0776] Prepared according to the general procedure of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide (Intermediate L15, Step C) from 1-(2,2-difluoroethyl)-1H-pyrazole-4-sulfonyl chloride to afford the title compound (422 mg, 92%) as a pale yellow solid.

[0777] .sup.1H NMR (DMSO-d.sub.6) δ 8.24 (d, J=0.7 Hz, 1H), 7.80 (d, J=0.7 Hz, 1H), 7.33 (s, 2H), 6.40 (tt, J=54.6, 3.6 Hz, 1H), 4.71 (td, J=15.2, 3.6 Hz, 2H).

[0778] .sup.19F NMR (DMSO-d.sub.6) δ −123.15 (dt, J=54.5, 15.1 Hz).

[0779] LCMS m/z 212.0 (M+H).sup.+ (ES.sup.+).

Intermediate L33: 1-Cyclobutyl-1H-pyrazole-3-sulfonamide

Step A: 1-Cyclobutyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0780] ##STR00129##

[0781] A solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L19, Step C) (5 g, 12.9 mmol) in DMF (60 mL) was cooled to 0° C., before NaH (60 wt % in mineral oil, 0.671 g, 16.8 mmol) was added. The mixture was warmed to room temperature and stirred for 30 minutes, before bromocyclobutane (1.3 mL, 13.8 mmol) was added slowly via syringe. The resulting mixture was stirred at 50 ° C. over the weekend. The mixture was diluted with EtOAc (100 mL). Water (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (3×80 mL), dried (phase separator) and concentrated in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (80 g column, 0-100% EtOAc/isohexane) to afford the title compound (4.72 g, 75%) as a pale yellow oil.

[0782] .sup.1H NMR (DMSO-d.sub.6) δ 8.03 (d, J=2.4 Hz, 1H), 7.04 (d, J=8.6 Hz, 4H), 6.81 (d, J=8.6 Hz, 4H), 6.71 (d, J=2.3 Hz, 1H), 4.94 (p, J=8.4 Hz, 1H), 4.22 (s, 4H), 3.72 (s, 6H), 2.49-2.38 (m, 4H), 1.87-1.77 (m, 2H).

[0783] LCMS m/z 464.2 (M+Na).sup.+ (ES.sup.+).

Step B: 1-Cyclobutyl-1H-pyrazole-3-sulfonamide

[0784] ##STR00130##

[0785] Prepared according to the general procedure of 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19, Step E) from 1-cyclobutyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (1.5 g, 66%) as a pale white solid.

[0786] .sup.1H NMR (DMSO-d.sub.6) δ 7.96 (d, J=2.4 Hz, 1H), 7.39 (s, 2H), 6.59 (d, J=2.4 Hz, 1H), 4.96-4.86 (m, 1H), 2.50-2.44 (m, 2H), 2.44-2.36 (m, 2H), 1.85-1.77 (m, 2H). LCMS m/z 202.0 (M+H).sup.+ (ES.sup.+).

Intermediate L34: 1-(1-((Dimethylamino)methyl)cyclobutyl)-1H-pyrazole-3-sulfonamide

[0787] Step A: Ethyl 1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate and ethyl 1-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate

##STR00131##

[0788] Prepared according to the general procedure of 1-cyclobutyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L33, Step A) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L19, Step C) and ethyl 1-bromocyclobutanecarboxylate to afford the title compounds (1.26 g, 23%) as a mixture of regioisomers (3:1 ratio ethyl 1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate:ethyl 1-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate) as a clear yellow oil.

[0789] LCMS m/z 536.2 (M+Na).sup.+ (ES.sup.+).

Step B: 1-(1-(Hydroxymethyl)cyclobutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0790] ##STR00132##

[0791] To a solution of a 3:1 mixture of ethyl 1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate and ethyl 1-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (710 mg, 1.04 mmol) in THF (20 mL) at 0° C. was added slowly LiAlH.sub.4 (2 M in THF, 2.1 mL, 4.20 mmol). Then the mixture was warmed to room temperature and stirred overnight. The reaction was sequentially quenched with H.sub.2O (0.2 mL), 2 M aq NaOH (0.5 mL) and H.sub.2O (1 mL). Na.sub.2SO.sub.4 was added, the mixture was stirred for 30 minutes and then filtered through a plug of Celite, rinsing with EtOAc. The filtrate was evaporated and the residue loaded onto silica and purified by chromatography (40 g column, 15-100% EtOAc/isohexane) to afford the title compound (410 mg, 83%) as a clear colourless oil.

[0792] .sup.1H NMR (DMSO-d.sub.6) δ 7.89 (d, J=2.4 Hz, 1H), 7.01 (d, J=8.7 Hz, 4H), 6.82 (d, J=8.7 Hz, 4H), 6.70 (d, J=2.4 Hz, 1H), 5.20 (t, J=5.6 Hz, 1H), 4.20 (s, 4H), 3.75 (d, J=5.6 Hz, 2H), 3.72 (s, 6H), 2.48-2.39 (m, 2H), 2.39-2.27 (m, 2H), 1.95-1.80 (m, 2H).

[0793] LCMS m/z 494.0 (M+Na)+ (ES.sup.+).

Step C: 1-(1-((Dimethylamino)methyl)cyclobutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0794] ##STR00133##

[0795] To an ice cooled solution of 1-(1-(hydroxymethyl)cyclobutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (472 mg, 1.00 mmol) and Et.sub.3N (0.3 mL, 2.15 mmol) in DCM (1 mL) was added MsCl (0.1 mL, 1.28 mmol). The reaction was warmed to room temperature and stirred for 1 hour, before being diluted with DCM (10 mL), washed with NaHCO.sub.3 (10 mL) and brine (10 mL), dried (phase separator) and concentrated in vacuo. The residue was dissolved in THF (1 mL) and dimethylamine (5.00 mL, 10.0 mmol) was added. The reaction was heated to 80° C. in a sealed vial over the weekend. Dimethylamine (5.00 mL, 10.0 mmol) and KI (166 mg, 1.00 mmol) were added to the reaction mixture which was stirred at 85° C. overnight. A further portion of diethylamine (5.00 mL, 10.0 mmol) was added to the reaction mixture and this was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and water (30 mL) and EtOAc (30 mL) were added. The organic phase was separated and the aqueous phase was extracted with EtOAc (3×20 mL). The organic phases were combined, dried (phase separator) and concentrated in vacuo. The crude product was loaded onto a column of SCX (about 10 g) in MeOH. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M ammonia in MeOH (50 mL). The resultant mixture was concentrated in vacuo to afford the title compound (187 mg, 36%) as a clear yellow oil.

[0796] LCMS m/z 499.3 (M+H).sup.+ (ES.sup.+).

Step D: 1-(1-((Dimethylamino)methyl)cyclobutyl)-1H-pyrazole-3-sulfonamide

[0797] ##STR00134##

[0798] Prepared according to the general procedure of 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19, Step E) from 1-(1-((dimethylamino)methyl)cyclobutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (65 mg, 64%) as a sticky yellow oil.

[0799] LCMS m/z 259.1 (M+H).sup.+ (ES.sup.+).

Intermediate L35: 5-Fluoro-1-isopropyl-1H-pyrazole-3-sulfonamide

Step A: 5-Fluoro-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0800] ##STR00135##

[0801] To a stirred solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L24, Step A) (0.500 g, 1.16 mmol) in THF (8 mL) at −78° C. under N.sub.2 was added n-BuLi (2.5 M in hexanes, 0.500 mL, 1.25 mmol) dropwise over 15 minutes. The resulting mixture was stirred at −78° C. for 1 hour, then N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI) (0.394 g, 1.25 mmol) in THF (2 mL) was added dropwise over 15 minutes. The resulting reaction mixture was stirred at −78° C. for 2 hours and then at room temperature overnight. The reaction mixture was quenched by the addition of water (20 mL) and extracted with DCM (3×20 mL). The combined organics were washed with sat aq NaHCO.sub.3 (30 mL), brine (30 mL), dried (phase separator) and concentrated in vacuo to afford a yellow oil. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-30% EtOAc/isohexane) to afford a 1.6:1 mixture of the title compound and 4,5-difluoro-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (124 mg) as a yellow oil which solidified is upon standing.

[0802] .sup.1H NMR (DMSO-d.sub.6) δ 7.08-7.02 (m, 4H), 6.87-6.80 (m, 4H), 6.53 (d, J=5.6 Hz, 1H), 4.69-4.57 (m, 1H), 4.23 (s, 4H), 3.73 (s, 6H), 1.41 (d, J=6.7 Hz, 6H).

[0803] LCMS m/z 470.3 (M+Na).sup.+ (ES.sup.+), 62% and 488.2 (M+Na).sup.+ (ES.sup.+).

Step B: 5-Fluoro-1-isopropyl-1H-pyrazole-3-sulfonamide

[0804] ##STR00136##

[0805] Prepared according to the general procedure of 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19, Step E) from a 1.6:1 mixture of 5-fluoro-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide and 4,5-difluoro-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (39 mg, 16% over 2 steps) as a white solid.

[0806] .sup.1H NMR (DMSO-d.sub.6) δ 7.52 (s, .sup.2H), 6.36 (d, J=5.7 Hz, 1H), 4.67-4.57 (m, 1H), 1.41 (d, J=6.7 Hz, 6H).

[0807] LCMS m/z 208.2 (M+H).sup.+ (ES.sup.+).

[0808] 4,5-Difluoro-1-isopropyl-1H-pyrazole-3-sulfonamide (18 mg, 6% over 2 steps) was also isolated as a white solid.

Intermediate L36: ((1-(2,2-Difluoroethyl)-1H-pyrazol-3-yl)sulfonyl)(4-(dimethylamino)pyridin-1-ium-1-carbonyl)amide

Step A: 1-(2,2-Difluoroethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0809] ##STR00137##

[0810] Prepared according to the general procedure of 1-ethyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L19, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L19, Step C) and 1,1-difluoro-2-iodoethane to afford the title compound (775 mg, 57%) as a clear colourless oil which solidified upon standing.

[0811] .sup.1H NMR (DMSO-d.sub.6) δ 8.02 (d, J=2.4 Hz, 1H), 7.04-6.98 (m, 4H), 6.85-6.75 (m, 5H), 6.55-6.29 (m, 1H), 4.85-4.74 (m, 2H), 4.21 (s, 4H), 3.72 (s, 6H).

[0812] LCMS m/z 474.3 (M+Na).sup.+ (ES.sup.+).

Step B: 1-(2,2-Difluoroethyl)-1H-pyrazole-3-sulfonamide

[0813] ##STR00138##

[0814] Prepared according to the general procedure of 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19, Step E) from 1-(2,2-difluoroethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (360 mg, 99%) as a white solid.

[0815] .sup.1H NMR (DMSO-d.sub.6) δ 7.93 (d, J=2.4 Hz, 1H), 7.49 (s, 2H), 6.66 (d, J=2.4 Hz, 1H), 6.40 (tt, J=54.6, 3.6 Hz, 1H), 4.73 (td, J=J=15.3, 3.6 Hz, 2H).

Step C: ((1-(2,2-Difluoroethyl)-1H-pyrazol-3-yl)sulfonyl)(4-(dimethylamino)pyridin-1-ium-1-carbonyl)amide

[0816] ##STR00139##

[0817] Prepared according to the general procedure of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate L21) from 1-(2,2-difluoroethyl)-1H-pyrazole-3-sulfonamide to afford the title compound (83 mg, 11%) as a white solid. The crude product was used without further purification or analysis.

Intermediate L37: 1-(2-Methyl-1-(pyrrolidin-1-yl)propan-2-yl)-1H-pyrazole-3-sulfonamide

Step A: N,N-bis(4-Methoxybenzyl)-1-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1H-pyrazole-3-sulfonamide

[0818] ##STR00140##

[0819] Prepared according to the general procedure of 1-(1-(azetidin-1-yl)-2-methyl-1-oxopropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L30, Step C) from 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid (Intermediate L30, Step B) and pyrrolidine to afford the title compound (862 mg, 73%) as a pale white solid.

[0820] .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J=2.5 Hz, 1H), 7.06 (d, J=8.6 Hz, 4H), 6.85 (d, J=2.5 Hz, 1H), 6.82 (d, J=8.7 Hz, 4H), 4.17 (s, 4H), 3.72 (s, 6H), 3.37-3.33 (m, 2H), 2.38-2.32 (m, 2H), 1.73 (s, 6H), 1.59 (br s, 4H).

Step B: N,N-bis(4-Methoxybenzyl)-1-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)-1H-pyrazole-3-sulfonamide

[0821] ##STR00141##

[0822] Prepared according to the general procedure of 1-(1-(azetidin-1-yl)-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate L30, Step D) from N,N-bis(4-methoxybenzyl)-1-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (388 mg, 42%).

[0823] .sup.1H NMR (DMSO-d.sub.6) δ 8.01 (d, J=2.5 Hz, 1H), 7.05 (d, J=8.6 Hz, 4H), 6.82 (d, J=8.6 Hz, 4H), 6.71 (d, J=2.4 Hz, 1H), 4.18 (s, 4H), 3.72 (s, 6H), 2.81 (s, 2H), 2.24-2.15 (m, 4H), 1.55 (s, 6H), 1.54-1.51 (m, 4H).

[0824] LCMS m/z 513.0 (M+H).sup.+ (ES.sup.+).

Step C: 1-(2-Methyl-1-(pyrrolidin-1-yl)propan-2-yl)-1H-pyrazole-3-sulfonamide

[0825] ##STR00142##

[0826] Prepared according to the general procedure of 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19, Step E) from N,N-bis(4-methoxybenzyl)-1-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (136 mg, 59%) as a sticky colourless oil.

[0827] LCMS m/z 273.1 (M+H).sup.+ (ES.sup.+).

Intermediate L38: ((1-Cyclopropyl-1H-pyrazol-3-yl)sulfonyl)(4-(dimethylamino)pyridin-1-ium-1-carbonyl)amide

[0828] ##STR00143##

[0829] Prepared according to the general procedure of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate L21) from 1-cyclopropyl-1H-pyrazole-3-sulfonamide to afford the title compound (1.57 g, 55%) as a solid.

[0830] .sup.1H NMR (DMSO-d.sub.6) δ 8.82-8.63 (m, 2H), 7.81 (d, J=2.3 Hz, 1H), 7.04-6.86 (m, 2H), 6.57 (d, J=2.4 Hz, 1H), 3.76 (m, 1H), 3.25 (s, 6H), 1.07-1.01 (m, 2H), 1.00-0.95 (m, 2H).

Intermediate R1: 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

[0831] ##STR00144##

[0832] To a solution of phosgene (4.45 mL, 20% weight in toluene, 8.4 mmol) in ethyl acetate (90 mL) was added dropwise a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in ethyl acetate (45 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 3 hours and upon cooling was filtered and concentrated in vacuo to afford the title compound as a brown oil (756 mg, 100%). The crude product was used directly in the next step without further purification.

[0833] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m, 4H).

Intermediate R2: 8-Isocyanato-1,2,3,5-tetrahydro-s-indacene

Step A: 1,2,3,7-Tetrahydro-s-indacen-4-amine

[0834] ##STR00145##

[0835] To a solution of 8-nitro-1,2,3,5-tetrahydro-s-indacene (Salla et al, ACS Med Chem Lett, 2016, vol. 7(12), pages 1034-1038) (700 mg, 3.48 mmol) in a mixture of dioxane/ethanol/water (10 ml/6 mL/4 mL) was added iron powder (1.17 g, 20.9 mmol) and ammonium chloride (0.93 g, 17.4 mmol). The mixture was refluxed for 15 minutes. Ethyl acetate (50 mL) was added and the mixture was filtered over Celite. The solids were washed with ethyl acetate. The combined ethyl acetate layers were evaporated. The crude product was filtered over silica, using ethyl acetate as the eluent, to afford the title compound (97%) as a brown oil that solidified upon standing.

[0836] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.88 (s, 1H), 6.85 (m, 1H), 6.39 (m, 1H), 3.68 (s, br, 2H) 3.36 (s, 2H), 2.93 (t, 2H), 2.75 (t, 2H), 2.14 (m, 2H).

Step B: 8-Isocyanato-1,2,3,5-tetrahydro-s-indacene

[0837] ##STR00146##

[0838] To a solution of phosgene (0.23 mL, 20% weight in toluene, 0.44 mmol) in ethyl acetate (5 mL) was added dropwise a solution of 1,2,3,7-tetrahydro-s-indacen-4-amine (30 mg, 0.18 mmol) in ethyl acetate (5 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 2 hours. The mixture was filtered and concentrated in vacuo to afford the title compound (35 mg, 100%) as a brown oil which solidified upon standing. The crude product was used directly in the next step without further purification.

[0839] .sup.1H NMR (CDCl.sub.3) δ 7.12 (s, 1H), 6.80 (m, 1H), 6.51 (m, 1H), 3.35 (q, 2H), 2.96 (m, 4H), 2.14 (p, 2H).

Intermediate R3: 4-Isocyanato-3,5,6,7-tetrahydro-s-indacen-1(2H)-one

[0840] ##STR00147##

[0841] A solution of 4-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (Salla et al, ACS Med Chem Lett, 2016, vol. 7(12), pages 1034-1038) (40 mg, 0.21 mmol) in ethyl acetate (5 mL) was added dropwise over 10 minutes to a solution of phosgene (20% in toluene, 0.5 mL, 0.54 mmol) in ethyl acetate (5 mL). The mixture was stirred at reflux for 1 hour. Then the mixture was concentrated to afford the title compound (45 mg, 100%) as an oil, which was used as such for the next step.

Intermediate R4: 8-Isocyanato-3,5,6,7-tetrahydro-s-indacen-1(2H)-one

[0842] ##STR00148##

[0843] To a solution of 8-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (57 mg, 0.30 mmol) in toluene was added a solution of phosgene (20% in toluene, 0.39 mL, 0.75 mmol) and the mixture was refluxed for 30 minutes. Concentration under reduced pressure gave the title compound (64.6 mg, 99%) as a green oil that was used without further purification.

[0844] .sup.1H NMR (CDCl.sub.3) δ 7.10 (s, 1H), 3.03 (m, 2H), 2.96 (t, 2H), 2.89 (t, 2H), 2.71 (m, 2H), 2.12 (p, 2H).

Intermediate R5: 3-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propanoyl chloride

[0845] Step A: tert-Butyl 3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acrylate

##STR00149##

[0846] A solution of 4-(2-bromo-5-fluoro-3-isopropylphenyl)-2-methoxypyridine (0.9 g, 3 mmol) and tert-butyl acrylate (1 g, 3 eq, 8 mmol) in DMF (10 ml) was purged with nitrogen. Potassium carbonate (0.8 g, 6 mmol), triphenylphosphine (0.1 g, 0.6 mmol) and palladium acetate (67 mg, 0.30 mmol) were added. The mixture was stirred for 18 hours at 120° C. The mixture was cooled and ethyl acetate was added. The organic layer was washed with water (4 times) and brine, dried (sodium sulfate), filtered and evaporated. The residue was purified over silica using ethyl acetate/heptane as the eluent to afford the title compound (0.6 g, 58%) as a pale red oil.

[0847] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.14 (d, 1H), 7.58 (d, 1H), 7.07 (dd, 1H), 6.85 (dd, 1H), 6.75 (dd, 1H), 6.66 (s, 1H), 5.58 (d, 1H), 3.98 (s, 3H), 3.24 (m, 1H), 1.44 (s, 9H), 1.25 (d, 6H).

Step B: tert-Butyl 3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propanoate

[0848] ##STR00150##

[0849] A mixture of tert-butyl 3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acrylate (0.6 g, 1.6 mmol) and Pd/C (10%, 50 mg) in ethyl acetate was stirred for 18 hours under hydrogen atmosphere (balloon). The mixture was filtered (Celite) and evaporated to afford the title compound (0.6 g, quantitative yield) as an oil.

[0850] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.20 (d, 7.02 (dd, 6.80 (d, 6.70 (dd, 6.64 (s, 1H), 3.98 (s, 3H), 3.21 (m, 2.81 (t, 2H), 2.20 (t, 2H), 1.37 (s, 9H), 1.27 (d, 6H).

Step C: 3-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propanoic acid

[0851] ##STR00151##

[0852] To a solution of tert-butyl 3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propanoate (0.60 g, 1.6 mmol) in dichloromethane (5 mL) was added TFA (5 mL). The mixture was stirred for 18 hours at room temperature. The solvents were evaporated to afford the title compound as TFA salt (0.63 g, 100%) as a colourless oil.

[0853] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.44 (d, 1H), 7.29 (d, 1H), 7.15 (dd, 1H), 7.11 (s, 1H), 6.73 (dd, 1H), 4.21 (s, 3H), 3.16 (m, 1H), 2.90 (t, 2H), 2.41 (t, 2H), 1.30 (d, 6H).

Step D: 3-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propanoyl chloride

[0854] ##STR00152##

[0855] 3-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propanoic acid (285 mg, 62 wt %, 0.56 mmol) was stirred in DCM (10 mL) and a drop of DMF was added, followed by the dropwise addition of oxalylchloride (0.24 mL, 2.8 mmol). The solution was stirred at room temperature for 4 hours and concentrated thoroughly to afford the title compound (190 mg, 99%) as a yellow oil.

[0856] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.45 (d, 1H), 7.34 (d, 1H), 7.17-7.07 (m, 2H), 6.72 (dd, 1H), 4.38 (s, 3H), 3.19 (dd, 1H), 2.96-2.82 (m, 2H), 2.41 (d, 2H), 1.28 (d, 6H).

Intermediate R6: 6-Fluoro-8-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carbonyl chloride

Step A: 2-(4-Fluoro-2-(prop-1-en-2-yl)phenyl)acetic acid mixed with 2,3-dimethylbutane-2,3-diol (1:1)

[0857] ##STR00153##

[0858] Potassium carbonate (120 g, 0.89 mol) was dissolved in water (100 mL) and added to a solution of 2-(2-bromo-4-fluorophenyl)acetic acid (69 g, 1 eq, 0.30 mol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (50 g, 1 eq, 0.30 mol) in 1,4-dioxane (100 mL). The mixture was brought under N.sub.2 atmosphere and PdCl.sub.2(dPPf)-CH.sub.2Cl.sub.2 adduct (4.9 g, 6.0 mmol) was added, after which the mixture was refluxed for 48 hours. The mixture was cooled to room temperature. Water was added until all salts were dissolved. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and solvent was removed by rotary evaporation, yielding the product (87 g, 94%) as a brown oil.

[0859] .sup.1H NMR (CDCl.sub.3) δ 7.22 (dd, 1H), 6.95 (dd, 1H), 6.88 (dd, 1H), 5.23 (s, 1H), 4.84 (s, 1H), 3.68 (s, 2H), 2.00 (s, 3H), 1.24 (s, 6H), 1.21 (s, 6H).

[0860] LCMS: m/z 193 (M−H).sup.− (ES.sup.−).

Step B: 2-(4-Fluoro-2-isopropylphenyl)acetic acid

[0861] ##STR00154##

[0862] A mixture of 2-(4-fluoro-2-(prop-1-en-2-yl)phenyl)acetic acid with 2,3-dimethylbutane-2,3-diol (1:1) (80 g, 0.26 mol) and platinum(IV) oxide (1 g, 4 mmol) were dissolved in ethanol (200 mL) and stirred overnight under 3 bar H.sub.2 pressure. Further platinum(IV) oxide (0.1 g, 0.4 mmol) was added, and the mixture was stirred for another 5 hours under 3 bar H.sub.2. The mixture was filtered over Celite and ethanol was removed by rotary evaporation. The resulting oil was subjected to falling film distillation to remove the pinacol. The residue was taken up in DCM (200 mL) and washed with 0.5 M aqueous HCl (100 mL). The organic layer was dried over sodium sulfate and plugged over SiO.sub.2 (d=10 cm, h=5 cm). The SiO.sub.2 was flushed with DCM (2 L). Rotary evaporation of the collected eluate yielded the product (45 g, 90%) as a light orange solid.

[0863] .sup.1H NMR (CDCl.sub.3) δ 7.18 (dd, 1H), 7.00 (dd, 1H), 6.82 (dt, 1H), 3.67 (s, 2H), 3.07 (m, 1H), 1.20 (d, 6H).

[0864] LCMS: m/z 195 (M−H).sup.− (ES.sup.−).

Step C: Ethyl 2-(4-fluoro-2-isopropylphenyl)acetate

[0865] ##STR00155##

[0866] 2-(4-Fluoro-2-isopropylphenyl)acetic acid (1.8 g, 9.2 mmol) was dissolved in ethanol (25 mL) under N.sub.2 atmosphere and cooled to 0° C. Thionyl chloride (1.6 g, 14 mmol) was added dropwise and the mixture was stirred overnight at room temperature. The mixture was evaporated to dryness to yield the title compound (2.1 g, 100%) as a clear oil.

[0867] .sup.1H NMR (CDCl.sub.3) δ 7.18 (dd, 1H), 6.99 (dd, 1H), 6.82 (dt, 1H), 4.15 (q, 2H), 3.62 (s, 2H), 3.09 (m, 1H), 1.24 (t, 3H), 1.21 (d, 6H).

Step D: Ethyl 2-(4-fluoro-2-isopropylphenyl)-5-methylhex-4-enoate

[0868] ##STR00156##

[0869] Ethyl 2-(4-fluoro-2-isopropylphenyl)acetate (1.6 g, 7.1 mmol) was dissolved in THF (10 mL) under N.sub.2 atmosphere and cooled to −78° C. LiHMDS (1.3 g, 8 mL, 7.8 mmol) was added and the mixture was stirred for 15 minutes at −78° C. 1-Bromo-3-methylbut-2-ene (1.2 g, 7.8 mmol) was added and the mixture was allowed to reach room temperature over the weekend. The mixture was evaporated to near dryness and 1 M HCl (20 mL) and ethyl acetate (20 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness to yield the title compound (2.0 g, 96%) as a clear oil.

[0870] .sup.1H NMR (CDCl.sub.3) δ 7.32 (dd, 1H), 6.95 (dd, 1H), 6.82 (dt, 1H), 5.02 (t, 1H), 4.10 (q, 2H), 3.82 (t, 1H), 3.22 (m, 1H), 2.75 (m, 1H), 2.38 (m, 1H), 1.62 (s, 3H), 1.56 (s, 3H), 1.23 (t, 3H), 1.20 (d, 6H).

[0871] LCMS: m/z 293 (M+H).sup.+ (ES.sup.+).

Step E: Ethyl 6-fluoro-8-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate

[0872] ##STR00157##

[0873] Ethyl 2-(4-fluoro-2-isopropylphenyl)-5-methylhex-4-enoate (2.0 g, 7 mmol) was dissolved in dichloroethane (40 mL) under N.sub.2 atmosphere. Bismuth(III) trifluoromethanesulfonate (0.2 g, 0.3 mmol) was added and the mixture was refluxed for 2 hours. The mixture was filtered over Celite, evaporated to dryness and subjected to column chromatography on silica (heptanes with an ethyl acetate gradient from 0 to 15%) yielding the title product (1.0 g, 48%) as a colourless oil.

[0874] .sup.1H NMR (CDCl.sub.3) δ 6.91 (dd, 1H), 6.80 (dd, 1H), 4.12 (q, 2H), 3.92 (m, 1H), 2.93 (m, 1H), 2.14 (m, 1H), 2.04 (m, 1H), 1.75 (m, 1H), 1.58 (m, 1H), 1.35 (s, 3H), 1.28 (s, 3H), 1.22 (t, 3H), 1.18 (d, 6H).

Step F: 6-Fluoro-8-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

[0875] ##STR00158##

[0876] Ethyl 6-fluoro-8-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate (0.8 g, 3 mmol) was dissolved in methanol (20 mL). Lithium hydroxide (1.0 g, 42 mmol) in water (10 mL) was added and the mixture was refluxed overnight. The reaction mixture was concentrated by rotary evaporation and partitioned between TBME (20 mL) and water (20 mL). The aqueous phase was acidified to pH 1 with 5 N HCl and extracted with DCM (2×20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated, yielding the title product (254 mg, 35%) as a white solid.

[0877] .sup.1H NMR (CDCl.sub.3) δ 6.91 (dd, 1H), 6.80 (dd, 1H), 3.97 (m, 1H), 2.97 (m, 1H), 2.20 (m, 1H), 2.04 (m, 1H), 1.72 (dt, 1H), 1.58 (m, 1H), 1.32 (s, 3H), 1.23 (s, 3H), 1.18 (dd, 6H).

[0878] LCMS: m/z 263 (M−H).sup.− (ES.sup.−).

Step G: 6-Fluoro-8-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carbonyl chloride

[0879] ##STR00159##

[0880] 6-Fluoro-8-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (100 mg, 0.38 mmol) was stirred in DCM (10 mL) and a drop of DMF was added, followed by the dropwise addition of oxalylchloride (0.17 mL, 1.89 mmol). The solution was stirred at room temperature for 4 hours and concentrated thoroughly to afford the title compound (107 mg, 99%) as a yellow oil.

[0881] .sup.1H NMR (300 MHz, Chloroform-d) δ 6.91 (dd, 1H), 6.84 (dd, 1H), 4.31 (dd, 1H), 2.96-2.82 (m, 1H), 2.56-2.39 (m, 1H), 2.27-2.05 (m, 1H), 1.72-1.62 (m, 2H), 1.32 (d, 6H), 1.26-1.19 (m, 6H).

Intermediate R7: 5-Fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carbonyl chloride

Step A: 3-(4-Fluoro-2-isopropylphenyl)-5,5-dimethyldihydrofuran-2(3H)-one

[0882] ##STR00160##

[0883] A solution of n-BuLi (2.5 M in hexanes, 0.69 mL, 4.3 mL, 11 mmol) was added via syringe to a cooled (−20° C.) solution of diisopropylamine (1.1 g, 1.5 mL, 11 mmol) in THF (15 mL). The reaction mixture was stirred at −20° C. for 20 minutes, then cooled to −78° C. and a solution of 3-(4-fluoro-2-isopropylphenyl)-4,4-dimethyldihydrofuran-2(3H)-one (1 g, 5.1 mmol) in THF (5 mL) was added via cannula. The reaction mixture was stirred at −78° C. for 20 minutes, then warmed to room temperature and stirred for 2 hours. The reaction mixture was then cooled to 0° C., and neat 2,2-dimethyloxirane (0.37 mmol, 0.45 mL, 5.1 mmol) was added via syringe, resulting in a clear yellow solution, which was stirred for 12 hours at room temperature. Water (7 mL) was added to the reaction mixture. The reaction mixture was heated for 1 hour towards reflux, and then allowed to cool. Most of the THF was removed by concentration. Then the reaction mixture was washed with TBME (2×). The aqueous phase was treated with EtOH (12 mL), acidified with 37% aqueous HCl (3.1 mL), stirred towards reflux for 3 hours, and then left standing overnight. The reaction mixture was extracted with CHCl.sub.3 (3×25 mL). The combined organic phases were washed with sat aq NaHCO.sub.3 (2×15 mL), then dried (Na.sub.2SO.sub.4), filtered and concentrated to obtain an oil (1.2 g) which crystallized partially upon standing. The material was stirred in TBME:heptanes (6:1) for 30 minutes, filtered and dried (430 mg). The filtrate was concentrated to an oil to give slightly less pure material (530 mg). Combined this afforded the title compound (0.96 g, 75%) as a yellow oil.

[0884] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.11 (dd, 1H), 6.99 (dd, 1H), 6.89 (td, 1H), 4.23 (dd, 1H), 3.13-2.93 (m, 1H), 2.55 (dd, 1H), 2.08 (t, 1H), 1.61-1.45 (m, 6H), 1.34-1.17 (m, 6H).

Step B: 5-Fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxylic acid

[0885] ##STR00161##

[0886] 3-(4-Fluoro-2-isopropylphenyl)-5,5-dimethyldihydrofuran-2(3H)-one (430 mg, 1.72 mmol) was dissolved in 1,2-dichloroethane (2 mL) and added dropwise over 1 hour to an ice cooled solution of AlCl.sub.3 (458 mg, 3.44 mmol) in 1,2-dichloroethane (2 mL). The mixture was stirred for 2 hours and poured in ice/water (10 mL). CHCl.sub.3 (10-15 mL) was used to rinse the reaction vessel. The reaction mixture was filtered over Celite and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered and the solution was concentrated to afford the title compound (0.43 g, 99%) as a yellow oil.

[0887] .sup.1H NMR (300 MHz, Chloroform-d) δ 6.82 (dd, 1H), 6.68 (dd, 1H), 4.07 (dd, 1H), 2.98-2.77 (m, 1H), 2.48-2.20 (m, 2H), 1.29 (m, 6H), 1.25-1.11 (m, 6H).

Step C: 5-Fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carbonyl chloride

[0888] ##STR00162##

[0889] 5-Fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxylic acid (65 mg, 0.26 mmol) was stirred in DCM (10 mL) and a drop of DMF was added, followed by the dropwise addition of oxalylchloride (0.11 mL, 1.3 mmol). The solution was stirred at room temperature for 3 hours and concentrated thoroughly to afford the title compound (70 mg, 99%) as a yellow oil.

[0890] .sup.1H NMR (300 MHz, Chloroform-d) δ 6.84 (dd, 1H), 6.69 (dd, 1H), 4.45 (ddd, 1H), 2.78 (pd, 1H), 2.57-2.34 (m, 2H), 1.36-1.23 (m, 9H), 1.19 (d, 3H).

Intermediate R8: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

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

[0891] ##STR00163##

[0892] To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol, 1 eq) in concentrated H.sub.2SO.sub.4 (30 mL) was added dropwise a solution of HNO.sub.3 (so mL, 69 wt % in aqueous solution) in concentrated H.sub.2SO.sub.4 (50 mL) at 0° C. over a period of 3.5 hours. The reaction mixture was stirred at 0° C. for 0.5 hour, and then poured into ice-water (600 mL) and extracted with ethyl acetate (2×400 mL). The combined organic layers were washed with water (500 mL), saturated aqueous NaHCO.sub.3 solution (500 mL) and brine (2×500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (55 g, contained another regio-isomer) as a colourless oil.

[0893] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.98 (d, 1H), 7.51 (d, 1H), 7.30 (t, 1H), 3.41 (t, 2H), 302 (t, 2H) and 2.22-2.20 (m, 2H).

Step B: 2,3-Dihydro-1H-inden-4-amine

[0894] ##STR00164##

[0895] To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g, contained another regio-isomer) in MeOH (500 mL) was added Pd/C (5 g, 10 wt % loading on activated carbon) under N.sub.2. The suspension was degassed in vacuo and purged with H.sub.2 several times. The reaction mixture was stirred at 20° C. for 12 hours under H.sub.2 (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:4) to give the title compound (19.82 g, 43% yield, 96.4% purity on LCMS) as a brown oil.

[0896] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.01 (t, 1H), 6.71 (d, 1H), 6.51 (d, 1H), 3.57 (br s, 2H), 2.93 (t, 2H), 2.75 (t, 2H) and 2.16-2.08 (m, 2H).

[0897] LCMS: m/z 134.2 (M+H).sup.+ (ES.sup.+).

Step C: N-(2,3-Dihydro-1H-inden-4-yl)acetamide

[0898] ##STR00165##

[0899] To a solution of 2,3-dihydro-1H-inden-4-amine (19.8 g, 148.66 mmol, 1 eq) and TEA (19.56 g, 193.26 mmol, 1.3 eq) in DCM (300 mL) was added dropwise Ac.sub.2O (17.45 g, 170.96 mmol, 1.15 eq) at 0° C. over 0.1 hour. Then the reaction mixture was warmed to 16° C., stirred for 1.4 hours, poured into water (500 mL) and extracted with DCM (2×300 mL). The combined organic phases were washed with brine (2×500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (25.74 g, 96% yield, 96.7% purity on LCMS) as a white solid.

[0900] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.70 (d, 1H), 7.15 (t, 1H), 7.02 (d, 1H), 2.95 (t, 2H), 2.81 (t, 2H), 2.18 (s, 3H) and 2.15-2.08 (m, 2H).

[0901] LCMS: m/z 176.2 (M+H).sup.+ (ES.sup.+).

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

[0902] ##STR00166##

[0903] A mixture of N-(2,3-dihydro-1H-inden-4-yl)acetamide (34.6 g, 197.46 mmol, 1 eq), 4-methylbenzenesulfonic acid (18.70 g, 108.60 mmol, 0.55 eq) and Pd(OAc).sub.2 (2.22 g, 9.87 mmol, 0.05 eq) were suspended in toluene (400 mL) and stirred at 20° C. for 0.5 hour under air atmosphere. NBS (38.66 g, 217.20 mmol, 1.1 eq) was added. The resulting reaction mixture was stirred at 20° C. for 2 hours, poured into water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic phases were washed with brine (2×500 mL), 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 2:1) to give the title compound (13.9 g, 27% yield, 98.1% purity on LCMS) as a white solid.

[0904] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.33 (d, 1H), 7.16 (s, 1H), 6.98 (d, 1H), 2.92-2.83 (m, 4H), 2.21 (s, 3H) and 2.10-2.02 (m, 2H).

[0905] LCMS: m/z 254.1 (M+H).sup.+ (ES.sup.+).

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

[0906] ##STR00167##

[0907] A mixture of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide (45.68 g, 179.76 mmol, 1 eq) in EtOH (200 mL) and concentrated HCl (300 mL, 36 wt % in water) was stirred at 80° C. for 36 hours. The reaction mixture was cooled to 0° C. in an ice bath and some solid precipitated out. The suspension was filtered. The filter cake was washed with ice-water (50 mL) and dried in vacuo to give the title compound (34.1 g, 72% yield, 94.1% purity on LCMS) as a grey solid.

[0908] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.67 (br s, 2H), 7.24 (d, 1H), 6.69 (d, 1H), 2.85 (t, 2H), 2.79 (t, 2H) and 2.04-1.96 (m, 2H).

[0909] LCMS: m/z 212.0 (M+H).sup.+ (ES.sup.+).

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

[0910] ##STR00168##

[0911] A mixture of (2-methoxypyridin-4-yl)boronic acid (25.11 g, 164.15 mmol, 1.2 eq), 5-bromo-2,3-dihydro-1H-inden-4-amine, hydrochloride salt (34 g, 136.80 mmol, 1 eq) and K.sub.2CO.sub.3 (60.50 g, 437.74 mmol, 3.2 eq) in dioxane (500 mL) and H.sub.2O (100 mL) was degassed with nitrogen for 15 minutes. Pd(dppeCl.sub.2.CH.sub.2Cl.sub.2 (6 g, 7.35 mmol, 0.053 eq) was added. The reaction mixture was heated to 80° C. for 12 hours under nitrogen, poured into water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic phases were washed with brine (2×700 mL), 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, 0:1 to 1:10) to give the title compound (27.4 g, 79% yield, 95% purity on LCMS) as a white solid.

[0912] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.22 (d, 1H), 7.03-7.00 (m, 1H), 6.99 (d, 1H), 6.87 (s, 1H), 6.77 (d, 1H), 3.99 (s, 3H), 3.77 (br s, 2H), 2.97 (t, 2H), 2.77 (t, 2H) and 2.21-2.13 (m, 2H).

[0913] LCMS: m/z 241.2 (M+H).sup.+ (ES.sup.+).

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

[0914] ##STR00169##

[0915] To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50.35 mmol, 1.1 eq) in THF (275 mL) was added in portions bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) at 0° C. The reaction mixture was stirred at 16° C. for 0.5 hour. The reaction mixture was filtered through a pad of silica gel and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacuo to give the title compound (9.04 g, 74%) as a light yellow solid.

[0916] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.28 (d, 1H), 7.20-7.16 (m, 3H), 7.02 (s, 1H), 4.16 (s, 3H), 3.04-2.99 (m, 4H) and 2.23-2.15 (m, 2H).

Intermediate R9: 2-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)acetyl chloride

Step A: 3-Chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one

[0917] ##STR00170##

[0918] A suspension of AlCl.sub.3 (225.67 g, 1.69 mol, 1 eq) in DCM (1 L) was cooled to −10° C. under N.sub.2 atmosphere. Then a mixture of 2,3-dihydro-1H-indene (200 g, 1.69 mol, 1 eq) and 3-chloropropanoyl chloride (214.88 g, 1.69 mol, 1 eq) in DCM (400 mL) was added dropwise. The reaction mixture was warmed to 27° C. and stirred for 2 hours. Then the reaction mixture was added slowly to an aqueous HCl solution (2 N, 2.8 L) below 10° C. The layers were separated and the aqueous layer was extracted with DCM (1 L). The combined organic layers were washed with water (1 L), saturated aqueous NaHCO.sub.3 solution (1 L) and brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was triturated with petroleum ether (500 mL) to give the title compound (260.44 g, 74%) as a white solid.

[0919] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.84 (s, 1H), 7.79-7.76 (m, 1H), 7.33 (d, 1H), 3.94 (t, 2H), 3.45 (t, 2H), 2.98 (t, 4H), 2.18-2.11 (m, 2H).

[0920] LCMS: m/z 209.1 (M+H).sup.+ (ES.sup.+).

Step B: 2,3,6,7-Tetrahydro-s-indacen-1(5H)-one

[0921] ##STR00171##

[0922] To a concentrated H.sub.2SO.sub.4 solution (1.84 kg, 18.39 mol, 98 wt % in aqueous solution, 37.25 eq) was added to 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (103 g, 493.57 mmol, 1 eq). The reaction mixture was stirred at 70° C. for 12 hours, poured into ice-water (4.5 L) and filtered. The filter cake was dissolved in EtOAc (500 mL) and saturated aqueous Na.sub.2CO.sub.3solution (500 mL) was added. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were concentrated in vacuo to give the title compound (60 g, 69% yield, 98% purity on LCMS) as a yellow solid.

[0923] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.58 (s, 1H), 7.30 (s, 1H), 3.08-2.96 (m, 2H), 2.95-2.91 (m, 4H), 2.70 (t, 2H) and 2.15-2.05 (m, 2H).

[0924] LCMS: m/z 173.2 (M+H).sup.+ (ES.sup.+).

Step C: 1,2,3,5,6,7-Hexahydro-s-indacene

[0925] ##STR00172##

[0926] To a solution of 2,3,6,7-tetrahydro-s-indacen-1(5H)-one (15 g, 87.10 mmol, 1 eq) in MeOH (200 mL) was added with MeSO.sub.3H (16.94 g, 176.22 mmol, 2.02 eq) and Pd(OH).sub.2/C (3.2 g, 20 wt % loading on activated carbon). The reaction mixture was degassed and purged with H.sub.2 three times. The resulting mixture was stirred at 25° C. for 12 hours under H.sub.2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, only eluting with petroleum ether) to give the title compound (12 g, 85%) as a white solid.

[0927] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.14 (s, 2H), 3.00-2.85 (m, 8H) and 2.16-2.09 (m, 4H).

Step D: 4-Bromo-1,2,3,5,6,7-hexahydro-s-indacene

[0928] ##STR00173##

[0929] To a solution of 1,2,3,5,6,7-hexahydro-s-indacene (11.5 g, 72.67 mmol, 1 eq) in CCl.sub.4 (200 mL) was added with 12 (922 mg, 3.63 mmol, 0.05 eq). Then a solution of Br.sub.2 (12.19 g, 76.31 mmol, 1.05 eq) in CCl.sub.4 (50 mL) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for 2 hours, quenched with saturated aqueous NH.sub.4Cl solution (100 mL), and extracted with DCM (3×200 mL). The combined 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, only eluting with petroleum ether) to give the title compound (15 g, 87%) as a red oil.

[0930] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.00 (s, 1H), 3.10-2.83 (m, 8H) and 2.11 (m, 4H).

Step E: (2-(tert-Butoxy)-2-oxoethyl) zinc (II) bromide

[0931] ##STR00174##

[0932] A mixture of Zn (80 g) in HCl (1 M, 308 mL) was stirred at 25° C. for 30 minutes. Then the mixture was filtered and the filter cake was dried in vacuo. To a mixture of this Zn (55 g, 841.11 mmol, 2.98 eq) in THF (550 mL) was added TMSCl (3.06 g, 28.20 mmol, 0.1 eq) and 1,2-dibromoethane (5.30 g, 28.20 mmol, 0.1 eq) at 20° C. under N.sub.2. Then tert-butyl 2-bromoacetate (55 g, 281.97 mmol, 1 eq) was added at 50° C. under N.sub.2. The reaction mixture was stirred at 50 ° C. for 2 hours. The mixture (theoretical amount: 0.5 M, 550 mL, in THF solution) was cooled and used in the next step without further purification.

Step F: tert-Butyl 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetate

[0933] ##STR00175##

[0934] To a solution of 4-bromo-1,2,3,5,6,7-hexahydro-s-indacene (20 g, 84.34 mmol, 1 eq), Pd.sub.2(dba).sub.3 (3.86 g, 4.22 mmol, 0.05 eq), and Xphos® (4.02 g, 8.43 mmol, 0.1 eq) in THF (1 mL) was added (2-(tert-butoxy)-2-oxoethyl) zinc (II) bromide (168.68 mmol, 500 mL, 0.5 M, in THF, 2 eq) at 0° C. Then the reaction mixture was stirred at 70° C. for 12 hours, quenched with saturated aqueous NH.sub.4Cl solution (500 mL), and extracted with ethyl acetate (3×500 mL). The combined 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, only eluting with petroleum ether) to give the title compound (20 g, 87%) as a yellow oil.

[0935] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.02 (s, 1H), 3.51 (s, 2H), 2.90-2.84 (m, 8H), 2.11-2.04 (m, 4H) and 1.44 (s, 9H).

Step G: 2-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)acetic acid

[0936] ##STR00176##

[0937] To a solution of tert-butyl 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetate (20 g, 73.43 mmol, 1 eq) in DCM (200 mL) was added TFA (308 g, 2.70 mol, 36.79 eq). The reaction mixture was stirred at 25° C. for 1 hour, and then concentrated in vacuo. The residue was dissolved in DCM (300 mL) and the mixture was adjusted to pH=9 with an aqueous NaOH solution (2 N). The aqueous phase was separated and adjusted to pH=2-3 with an aqueous HCl solution (1 N). Large white solids were formed, and the mixture was filtered. The collected solid was dried to give the title compound (12 g, 76%) as a white solid.

[0938] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.20 (s, 1H), 6.95 (s, 1H), 3.70 (s, 2H), 2.82-2.70 (m, 8H) and 2.03-1.94 (m, 4H).

Step H: 2-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)acetyl chloride

[0939] ##STR00177##

[0940] A solution of 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetic acid (500 mg, 2.31 mmol, 1 eq) in SOCl.sub.2 (10 mL) was heated to 80° C. for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound (542.6 mg, 100%) as a yellow oil, which was used directly in the next step.

Intermediate R10: 2-(5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid

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

[0941] ##STR00178##

[0942] To a mixture of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate R8, Step F) (28 g, 116.52 mmol, 1 eq) in MeCN (300 mL) was added isopentyl nitrite (16.38 g, 139.83 mmol, 1.2 eq) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes under N.sub.2. CuBr (17.05 g, 118.85 mmol, 1.02 eq) was added at 0° C. and the resulting mixture was stirred at 60° C. for 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 20:1) to give the title compound (15 g, 37% yield, 87.7% purity on LCMS) as a yellow solid.

[0943] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.20 (d, 1H), 7.21 (d, 1H), 7.06 (d, 1H), 6.94 (dd, 1H), 6.78 (s, 1H), 3.99 (s, 3H), 3.08 (t, 2H), 3.03 (t, 2H) and 2.20-2.10 (m, 2H).

[0944] LCMS: m/z 304.0 (M+H).sup.+ (ES.sup.+).

Step B: tert-Butyl 2-(5(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate

[0945] ##STR00179##

[0946] To a mixture of 4-(4-bromo-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (15 g, 49.31 mmol, 1 eq), Xphos® (2.35 g, 4.93 mmol, 0.1 eq) and Pd.sub.2(dba).sub.3 (2.26 g, 2.47 mmol, 0.05 eq) in THF (50 mL) was added a solution of (2-(tert-butoxy)-2-oxoethyl) zinc (II) bromide (Intermediate R9, Step E) in THF (0.5 M, 296 mL, 3 eq) at 20° C. under N.sub.2. The reaction mixture was stirred at 70° C. for 12 hours under N.sub.2. The mixture was poured into saturated aqueous NH.sub.4Cl solution (200 mL). The aqueous phase was extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with brine (20 mL), 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, 1:0 to 20:1) to give the title compound (15 g, 83% yield, 92.9% purity on LCMS) as a yellow oil.

[0947] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.17 (dd, 1H), 7.20 (d, 1H), 7.04 (d, 1H), 6.86 (dd, 1H), 6.72 (s, 1H), 3.98 (s, 3H), 3.47 (s, 2H), 3.01 (t, 2H), 2.90 (t, 2H), 2.18-2.10 (m, 2H) and 1.43 (s, 9H).

[0948] LCMS: m/z 340.1 (M+H).sup.+ (ES.sup.+).

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

[0949] ##STR00180##

[0950] To the solution of tert-butyl 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate (16 g, 47.14 mmol, 1 eq) in DCM (100 mL) was added TFA (154 g, 1.35 mol, 28.65 eq) at 20° C. The reaction mixture was stirred at 20° C. for 12 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 20:1 to 5:1) to give the title compound (12 g, 87% yield, 97% purity on LCMS) as a yellow solid.

[0951] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.89 (br s, 1H), 8.35 (d, 1H), 7.25 (s, 1H), 7.11 (d, 1H), 7.05 (d, 1H), 6.98 (s, 1H), 4.05 (s, 3 FT), 3.58 (s, 2H), 3.00 (t, 2H), 2.92 (t, 2H) and 2.19-2.10 (m, 2H).

[0952] LCMS: m/z 284.1 (M+H).sup.+ (ES.sup.+).

Intermediate R11: 2-(4-Fluoro-2,6-diisopropylphenyl)acetic acid

Step A: 4-Fluoro-2,6-di(prop-1-en-2-yl)aniline

[0953] ##STR00181##

[0954] A solution of 2,6-dibromo-4-fluoroaniline (10 g, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (16.67 g, 2.67 eq), Cs.sub.2CO.sub.3 (36.35 g, 3 eq) and Pd(dppf)Cl.sub.2 (2.72 g, 3.72 mmol, 0.1 eq) in dioxane (100 mL) and H.sub.2O (10 mL) was degassed under reduced pressure. Then the reaction mixture was heated to 100° C. for 3 hours under nitrogen. The reaction mixture was quenched by addition of H.sub.2O (200 mL), and diluted with EtOAc (150 mL). The mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (8 g, 89% yield, 78.9% purity on LCMS) as a yellow oil.

[0955] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.68 (d, 2H), 5.32-5.31 (m, 2H), 5.08 (d, 2H), 3.84 (s, 2H) and 2.07 (d, 6H).

[0956] LCMS: m/z 192.2 (M+H).sup.+(ES.sup.+).

Step B: 4-Fluoro-2,6-diisopropylaniline

[0957] ##STR00182##

[0958] To a solution of 4-fluoro-2,6-di(prop-1-en-2-yl)aniline (8 g, 1 eq) in MeOH (150 mL) was added Pd/C (624 mg, 10 wt % loading on activated carbon). The mixture was degassed and purged with H.sub.2 (20 psi). The reaction mixture was stirred at 25° C. for 12 hours under H.sub.2 (20 psi), and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, only eluting with petroleum ether) to give the title compound (4 g, 63% yield, 100% purity on LCMS) as a colourless oil.

[0959] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.76 (d, 2H), 3.56 (s, 2H), 2.99-2.89 (m, 2H) and 1.26 (d,12H).

[0960] LCMS: m/z 196.2 (M+H).sup.+ (ES.sup.+).

Step C: 2-Bromo-5-fluoro-1,3-diisopropylbenzene

[0961] ##STR00183##

[0962] To a solution of 4-fluoro-2,6-diisopropylaniline (3.7 g, 18.95 mmol, 1 eq) in MeCN (180 mL) was added CuBr (4.08 g, 1.5 eq). Then tert-butyl nitrite (2.93 g, 1.5 eq) was added dropwise at 0° C. The resulting mixture was stirred at 60° C. for 1.5 hours, and then concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, only eluting with petroleum ether) to give the title compound (2.02 g, 41%) as a white solid.

[0963] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.85 (d, 2H), 3.55-3.48 (m, 2H) and 1.24 (d, 12H).

Step D: tert-Butyl 2-(4-fluoro-2,6-diisopropylphenyl)acetate

[0964] ##STR00184##

[0965] A solution of 2-bromo-5-fluoro-1,3-diisopropylbenzene (16 g, 61.74 mmol, 1 eq) in THF (100 mL) was cooled to 0° C. Then Pd.sub.2(dba).sub.3 (2.83 g, 3.09 mmol, 0.05 eq), Xphos® (2.94 g, 6.17 mmol, 0.1 eq) and (2-(tert-butoxy)-2-oxoethyl) zinc (II) bromide (Intermediate R9, Step E) (0.5 M, 246.95 mL, in THF solution, 2 eq) were added. The reaction mixture was stirred at 70° C. for 12 hours, and then concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 100:0 to 10:1) to give the title compound (12 g, 59% yield, 90% purity on .sup.1H NMR) as a red oil.

[0966] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.83 (d, 2H), 3.66 (s, 2H), 3.21-3.14 (m, 2H), 1.43 (s, 9H) and 1.21 (d, 12H).

Step E: 2-(4-Fluoro-2,6-diisopropylphenyl)acetic acid

[0967] ##STR00185##

[0968] To a solution of tert-butyl 2-(4-fluoro-2,6-diisopropylphenyl)acetate (12 g, 40.76 mmol, 1 eq) in DCM (120 mL) was added TFA (184.80 g, 39.76 eq). The reaction mixture was stirred at 25° C. for 3 hours. Most of solvents were evaporated under reduced pressure. The residue was diluted with H.sub.2O (300 mL) and the mixture was adjusted to pH=10 with 2 M aqueous NaOH solution. The mixture was washed with EtOAc (3×500 mL) and the organic phases were discarded. Then the aqueous layer was adjusted to pH=.sub.3 with 1 M aqueous HCl solution and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (8 g, 82%) as a yellow solid.

[0969] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.24 (br s, 1H), 6.91 (d, 2H), 3.78 (s, 2H), 3.16-3.06 (m, 2H) and 1.18 (d, 12H).

Intermediate R12: 7-Chloro-5-isopropyl-2,3-dihydro-1H-inden-4-amine

Step A: 5-Bromo-7-chloro-2,3-dihydro-1H-inden-4-amine

[0970] ##STR00186##

[0971] 7-Chloro-2,3-dihydro-1H-inden-4-amine, HCl (1.00 g, 4.90 mmol) (J Med Chem, 2015, vol. 58(2), pages 878-887) was dissolved in water (20 mL). Sat aq NaHCO.sub.3 (10 mL) was added to neutralise the solution. The mixture was extracted with EtOAc (4×30 mL) and the combined organics were washed with brine (30 mL), dried (MgSO.sub.4) and concentrated in vacuo. The residue was dissolved in DCM (10 mL) and cooled to 0° C. NBS (959 mg, 5.39 mmol) was added and the mixture stirred at 0° C. for 2 hours. The precipitate was filtered off and the filtrate washed with 1 N NaOH (2×20 mL), dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g column, 0-5% MeOH/DCM) to afford the title compound (895 mg, 67%) as a brown oil.

[0972] LCMS m/z 246/248 (M+H).sup.− (ES.sup.+).

Step B: 7-Chloro-5-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-4-amine

[0973] ##STR00187##

[0974] 5-Bromo-7-chloro-2,3-dihydro-1H-inden-4-amine (440 mg, 1.78 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (900 mg, 5.35 mmol), potassium phosphate, dibasic (933 mg, 5.35 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (88 mg, 0.214 mmol), Pd.sub.2(dba).sub.3 (49.0 mg, 0.054 mmol) and water (0.5 mL) were added to degassed toluene (10 mL). The solution was refluxed for 16 hours under N.sub.2 and then cooled to room temperature. The reaction was diluted with EtOAc (10 mL) and the organic phase was washed with sat aq NaHCO.sub.3 (2×10 mL), dried (MgSO.sub.4) and concentrated in vacuo. The product was purified by chromatography on silica gel (40 g column, 10-30% EtOAc/isohexane) to afford the title compound (80 mg, 20%) as a colourless oil.

[0975] LCMS m/z 208/210 (M+H).sup.+ (ES.sup.+).

Step C: 7-Chloro-5-isopropyl-2,3-dihydro-1H-inden-4-amine

[0976] ##STR00188##

[0977] A mixture of 7-chloro-5-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-4-amine (50 mg, 0.241 mmol) and 5% Pd/C (50% weight, Type 87L, 5.1 mg, 0.024 mmol) in ethanol (5 mL) was hydrogenated (5 bar) for 16 hours. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g column, 5-20% ethyl acetate/isohexane) to afford the title compound (20 mg, 37%) as a colourless oil.

[0978] .sup.1H NMR (CDCl.sub.3) δ 6.88 (s, 1H), 2.91-2.80 (m, 3H), 2.76 (t, J=7.0 Hz, 2H), 2.05 (tt, J=8.2, 7.0 Hz, 2H), 1.17 (d, J=6.8 Hz, 6H). Two exchangeable protons not observed.

[0979] LCMS m/z 210/212 (M+H).sup.+ (ES.sup.+).

Intermediate R13: 4-Bromo-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

[0980] ##STR00189##

[0981] Triphosgene (141 mg, 0.476 mmol) was added to a mixture of 8-bromo-1,2,3,4,6,7-hexahydro-s-indacen-4-amine (182 mg, 0.722 mmol) and Et.sub.3N (302 μL, 2.16 mmol) in THF (8 mL). The reaction mixture was heated at reflux for 2 hours and then concentrated in vacuo and dried azeotropically with toluene (3×1 mL). The residue was taken up in toluene and filtered through a plug of silica, washing with toluene. The filtrate was concentrated to afford the title compound (197 mg, 97%) as a colourless solid.

[0982] LCMS m/z 365/367 (M+H).sup.− (ES.sup.−).

Intermediate R14: 8-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile

[0983] ##STR00190##

[0984] Prepared according to the general procedure of 4-bromo-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R13) from 8-amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile (prepared as described in WO 2017/184623) to afford the title compound (101 mg, 87%) as a colourless solid.

[0985] LCMS m/z 312.1 (M+H).sup.+(ES.sup.+).

Intermediate R15: 5-Chloro-2-isocyanato-1,3-diisopropylbenzene

[0986] ##STR00191##

[0987] Prepared according to the general procedure of 4-bromo-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R13) from 4-chloro-2,6-diisopropylaniline to afford the title compound (1.05 g, 94%) as a pale orange oil.

[0988] LCMS m/z 325 (M+H).sup.− (ES.sup.−); 323 (M−H).sup.− (ES.sup.−).

Intermediate R16: 5-Fluoro-2-isocyanato-1,3-diisopropylbenzene

[0989] ##STR00192##

[0990] Prepared according to the general procedure of 4-bromo-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R13) from 4-fluoro-2,6-diisopropylaniline (Intermediate R11, Step B) to afford the title compound (1.04 g, 92%) as a dear colourless oil.

[0991] .sup.1H NMR (DMSO-d.sub.6) δ 7.01 (d, J=9.7 Hz, 2H), 3.21-3.08 (m, 2H), 1.20 (d, J=6.9 Hz, 12H).

[0992] LCMS m/z 309.4 (M+Na)+ (ES.sup.+).

Intermediate R17: 8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Step A: N-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)acetamide

[0993] ##STR00193##

[0994] Acetic anhydride (6.00 mL, 63.5 mmol) was added dropwise to a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (10 g, 57.7 mmol) and Et.sub.3N (9.65 mL, 69.3 mmol) in DCM (140 mL) at 0° C. The solution was stirred at room temperature overnight. Water (100 mL) was added and the solid collected by filtration, washed with water and dried in vacuo to afford the title compound (9.63 g, 77%) as an off-white solid.

[0995] .sup.1H NMR (DMSO-d.sub.6) δ 9.31 (s, 1H), 6.94 (s, 1H), 2.81 (t, J=7.4 Hz, 4H), 2.67 (t, J=7.4 Hz, 4H), 2.00 (s, 3H), 1.96 (p, J=7.4 Hz, 4H).

Step B: N-(8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide

[0996] ##STR00194##

[0997] A solution of N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide (4.0 g, 18.6 mmol) and HF-pyridine (20 mL, 222 mmol) in DCM (13 mL) was cooled in an ice bath. A solution of PhI(OCOCF.sub.3).sub.2 (12 g, 27.9 mmol) in DCM (13 mL) was added dropwise and the reaction was stirred in an ice bath for 1 hour. The reaction mixture was quenched with sat aq calcium hydroxide and the phases were separated. The organics were passed through a hydrophobic frit and the solvent was removed in vacuo. The crude product was split into 2 batches and purified by chromatography on silica gel (220 g and 120 g column, 0-100% EtOAc/isohexane) to afford the title compound (747 mg, 16%) as a pale yellow solid.

[0998] .sup.1H NMR (DMSO-d.sub.6) δ 9.32 (br s, 1H), 2.84 (t, J=7.5 Hz, 4H), 2.71 (t, J=7.5 Hz, 4H), 2.03 (p, J=7.5 Hz, 4H), 1.99 (3H, s).

[0999] .sup.19F NMR (DMSO-d.sub.6) δ −125.83.

Step C: 8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

[1000] ##STR00195##

[1001] A solution of N-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide (0.350 g, 1.50 mmol) in EtOH (6.5 mL) and conc HCl (6.5 mL) was heated under reflux for 4 days. The solution was cooled to room temperature and 2 M NaOH was added (20 mL). The product was extracted into DCM (3×50 mL) and the organic extracts were passed through a hydrophobic frit and evaporated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-50% EtOAc/isohexane) to afford the title compound (240 mg, 79%) as a pale brown solid.

[1002] .sup.1H NMR (CDCl.sub.3) δ 3.83 (br s, 2H), 2.90 (t, J=7.4 Hz, 4H), 2.73 (t, J=7.4 Hz, 4H), 2.23-2.04 (m, 4H).

[1003] LCMS m/z 192.1 (M+H).sup.+ (ES.sup.+).

Preparation of Examples

Example 1

5-Fluoro-N-((4-(2-hydroxypropan-2-yl)-2-methylphenyl) sulfonyl)-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxamide

[1004] ##STR00196##

[1005] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate L1) (36 mg, 0.16 mmol) and 5-fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxylic acid (Intermediate R7, Step B) (39 mg, 0.16 mmol) were stirred in DCM (6 mL). EDC (60 mg, 0.31 mmol) and DMAP (38 mg, 0.31 mmol) were added to the reaction mixture. The mixture was stirred at room temperature overnight, diluted with DCM (5 mL) and washed with 1M aqueous HCl (3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (52 mg, 0.47 mmol) was added. The mixture was purified by reversed phase prep-HPLC method 2 to afford the title compound (12 mg, 17%) as a white solid.

[1006] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.95 (d, 1H), 7.36 (s, 1H), 7.31 (d, 1H), 6.69-6.60 (m, 1H), 6.60-6.51 (m, 1H), 3.96 (s, 1H), 2.71 (s, 4H), 2.27 (dd, 1H), 2.05 (dd, 1H), 1.49 (d, 6H), 1.24 (s, 3H), 1.14 (s, 3H), 1.04 (d, 3H), 0.80 (d, 3H).

[1007] LCMS: m/z 462 (M+H).sup.+ (ES.sup.+); 460 (M−H).sup.− (ES.sup.−).

Example 2

2-(4-Fluoro-2,6-diisopropylphenyl)-N-((4-(2-hydroxypropan-2-yl)-2-methylphenyl)sulfonyl)acetamide, potassium salt

[1008] ##STR00197##

[1009] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate L1) (50 mg, 0.17 mmol) and 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate R11) (42 mg, 0.17 mmol) were stirred in DCM (6 mL). EDC (67 mg, 0.35 mmol) and DMAP (43 mg, 0.35 mmol) were added to the reaction mixture. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M aqueous HCl (mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (59 mg, 0.52 mmol) was added. The mixture was purified by reversed phase prep-HPLC method 2 to afford the title compound (41 mg, 52%) as a white solid.

[1010] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.90 (d, 1H), 7.34 (d, 1H), 7.28 (dd, 1H), 6.69 (d, 2H), 3.64 (s, 2H), 3.19-2.98 (m, 2H), 2.68 (s, 3H), 1.48 (d, 6H), 1.07 (d, 12H).

[1011] LCMS: m/z 450 (M+H).sup.+ (ES.sup.+); 448 (M−H).sup.− (ES.sup.−).

Example 3

3-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)-2-methylphenyl)sulfonyl)propanamide

[1012] ##STR00198##

[1013] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate L1) (85 mg, 0.37 mmol) and Et.sub.3N (38 mg, 0.37 mmol) were stirred in DCM (6 mL). Then 3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propanoyl chloride (Intermediate R.sub.5) (63 mg, 0.19 mmol) in DCM (1 mL) was added dropwise and stirred overnight. EDC (36 mg, 0.19 mmol) and DMAP (23 mg, 0.35 mmol) were added to the reaction mixture. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M aqueous HCl (3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and purified by reversed phase prep-HPLC method 2 to afford the title compound (22 mg, 22%) as a white solid.

[1014] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.14-8.09 (m, 1H), 7.87 (d, 1H), 7.34 (d, 2H), 7.10-7.00 (m, 1H), 6.83 (dd, 1H), 6.72-6.61 (m, 2H), 3.92 (s, 3H), 3.23 (q, 1H), 2.83-2.66 (m, 2H), 2.54 (s, 3H), 2.22 (dd, 2H), 1.51 (s, 6H), 1.22 (d, 6H).

[1015] LCMS: m/z 529 (M+H).sup.− (ES.sup.−); 527 (M−H).sup.− (ES.sup.−).

Example 4

N-((4-((Dimethylamino)methyl)phenyl)sulfonyl)-3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propanamide, potassium salt

[1016] ##STR00199##

[1017] 4-((Dimethylamino)methyl)benzenesulfonamide (Intermediate L13) (80 mg, 0.37 mmol) and KO.sup.tBu (63 mg, 0.56 mmol) were stirred in THF (6 mL). Then 3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propanoyl chloride (Intermediate R5) (63 mg, 0.19 mmol) in THF (1 mL) was added dropwise and stirred overnight. EDC (36 mg, 0.19 mmol) and DMAP (23 mg, 0.35 mmol) were added to the reaction mixture. The mixture was stirred for 2 hours and concentrated. The residue was dissolved in DMSO (0.5 mL) and purified by reversed phase prep-HPLC method 2 to afford the title compound (19 mg, 20%) as a white solid.

[1018] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.11 (d, 1H), 7.81 (d, 2H), 7.38 (d, 2H), 7.03 (dd, 1H), 6.86 (d, 1H), 6.65 (m, 2H), 3.93 (s, 3H), 3.54 (s, 2H), 3.30 (m, 1H), 2.78-2.63 (m, 2H), 2.25 (s, 6H), 2.23-2.13 (m, 2H), 1.22 (d, 6H).

[1019] LCMS: m/z 514 (M+H).sup.+ (ES.sup.+); 512 (M−H).sup.− (ES.sup.−).

Example 5

3-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)propanamide

[1020] ##STR00200##

[1021] 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide (120 mg, 0.55 mmol) and Et.sub.3N (55 mg, 0.55 mmol) were stirred in DCM (6 mL). Then 3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propanoyl chloride (Intermediate R.sub.5) (90 mg, 0.27 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight and concentrated. The residue was purified by reversed phase prep-HPLC method 3 to afford the title compound (5 mg, 4%) as a white solid.

[1022] 1H NMR (300 MHz, Methanol-d.sub.4) δ 8.18-8.10 (m, 1H), 7.77 (d, 1H), 7.66 (d, 1H), 7.09 (dd, 1H), 6.88 (dd, 1H), 6.78-6.68 (m, 2H), 3.96 (s, 3H), 3.17 (m, 1H), 2.89-2.70 (m, 2H), 2.36-2.22 (m, 2H), 1.52 (s, 6H), 1.24 (d, 6H).

[1023] LCMS: m/z 521 (M+H).sup.+(ES.sup.+); 519 (M−H).sup.− (ES.sup.−).

Example 6

N-((1-Cyclopropyl-1H-pyrazol-3-yl)sulfonyl)-6-fluoro-8-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide

[1024] ##STR00201##

[1025] 1-Cyclopropyl-1H-pyrazole-3-sulfonamide (70 mg, 0.37 mmol) and Et.sub.3N (38 mg, 0.37 mmol) were stirred in DCM (6 mL). Then 6-fluoro-8-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-carbonyl chloride (Intermediate R6) (53 mg, 0.19 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight. DMAP (23 mg, 0.19 mmol) was added to the reaction mixture. The mixture was stirred for another day and then concentrated. The residue was purified by reversed phase prep-HPLC method 3 to afford the title compound (8 mg, 10%) as a white solid.

[1026] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.76 (d, 1H), 6.90 (dd, 1H), 6.75 (m, 2H), 3.88 (t, 1H), 3.77 (tt, 1H), 2.82-2.65 (m, 1H), 2.07 (dt, 2H), 1.73-1.58 (m, 1H), 1.58-1.39 (m, 1H), 1.24 (d, 6H), 1.20-1.01 (m, 6H), 0.89 (d, 4H).

[1027] LCMS: m/z 434 (M+H).sup.+ (ES.sup.+); 432(M−H).sup.− (ES.sup.−).

Example 7

N-((1-Cyclopropyl-1H-pyrazol-4-yl)sulfonyl)-5-fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxamide

[1028] ##STR00202##

[1029] 5-Fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxylic acid (Intermediate R7, Step B) (60 mg, 0.24 mmol), DIPEA (93 mg, 0.72 mmol) and HATU (110 mg, 0.29 mmol) were stirred in DCM (6 mL) for 50 minutes. Then 1-cyclopropyl-1H-pyrazole-4-sulfonamide (45 mg, 0.24 mmol) was added. The mixture was stirred overnight, diluted with DCM and washed with water. The organic phase was concentrated. The residue was purified by reversed phase prep-HPLC method 3 to afford the title compound (main rotamer) (5 mg, 5%) as a white solid.

[1030] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.25 (s, 1H), 7.83 (s, 1H), 6.81-6.61 (m, 2H), 4.01-3.89 (m, 1H), 3.71 (dt, 1H), 2.47 (dt, 1H), 2.31 (dd, 1H), 2.06-1.92 (m, 1H), 1.21 (d, 6H), 1.11-1.00 (m, 6H), 0.89 (d, 4H).

[1031] LCMS: m/z 420 (M+H).sup.+ (ES.sup.+); 418 (M−H).sup.− (ES.sup.−).

Example 8

5-Fluoro-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxamide, potassium salt (rotamer P1) and

Example 9

5-Fluoro-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxamide, potassium salt (rotamer P2)

[1032] ##STR00203##

[1033] 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide (110 mg, 0.48 mmol) and KO.sup.tBu (54 mg, 0.48 mmol) were stirred in THF (6 mL). Then 5-fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carbonyl chloride (Intermediate R7) (65 mg, 0.24 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred overnight and concentrated. The residue was purified by reversed phase prep-HPLC method 3 to afford the title compounds as separate rotamers. Rotamer P1 was the first eluting rotamer (10 mg, 9%) and rotamer P2 was the second eluting rotamer (2 mg, 2%), both as white solids.

[1034] Rotamer P1:

[1035] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.80 (d, 1H), 7.64 (d, 1H), 6.75 (dd, 1H), 6.67 (dd, 1H), 3.97 (ddd, 1H), 2.62-2.44 (m, 1H), 2.32 (dd, 1H), 1.98 (dd, 1H), 1.50 (s, 6H), 1.21 (d, 6H), 1.08 (d, 3H), 0.94 (d, 3H).

[1036] LCMS: m/z 454 (M+H).sup.− (ES.sup.−); 452 (M−H).sup.− (ES.sup.−).

[1037] Rotamer P2:

[1038] LCMS: m/z 454 (M+H).sup.+ (ES.sup.+); 452 (M−H).sup.− (ES.sup.−).

Example 10

5-Fluoro-7-isopropyl-N-((1-isopropyl-1H-pyrazol-3-yl) sulfonyl)-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxamide, potassium salt (rotamer P2)

[1039] ##STR00204##

[1040] 1-Isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (91 mg, 0.48 mmol) and KO.sup.tBu (81 mg, 0.72 mmol) were stirred in THF (6 mL). Then 5-fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carbonyl chloride (Intermediate R7) (65 mg, 0.24 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred overnight and concentrated. The residue was purified by reversed phase prep-HPLC method 3. The title compound was isolated as the second eluting rotamer (3 mg, 3%) as a white solid.

[1041] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.79 (d, 1H), 7.03 (d, 1H), 6.85-6.75 (m, 2H), 4.69-4.54 (m, 1H), 4.00 (t, 1H), 3.13 (p, 1H), 2.27-2.03 (m, 2H), 1.54-1.44 (m, 6H), 1.29 (s, 3H), 1.25-1.13 (m, 9H).

[1042] LCMS: m/z 422 (M+H).sup.+ (ES.sup.+); 418 (M−H).sup.− (ES.sup.−).

Example 11

3-(N-(5-Fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

[1043] ##STR00205##

[1044] N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (120 mg, 0.52 mmol) and Et.sub.3N (110 mg, 1 mmol) were stirred in DCM (6 mL). Then 5-fluoro-7-isopropyl-3,3-dimethyl-2,3-dihydro-1H-indene-1-carbonyl chloride (Intermediate R7) (70 mg, 0.26 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight and then concentrated. The residue was purified by reversed phase prep-HPLC method 3 to afford the title compound (4 mg, 3%) as a white solid.

[1045] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 6.95 (s, 1H), 6.73 (dd, 1H), 6.64 (dd, 1H), 3.96 (s, 3H), 3.95 (m, 1H), 3.09 (d, 6H), 2.80-2.66 (m, 1H), 2.31 (dd, 1H), 2.05 (dd, 1H), 1.21 (d, 6H), 1.10 (d, 3H), 0.99 (d, 3H).

[1046] LCMS: m/z 465 (M+H).sup.+ (ES.sup.+); 463 (M−H).sup.− (ES.sup.−).

Example 12

1-(2-(Bis(methyl-d3)amino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, potassium salt

[1047] ##STR00206##

[1048] 1-(2-(Bis(methyl-d3)amino)ethyl)-1H-pyrazole-3-sulfonamide, 2,2,2-trifluoroacetate salt (Intermediate L5) (367 mg, 1.08 mmol) and KO.sup.tBu (365 mg, 3.25 mmol) were stirred in THF (6 mL). Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) (230 mg, 1.08 mmol) in THF (1 mL) was added dropwise. The mixture was stirred overnight and concentrated. The residue was dissolved in DMSO (1 mL) and purified by reversed phase prep-HPLC method 2 to afford the title compound (114 mg, 25%) as a white solid.

[1049] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.67 (d, 1H), 6.85 (s, 1H), 6.63 (d, 1H), 4.29 (t, 2H), 2.80 (td, 6H), 2.71 (t, 4H), 1.98 (p, 4H).

[1050] LCMS: m/z 424 (M+H).sup.+ (ES.sup.+); 422 (M−H).sup.− (ES.sup.−).

Example 13

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, potassium salt

[1051] ##STR00207##

[1052] To a solution of tert-butyl 3-sulfamoyl-1H-pyrazole-1-carboxylate (Intermediate L3) (62 mg, 0.25 mmol) in THF (1 mL) was added KO.sup.tBu (28 mg, 0.25 mmol). The suspension that formed was stirred for 1 hour, before adding a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) (50 mg, 0.25 mmol) in THF (1 mL). The resulting reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was analysed by HPLC to observe a mixture of the title compound and the BOC-protected derivative. The crude product was dissolved in DMSO (0.5 mL) and purified by reversed phase prep-HPLC method 2 to afford the title compound (17 mg, 20%) as a white solid.

[1053] .sup.1H NMR (CD.sub.3OD) δ 7.60 (s, 1H), 6.85 (d, 1H), 6.69 (t, 1H), 2.81 (t, 4H), 2.71 (t, 4H), 1.98 (m, 4H).

[1054] LCMS: m/z 347 (M+H).sup.+ (ES.sup.+); 346 (M−H).sup.− (ES).

Example 14

N-((1,2,3,5-Tetrahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, potassium salt

[1055] ##STR00208##

[1056] To a solution of tert-butyl 3-sulfamoyl-1H-pyrazole-1-carboxylate (Intermediate L3) (41 mg, 0.17 mmol) in THF (1 mL) was added KO.sup.tBu (19 mg, 0.17 mmol). The suspension that formed was stirred for 1 hour, before adding a solution of 8-isocyanato-1,2,3,5-tetrahydro-s-indacene (Intermediate R2) (33 mg, 0.17 mmol) in THF (0.8 mL). The resulting reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was analysed by HPLC to observe a mixture of the title compound and the BOC-protected derivative. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography to afford the title compound (13 mg, 22%) as a white solid.

[1057] .sup.1H NMR (CD.sub.3OD) δ 7.61 (s, 1H), 7.04 (s, 1H), 6.73 (m, 2H), 6.41 (s, 1H), 2.85 (dt, 6H), 2.03 (m, 2H).

[1058] LCMS: m/z 345 (M+H).sup.+ (ES.sup.+); 343 (M−H).sup.− (ES.sup.−).

Example 15

1-Isopropyl-N-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, potassium salt

[1059] ##STR00209##

[1060] To a solution of 1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (57 mg, 0.30 mmol) in THF (1 mL) was added KO.sup.tBu (34 mg, 0.30 mmol). The suspension that formed was stirred for 1 hour, before adding a solution of 8-isocyanato-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (Intermediate R4) (64 mg, 0.30 mmol) in THF (1 mL). The resulting reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (1 mL) and submitted for purification by reversed phase column chromatography to afford the title compound (25 mg, 20%) as a white solid.

[1061] .sup.1H NMR (CD.sub.3OD) δ 7.61 (d, 1H), 7.00 (s, 1H), 6.66 (d, 1H), 4.53 (p, 1H), 3.00 (m, 2H), 2.88 (t, 2H), 2.77 (t, 2H), 2.64 (m, 2H), 1.96 (p, 2H), 1.47 (d, 6H).

[1062] LCMS: m/z 403 (M+H).sup.+ (ES.sup.+); 401 (M−H).sup.− (ES.sup.−).

Example 16

1-(2-(3-(But-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, potassium salt

[1063] ##STR00210##

[1064] 1-(2-(3-(But-3-yn-1-yl)-3H-diazirin-3-yl)ethyl)-1H-pyrazole-3-sulfonamide, 2,2,2-trifluoroacetate salt (Intermediate L4) (12 mg, 0.047 mmol) and KO.sup.tBu (8 mg, 0.071 mmol) were stirred in THF (3 mL). Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) (9 mg, 0.047 mmol) in THF (1 mL) was added dropwise. The resulting reaction mixture was stirred overnight and concentrated. The residue was dissolved in DMSO (1 mL) and purified by reversed phase prep-HPLC method 2 to afford the title compound (10 mg, 45%) as a white solid.

[1065] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 6.85 (s, 1H), 6.67 (d, 1H), 4.07 (t, 2H), 3.72 (s, 1H), 2.76 (dt, 9H), 1.96 (ddt, 8H), 1.47 (t, 2H).

[1066] LCMS: m/z 467 (M+H).sup.+(ES.sup.+); 465 (M−H).sup.− (ES.sup.−).

Example 17

4-((2-(Aminomethyl)-3-fluoroallyl)oxy)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide, 2,2,2-trifluoroacetate salt

[1067] ##STR00211##

[1068] tert-Butyl-(3-fluoro-2-((4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)phenoxy)methyl)allyl)carbamate, potassium salt (Example 18) (7 mg, 0.013 mmol) was dissolved in DCM (0.3 mL) and TFA (0.3 mL). The mixture was stirred for 4 hours at room temperature and concentrated. The residue was taken up in water and freeze-dried to afford the title compound (3 mg, 43%) as a white solid.

[1069] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.86 (m, 2H), 7.13 (m, 1H), 7.02 (m, 2H), 6.85 (m, 1H), 4.68-4.51 (m, .sup.2H), 3.61-3.43 (m, 2H), 2.87-2.61 (m, 8H), 1.97 (p, 4H).

[1070] LCMS: m/z 460 (M+H).sup.+ (ES.sup.+); 458 (M−H).sup.− (ES.sup.−).

Example 18

tert-Butyl-(3-fluoro-2-((4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenoxy)methyl)allyl)carbamate, potassium salt

[1071] ##STR00212##

[1072] tert-Butyl-(3-fluoro-2-((4-sulfamoylphenoxy)methyl)allyl)carbamate (prepared as described in WO 2013/163675, 95 mg, 0.26 mmol) and KO.sup.tBu (30 mg, 0.26 mmol) were stirred in THF (3 mL). Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) (52 mg, 0.26 mmol) in THF (1 mL) was added dropwise. The mixture was stirred overnight and concentrated. The residue was dissolved in DMSO (1 mL) and purified by reversed phase prep-HPLC method 2 to afford the title compound (9 mg, 6%) as a white solid.

[1073] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.87 (d, 2H), 7.07-6.93 (m, 3H), 6.79 (d, 1H), 4.55-4.46 (m, 1H), 3.92 (s, 1H), 2.80 (t, 4H), 2.75-2.60 (m, 6H), 1.98 (q, 4H), 1.39 (s, 9H).

[1074] LCMS: m/z 560 (M+H).sup.+ (ES.sup.+); 558 (M−H).sup.− (ES.sup.−).

Example 19

1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-1,2,3-triazole-4-sulfonamide, potassium salt

[1075] ##STR00213##

[1076] 1-Ethyl-1H-1,2,3-triazole-4-sulfonamide (Chemspace, 49 mg, 0.28 mmol) and KO.sup.tBu (31 mg, 0.28 mmol) were stirred in THF (6 mL). Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) (55 mg, 0.28 mmol) in THF (1 mL) was added dropwise. The mixture was stirred overnight and concentrated. The residue was dissolved in DMSO (1 mL) and purified by reversed phase prep-HPLC method 2 to afford the title compound (65 mg, 63%) as a white solid.

[1077] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.29 (s, 1H), 6.87 (s, 1H), 4.47 (q, 2H), 2.77 (m, 8H), 2.00 (m, 4H), 1.54 (t, 3H).

[1078] LCMS: m/z 376 (M+H).sup.+ (ES.sup.+); 374 (M−H).sup.− (ES.sup.−).

Example 20

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(propan-2-yl-d7)-1H-pyrazole-3-sulfonamide, potassium salt

[1079] ##STR00214##

[1080] 1-(Propan-2-yl-d7)-1H-pyrazole-3-sulfonamide (Intermediate L2) (146 mg, 0.47 mmol) and KO.sup.tBu (106 mg, 0.94 mmol) were stirred in THF (6 mL). Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) (100 mg, 0.47 mmol) in THF (1 mL) was added dropwise. The mixture was stirred overnight and concentrated. The residue was dissolved in DMSO (1 mL) and purified by reversed phase prep-HPLC method 2 to afford the title compound (112 mg, 60%) as a white solid.

[1081] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.65 (t, 1H), 6.84 (s, 1H), 6.63 (d, 1H), 2.75 (m, 8H), 2.19-1.79 (m, 4H).

[1082] LCMS: m/z 396 (M+H).sup.+ (ES.sup.+); 394 (M−H).sup.− (ES.sup.−).

Example 21

N-((1-Hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

Step A: 1-Isopropyl-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

[1083] ##STR00215##

[1084] A solution of 1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (45 mg, 0.22 mmol) in THF (4 mL) was cooled to 0° C. Then KO.sup.tBu (27 mg, 0.24 mmol) was added and the mixture was stirred for 30 minutes at 21° C. Next a solution of 4-isocyanato-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (Intermediate R3) (46 mg, 0.24 mmol) in THF (4 mL) was added and the mixture was stirred for 18 hours at 21° C. The mixture was filtered to afford the title compound (70 mg, 80%) as a white solid.

[1085] LCMS: m/z 403 (M+H).sup.+ (ES.sup.+); 401 (M−H).sup.− (ES.sup.−).

Step B: N-((1-Hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1086] ##STR00216##

[1087] 1-Isopropyl-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (70 mg, 0.17 mmol) in methanol (4 mL) was cooled to 0° C. Next sodium borohydride (66 mg, 1.74 mmol) was added and the mixture was stirred for 18 hours at room temperature. Water (2 mL) was added and the mixture was evaporated. The residue was purified by reversed phase prep-HPLC method 3 to afford the title compound (64 mg, 91%) as a white solid.

[1088] .sup.1H NMR (300 MHz, D.sub.2O) δ 7.65 (d, 1H), 7.08 (s, 1H), 6.59 (d, 1H), 5.10 (t, 1H), 4.49 (m, 1H), 2.80 (t, 2H), 2.71 (m, 1H), 2.60 (t, 2H), 2.52 (m, 1H), 2.33 (m, 1H), 1.93 (m, 2H), 1.81 (m, 1H), 1.39 (d, 6H).

[1089] LCMS: m/z 463 (M+59).sup.+ (ES.sup.+ ); 403 (M−H).sup.− (ES.sup.−).

Example 22

1-Isopropyl-N-((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, potassium salt and 1-isopropyl-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, potassium salt

[1090] ##STR00217##

[1091] To a solution of 1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (31 mg, 0.16 mmol) in THF (4 mL) was added KO.sup.tBu (18 mg, 0.16 mmol) at 0° C. The mixture was stirred for 1 hour at 21° C. Next 8-isocyanato-1,2,3,5-tetrahydro-s-indacene (Intermediate R2) (35 mg, 0.18 mmol) in THF (3 mL) was added and the mixture was stirred for 18 hours at 21° C. The solvents were evaporated and the residue was purified by reversed phase column chromatography to afford the title compound (65 mg, 100%) as a white solid.

[1092] .sup.1H NMR (300 MHz, D.sub.2O), mixture of two isomers, ratio 3/2, δ 7.65 (d, 1H), 7.22 and 7.16 (s, 1H), 6.77 and 6.68 (d, J=32.6, 5.6 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 6.55-6.37 (m, 1H), 4.49 (dt, J=13.4, 6.6 Hz, 1H), 3.31 and 3.16 (s, 2H), 2.74 (dt, J=54.3, 7.4 Hz, 4H), 1.95 (m, J=7.5 Hz, 2H), 1.39 (d, J=6.7 Hz, 7H).

[1093] LCMS: m/z 387 (M+H).sup.+ (ES.sup.+); 385 (M−H).sup.− (ES.sup.−).

Example 23

1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfinamide

[1094] ##STR00218##

[1095] To a solution of 1-isopropyl-1H-pyrazole-3-sulfinamide (Intermediate L6) (0.1 g, 577.25 μmol, 1 eq) in THF (2 mL) was added t-BuONa (56 mg, 577.25 μmol, 1 eq). The mixture was stirred at 25° C. for 30 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate R8) (150 mg, 563.29 μmol, 0.98 eq) was added. The resulting mixture was stirred at 25° C. for 1 hour, and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm×25 mm×5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v/v), B: MeCN]; B %: 20%-50%, 10 min) to give the title compound (81.42 mg, 31% yield, 98% purity on LCMS) as a white solid.

[1096] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (d, 1H), 7.92 (s, 1H), 7.22-7.19 (m, 1H), 7.14-7.11 (m, 1H), 6.95 (d, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 4.60-4.53 (m, 1H), 3.87 (s, 3H), 2.94 (t, 2H), 2.82 (t, 2H), 2.04-2.00 (m, 2H) and 1.44 (d, 6H).

[1097] LCMS: m/z 440.2 (M+H).sup.+ (ES.sup.+).

Example 24

2-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-N-(1-isopropyl-1H-pyrazole-3-sulfonimidoyl)acetamide

Step A: 2-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-N-((1-isopropyl-1H-pyrazol-3-yl)sulfinyl)acetamide

[1098] ##STR00219##

[1099] To a solution of 1-isopropyl-1H-pyrazole-3-sulfinamide (Intermediate L6) (400 mg, 2.31 mmol, 1 eq) in THF (20 mL) was added n-BuLi (2 M, 1.27 mL, 1.1 eq) at −70° C. The reaction mixture was stirred for 30 minutes. To this reaction mixture was added a solution of 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetyl chloride (Intermediate R9) (542 mg, 2.31 mmol, 1 eq) in THF (1 mL) at 20° C. The reaction mixture was stirred at −70° C. for 2.5 hours, poured into water (50 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.01% TFA-MeCN) to give the title compound (170 mg, 20%) as a yellow solid.

[1100] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.31 (br s, 1H), 8.05 (d, 1H), 6.97 (s, 1H), 6.75 (d, 1H), 4.65-4.58 (m, 1H), 3.62 (s, 2H), 2.83-2.74 (m, 8H), 2.02-1.94 (m, 4H) and 1.46 (m, 6H).

[1101] LCMS: m/z 372.1 (M+H).sup.+ (ES.sup.+).

Step B: 2-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-N-(1-isopropyl-1H-pyrazole-3-sulfonimidoyl)acetamide

[1102] ##STR00220##

[1103] To a solution of 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-N-((1-isopropyl-1H-pyrazol-3-yl)sulfinyl)acetamide (150 mg, 403.77 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (68 mg, 444.15 μmol, 1.1 eq). The reaction mixture was stirred at 20° C. for 0.5 hour. The resulting mixture was added dropwise at −70° C. into a solution of NH.sub.3 in THF, which had been prepared by bubbling NH.sub.3 (15 psi) into THF (20 mL) at −70° C. for 10 minutes. The reaction mixture was stirred at 20° C. for 2 hours, and then concentrated in vacuo. The residue was diluted with EtOAc (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, petroleum ether:ethyl acetate, 2:1) and then further purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm×25 mm×10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 25%-55%, 10 min) to give the title compound (28.28 mg, 17% yield, 95.2% purity on LCMS) as a yellow oil.

[1104] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ7.45 (d, 1H), 7.01 (s, 1H), 6.54 (d, 1H), 6.19 (br s, 1H), 4.60-4.50 (m, 1H), 3.71 (s, 2H), 2.90-2.80 (m, 8H), 2.09-2.02 (m, 4H) and 1.53 (d, 6H).

[1105] LCMS: m/z 387.1 (M+H).sup.+(ES.sup.+).

Example 25

N-(1-Isopropylazetidine-3-sulfonimidoyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

Step A: tert-Butyl 3-(N-(2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl)sulfinamoyl)azetidine-1-carboxylate

[1106] ##STR00221##

[1107] To a solution (A) of 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Intermediate R10) (600 mg, 2.12 mmol, 1 eq) in THF (10 mL) was added CDI (343 mg, 2.12 mmol, 1 eq), and the reaction mixture was stirred at 70° C. for 1 hour. To another solution (B) of tert-butyl 3-sulfinamoylazetidine-1-carboxylate (Intermediate L7) (560 mg, 2.54 mmol, 1.2 eq) in THF (10 mL) was added n-BuLi (2.5 M, 1.02 mL, 1.2 eq) at −70° C., and the reaction mixture was stirred at −70° C. for 0.5 hour. The solution (A) was added into the solution (B) at −70° C. The resulting mixture was warmed to 20° C. and stirred another 1 hour. The reaction mixture was quenched with water (80 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (60 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (400 mg, 39%) as yellow oil.

[1108] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.82 (br s, 1H), 8.18 (d, 1H), 7.23 (d, 1H), 7.03 (d, 1H), 6.87-6.85 (m, 1H), 6.66 (s, 1H), 4.13-4.11 (m, 3H), 3.88 (s, 3H), 3.87-3.84 (m, 1H), 3.75-3.70 (m, 1H), 3.54-3.47 (m, 2H), 2.94 (t, 2H), 2.79 (t, 2H), 2.07-2.02 (m, 2H) and 1.39 (s, 9H).

[1109] LCMS: m/z 486.2 (M+H).sup.+ (ES.sup.+).

Step B: tert-Butyl 3-(N-(2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl)sulfamimidoyl)azetidine-1-carboxylate

[1110] ##STR00222##

[1111] To a solution of tert-butyl 3-(N-(2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl)sulfinamoyl)azetidine-1-carboxylate (380 mg, 782.55 μmol, 1 eq) in THF (10 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (132 mg, 860.80 μmol, 1.1 eq). The reaction mixture was stirred at 20° C. for 0.5 hours. The resulting mixture was added dropwise at −70° C. into a solution of NH.sub.3 in THF, which had been prepared by bubbling NH.sub.3 (15 psi) into THF (30 mL) at −70° C. for 10 minutes. The reaction mixture was stirred at 20° C. for 2 hours, and then 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 (102 mg, 21% yield, 80.1% purity on LCMS) as a yellow oil.

[1112] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.10-8.08 (m, 1H), 7.17-7.08 (m, 1H), 6.96-6.93 (m, 1H), 6.79-6.72 (m, 1H), 6.63-6.55 (m, 1H), 4.12-4.01 (m, 5H), 3.89 (s, 3H), 3.52-3.48 (m, 2H), 2.92-2.79 (m, 4H), 2.07-2.01 (m, 2H) and 1.36 (s, 9H).

[1113] LCMS: m/z 501.1 (M+H).sup.+ (ES.sup.+).

Step C: N-(Azetidine-3-sulfonimidoyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

[1114] ##STR00223##

[1115] To a solution of tert-butyl 3-(N-(2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl)sulfamimidoyl)azetidine-1-carboxylate (90 mg, 179.78 μmol, 1 eq) in DCM (8 mL) was added TFA (0.8 mL). The reaction mixture was stirred at 25° C. for 1 hour. N.sub.2 was bubbled through the reaction mixture to remove the solvent, and the residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (30 mg, 42%) as a yellow oil.

[1116] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.19-8.16 (m, 1H), 7.19 (dd, 1H), 7.04-7.00 (m, 1H), 6.90 (dd, 1H), 6.72 (d, 1H), 4.56-4.48 (m, 1H), 3.91 (s, 3H), 3.89-3.51 (m, 4H), 3.49 (d, 2H), 2.93-2.90 (m, 2H), 2.81-2.78 (m, 2H) and 2.08-2.00 (m, 2H).

[1117] LCMS: m/z 401.2 (M+H).sup.+ (ES.sup.+).

Step D: N-(1-Isopropylazetidine-3-sulfonimidoyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

[1118] ##STR00224##

[1119] To a solution of N-(azetidine-3-sulfonimidoyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide (26 mg, 64.92 μmol, 1 eq) in DMSO (0.5 mL) was added DIPEA (17 mg, 129.84 μmol, 2 eq) and 2-iodopropane (22 mg, 129.84 μmol, 2 eq). The reaction mixture was stirred at 30° C. for 21 hours. The reaction mixture was purified directly by reversed phase flash chromatography (0.1% TFA in water-MeCN). The product was further purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm×25 mm×10 μm; mobile phase: [A: water (0.04% NH.sub.3.H.sub.2O+10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 20%-64%, 43 min) to give the title compound (3 mg, 10%) as a white solid.

[1120] .sup.1H NMR (400 MHz, CD.sub.3Cl) δ 8.17 (d, 1H), 7.20 (d, 1H), 7.04 (d, 1H), 6.88 (dd, 1H), 6.73 (s, 1H), 4.20-4.15 (m, 1H), 3.98 (s, 3H), 3.62 (s, 2H), 3.59-3.53 (m, 2H), 3.46-3.42 (m, 2H), 2.99 (t, 2H), 2.89 (t, 2H), 2.36-2.34 (m, 1H), 2.15-2.11 (m, 2H) and 0.92 (d, 6H).

[1121] LCMS: m/z 443.2 (M+H).sup.+ (ES.sup.+).

Example 26

2-(4-Fluoro-2,6-diisopropylphenyl)-N-((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)acetamide

[1122] ##STR00225##

[1123] To a solution of 1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (50 mg, 264.22 μmol, 1 eq) in DMF (1.5 mL) and DCM (1.5 mL) was added EDCI (101 mg, 528.44 μmol, 2 eq), DMAP (64 mg, 528.44 μmol, 2 eq) and 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate R11) (62 mg, 264.22 μmol, 1 eq). The reaction mixture was stirred at 25° C. for 2 hours, diluted with water (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with 1 N aqueous HCl solution until their pH was 7. Then the organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18, 150 mm×25 mm×10 μm, mobile phase: [A: water (0.1% TFA); B: MeCN], B %: 50%-78%, 10 min) to give the title compound (24.15 mg, 22% yield, 99% purity on LCMS) as a white solid.

[1124] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.33 (s, 1H), 7.96 (d, 1H), 6.87 (d, 2H), 6.71 (d, 1H), 4.63-4.55 (m, 1H), 3.75 (s, 2H), 2.92-2.85 (m, 2H), 1.41 (d, 6H) and 1.03 (d, 12H).

[1125] LCMS: m/z 410.3 (M+H).sup.+ (ES.sup.+).

Example 27

2-(4-Fluoro-2,6-diisopropylphenyl)-N-((2-(2-hydroxypropan-2-yl)thiazol-5-yl)sulfonyl)acetamide

[1126] ##STR00226##

[1127] To a solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (Intermediate L9) (80 mg, 359.90 μmol, 1 eq), 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate R11) (94 mg, 395.89 μmol, 1.1 eq) and DMAP (65 mg, 539.85 μmol, 1.5 eq) in DMF (2 mL) was added EDCI (103 mg, 539.85 μmol, 1.5 eq) at 25° C. The reaction mixture was stirred at 25° C. for 1 hour, and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18, 150 mm×25 mm×10 μm; mobile phase: [A: water (0.1% TFA), B: MeCN]; B %: 42%-72%, 10 min) to give the title compound (65.13 mg, 41% yield, 100% purity on LCMS) as a white solid.

[1128] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.73 (br s, 1H), 8.25 (s, 1H), 6.89 (dd, 2H), 3.77 (s, 2H), 2.89-2.85 (m, 2H), 1.46 (s, 6H) and 1.00 (d, 12H).

[1129] LCMS: m/z 443.1 (M+H).sup.+ (ES.sup.+).

Example 28

N-((5-Bromo-2-((1-methyl-1H-tetrazol-5-yl)thio)phenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1130] ##STR00227##

[1131] A solution of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate L21) (30 mg, 88.92 μmol, 1 eq) and 5-bromo-2-((1-methyl-1H-tetrazol-5-yl)thio)aniline (28 mg, 97.81 μmol, 1.1 eq) in MeCN (1 mL) was stirred at 70° C. for 1 hour, and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm×25 mm×10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v/v), B: MeCN]; B %: 10%-40%, 12 min) to give the title compound (13.34 mg, 29% yield, 96.1% purity on LCMS) as a white solid.

[1132] LCMS: m/z 502.9 (M+H).sup.+ (ES.sup.+).

Example 29

2-(4-Fluoro-2,6-diisopropylphenyl)-N-((5-(2-hydroxypropan-2-yl)-1-isopropyl-1H-pyrazol-3-yl)sulfonyl)acetamide

[1133] ##STR00228##

[1134] To a solution of 5-(2-hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L24) (100 mg, 404.34 μmol, 1 eq), 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate R11) (106 mg, 444.78 μmol, 1.1 eq) and DMAP (74 mg, 606.52 μmol, 1.5 eq) in DMF (2 mL) was added EDCI (116 mg, 606.52 μmol, 1.5 eq). The reaction mixture was stirred at 25° C. for 1 hour, and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18, 150 mm×25 mm×10 μm; mobile phase: [A: water (0.1% TFA), B: MeCN]; B %: 49%-79%, 10 min) to give the title compound (38.27 mg, 20% yield, 100% purity on LCMS) as a yellow solid.

[1135] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.30 (br s, 1H), 6.87 (d, 2H), 6.46 (s, 1H), 5.54 (s, 1H), 5.31-5.27 (m, 1H), 3.76 (s, 2H), 2.91-2.87 (m, 2H), 1.47 (s, 6H), 1.38 (d, 6H) and 1.04 (d, 12H).

[1136] LCMS: m/z 468.2 (M+H).sup.+ (ES.sup.+).

Example 30

2-(4-Fluoro-2,6-diisopropylphenyl)-N-((5-(2-hydroxypropan-2-yl)thiazol-2-yl)sulfonyl)acetamide

[1137] ##STR00229##

[1138] To a solution of 5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (Intermediate L10) (80 mg, 359.90 μmol, 1 eq), 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate R11) (94 mg, 395.89 μmol, 1.1 eq) and DMAP (66 mg, 539.85 μmol, 1.5 eq) in DMF (1.5 mL) was added EDCI (104 mg, 539.85 μmol, 1.5 eq) at 25° C. The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was purified directly by prep-HPLC (column: Phenomenex Luna C18, 150 mm×25 mm×5 μm; mobile phase: [A: water (0.075% TFA v/v), B: MeCN]; B %: 50%-80%, 9 min) to give the title compound (95 mg, 59% yield, 99.4% purity on LCMS) as a white solid.

[1139] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.97 (br s, 1H), 7.89 (s, 1H), 6.86 (d, 2H), 6.00 (s, 1H), 3.78 (s, 2H), 2.92-2.85 (m, 2H), 1.50 (s, 6H) and 1.02 (d, 12H).

[1140] LCMS: m/z 443.1 (M+H).sup.+ (ES.sup.+).

Example 31

1-isopropyl-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1141] ##STR00230##

[1142] Prepared according to the general procedure of N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 61) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate L21) and 4-amino-2,3,6,7-tetrahydro-s-indacen-1(5H)-one to afford the title compound (46 mg, 40%) as a white solid.

[1143] .sup.1H NMR (DMSO-d.sub.6) δ 7.90 (s, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.17 (s, 1H), 6.40 (d, J=2.3 Hz, 1H), 4.50 (sept, J=6.7 Hz, 1H), 2.92-2.88 (m, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.55-2.52 (m, 2H), 1.96 (p, J=7.5 Hz, 2H), 1.40 (d, J=6.7 Hz, 6H). One exchangeable proton not observed.

[1144] LCMS m/z 403.2 (M+H).sup.+ (ES.sup.+); 401.1 (M−H).sup.− (ES.sup.−).

Example 32

2-(4-Fluoro-2,6-diisopropylphenyl)-N-((5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)acetamide, ammonium salt

[1145] ##STR00231##

[1146] To a solution of 5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L12) (80 mg, 364.86 μmol, 1 eq), 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate R11) (96 mg, 401.35 μmol, 1.1 eq) and DMAP (67 mg, 547.29 μmol, 1.5 eq) in DMF (2 mL) was added EDCI (105 mg, 547.29 μmol, 1.5 eq). The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm×25 mm×5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v/v), B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (38.5 mg, 23% yield, 100% purity on LCMS) as a white solid.

[1147] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.4 (br s, 1H), 7.07 (br s. 1H), 6.84 (d, 2H), 6.39 (s, 1H), 5.42 (s, 1H), 3.98 (s, 3H), 3.66 (s, 2H), 3.02-2.99 (m, 2H), 1.45 (s, 6H) and 1.05 (d, 12H).

[1148] LCMS: m/z 440.2 (M+H).sup.+ (ES.sup.+).

Example 33

N-((4-((Dimethylamino)methyl)phenyl)sulfonyl)-2-(4-fluoro-2,6-diisopropylphenyl)acetamide, 2,2,2-trifluoroacetate salt

[1149] ##STR00232##

[1150] To a solution of 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate R11) (222 mg, 933.34 μmol, 1 eq) in DMF (2 mL) was added CDI (166 mg, 1.03 mmol, 1.1 eq) at 20° C. The reaction mixture was stirred for 30 minutes, and then added to a solution of NaH (56 mg, 1.40 mmol, 60 wt % in mineral oil, 1.5 eq) and 4-((dimethylamino)methyl)benzenesulfonamide (Intermediate L13) (200 mg, 933.34 μmol, 1 eq) in DMF (2 mL) at 0° C. The resulting mixture was stirred at 20° C. for 2 hours. Then the reaction mixture was poured into ice-water (30 mL), stirred for 10 minutes and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18, 150 mm×25 mm×10 μm; mobile phase: [A: water (0.1% TFA), B: MeCN]; B %: 24%-54%, 10 min) to give the title compound (38.9 mg, 8% yield, 100% purity on LCMS) as a white solid.

[1151] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (d, 2H), 7.66 (d, 2H), 6.83 (d, 2H), 4.26 (s, 2H), 3.76 (s, 2H), 2.89-2.83 (m, 2H), 2.81 (s, 6H) and 1.09 (d, 12H).

[1152] LCMS: m/z 435.2 (M+H).sup.+ (ES.sup.+).

Example 34

N-((7-Chloro-5-isopropyl-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1153] ##STR00233##

[1154] Triphosgene (22.6 mg, 0.076 mmol) was added to 7-chloro-5-isopropyl-2,3-dihydro-1H-inden-4-amine (Intermediate R12) (20 mg, 0.095 mmol) and Et.sub.3N (0.016 mL, 0.114 mmol) in THF (2 mL). The mixture was stirred at room temperature for 15 hours. An additional portion of triphosgene (22.6 mg, 0.076 mmol) was added and the mixture was stirred for an additional 2 hours. The mixture was concentrated in vacuo and dried azeotropically with toluene (3×1 mL). THF (2 mL) was added to the residue, followed by 1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (18.1 mg, 0.095 mmol). After 30 minutes, NaH (60 wt % in mineral oil, 9.54 mg, 0.238 mmol) was added and the mixture was heated at 60° C. for 15 hours. After cooling to room temperature, sat aq NH.sub.4Cl (10 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The organic layer was washed with brine (5 mL), dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by chromatography on silica gel (25 g column, 5-100% EtOAc/isohexane) to afford the title compound (7.5 mg, 18%) as a white solid.

[1155] .sup.1H NMR (DMSO-d.sub.6) δ 10.98 (br s, 1H), 7.98-7.95 (m, 2H), 7.07-7.04 (m, 1H), 6.70 (s, 1H), 4.62-4.59 (m, 1H), 2.97-2.95 (m, 1H), 2.85 (t, J=7.5 Hz, 2H), 2.66-2.64 (m, 2H), 1.97-1.95 (m, 2H), 1.44 (d, J=6.7 Hz, 6H), 1.30-0.82 (m, 6H).

[1156] LCMS m/z 425/427 (M+H).sup.+ (ES.sup.+).

Example 35

N-((8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1157] ##STR00234##

[1158] Triphosgene (42 mg, 0.142 mmol) was added to a mixture of 8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (48 mg, 0.231 mmol) and Et.sub.3N (0.088 mL, 0.634 mmol) in THF (2 mL). The mixture was heated at reflux for 4 hours, concentrated in vacuo and dried azeotropically with toluene (3×1 mL) to afford 4-chloro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene.

[1159] 1-Isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (40 mg, 0.211 mmol) was dissolved in THF (2 mL) and NaH (60 wt % in mineral oil, 10 mg, 0.250 mmol) was added. The reaction was stirred at room temperature for 30 minutes and the crude 4-chloro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene in THF (2 mL) was added. The reaction was stirred at room temperature for 2 days. Sat aq NH.sub.4Cl (10 mL) was added and the mixture extracted with EtOAc (3×10 mL). The organic phase was washed with brine (5 mL), dried (MgSO.sub.4) and concentrated in vacuo. The product was purified by chromatography on silica gel (25 g column, 5-100% EtOAc/isohexane).The isolated product was triturated with MTBE (10 mL) and filtered to afford the title compound (17 mg, 18%) as a colourless solid.

[1160] .sup.1H NMR (DMSO-d.sub.6) δ 10.91 (s, 1H), 8.09 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.62 (sept, J=6.7 Hz, 1H), 2.84 (t, J=7.4 Hz, 4H), 2.68 (t, J=7.5 Hz, 4H), 1.99 (1), J=7.5 Hz, 4H), 1.44 (d, J=6.7 Hz, 6H).

[1161] LCMS m/z 423.0/425.0 (M+H).sup.+ (ES.sup.+).

Example 36

N-((8-Bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-1-isopropyl-1H-pyrazole-4-sulfonamide

[1162] ##STR00235##

[1163] 1-Isopropyl-1H-pyrazole-4-sulfonamide (38 mg, 0.201 mmol) was dissolved in THF (2 mL) and NaH (60 wt % in mineral oil, 10 mg, 0.250 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. 4-Bromo-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R13) (62 mg, 0.22 mmol) in THF (2 mL) was added and the reaction mixture was stirred at room temperature overnight, before being diluted with water (2 mL) and concentrated in vacuo. The crude product was purified by reversed phase chromatography on RP Flash C18 (12 g column, 5-40% MeCN/10 mM ammonium bicarbonate) to afford the title compound (18 mg, 18%) as a colourless solid.

[1164] .sup.1H NMR (DMSO-d.sub.6) δ 10.65 (s, 1H), 8.44 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 4.61 (sept, J=6.7 Hz, 1H), 2.82 (t, J=7.4 Hz, 4H), 2.70 (t, J=7.5 Hz, 4H), 1.98 (p, J=7.5 Hz, 4H), 1.42 (d, J=6.6 Hz, 6H).

[1165] LCMS m/z 467/469 (M+H).sup.+ (ES.sup.+).

Example 37

N-((8-Cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1166] ##STR00236##

[1167] 1-Isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (28 mg, 0.148 mmol) was dissolved in THF (2 mL) and NaH (60 wt % in mineral oil, 8 mg, 0.200 mmol) was added. The reaction was stirred at room temperature for 30 minutes and 8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile (Intermediate R14) (37 mg, 0.165 mmol) in THF (2 mL) was added. The reaction mixture was stirred at room temperature for 4 hours, diluted with water (2 mL) and concentrated in vacuo. Water (1.5 mL) was added to the residue and it was washed with MTBE (2×3 mL). The aqueous layer was filtered through a syringe filter and purified by reversed phase chromatography on RP Flash C18 (12 g column, 5-40% MeCN/10 mM ammonium bicarbonate) to afford the title compound (45 mg, 73%) as a colourless solid.

[1168] .sup.1H NMR (DMSO-d.sub.6) δ 11.06 (s, 1H), 8.43 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 4.61 (sept, J=6.8 Hz, 1H), 2.95 (t, J=7.4 Hz, 4H), 2.66 (t, J=7.4 Hz, 4H), 2.03 (p, J=7.5 Hz, 4H), 1.43 (d, J=6.7 Hz, 6H).

[1169] LCMS m/z 414.4 (M+H).sup.+ (ES.sup.+).

Example 38

N-((8-Bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1170] ##STR00237##

[1171] Prepared according to the general procedure of N-((8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-4-sulfonamide (Example 36) from 1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) and 4-bromo-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R13) to afford the title compound (57 mg, 55%) as a colourless solid.

[1172] .sup.1H NMR (DMSO-d.sub.6) δ 10.91 (s, 1H), 8.08 (s, 1H), 7.97 (d, J=2.4 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 4.69-4.49 (m, 1H), 2.81 (t, J=7.4 Hz, 4H), 2.71 (t, J=7.5 Hz, 4H), 2.04-1.91 (m, 4H), 1.43 (d, J=6.7 Hz, 6H).

[1173] LCMS m/z 467/469 (M+H).sup.+ (ES.sup.+).

Example 39

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[1174] ##STR00238##

[1175] Triphosgene (11 mg, 0.037 mmol) was added to a mixture of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (11 mg, 0.063 mmol) and Et.sub.3N (24 μL, 0.172 mmol) in THF (2 mL). The reaction mixture was stirred for 15 hours, evaporated in vacuo and azeotroped with toluene (3×1 mL). THF (2 mL) was added and the mixture was filtered. The filtrate was added to a mixture of 5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L14) (50 mg, 0.054 mmol) and NaH (60 wt % in mineral oil, 6 mg, 0.150 mmol) in THF (2 mL). The reaction was stirred for 20 hours at room temperature, before being quenched with water (2 mL). The THF was evaporated in vacuo and the aqueous residue was washed with TBME (2×3 mL), buffered with sodium dihydrogenphosphate (73.1 mg) and purified by reversed phase chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (5 mg, 21%) as a white solid.

[1176] .sup.1H NMR (DMSO-d.sub.6) δ 10.81 (s, 1H), 8.02 (s, 1H), 6.94 (s, 1H), 6.68 (s, 1H), 3.99 (s, 3H), 3.00 (s, 3H), 2.79 (t, J=7.4, Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 1.94 (p, J=7.5 Hz, 4H), 1.53 (s, 6H).

[1177] LCMS m/z 433.5 (M+H).sup.+ (ES.sup.+); 431.3 (M−H).sup.− (ES.sup.−).

Example 40

N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide

[1178] ##STR00239##

[1179] NaH (60 wt % in mineral oil, 20.14 mg, 0.504 mmol) was added to 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide (Intermediate L15) (55.4 mg, 0.242 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature for 30 minutes. 5-Chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate R15) was added. The reaction mixture was heated at 60° C. for 15 hours and quenched with water (2 mL). The THF was evaporated in vacuo. The aqueous residue was washed with TBME (2×3 mL) and purified by reversed phase chromatography RP Flash C18 (12 g column, 0-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (15.5 mg, 16%) as a white solid.

[1180] .sup.1H NMR (DMSO-d.sub.6) δ 8.14 (br s, 1H), 7.72 (s, 1H), 7.46 (s, 1H), 7.03 (s, 2H), 5.15-5.11 (m, 2H), 3.08-3.05 (m, 2H), 1.02 (d, J=6.9 Hz, 12H). One exchangeable proton not observed.

[1181] LCMS m/z 467/469 (M+H).sup.+ (ES.sup.+).

Example 41

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide, sodium salt

[1182] ##STR00240##

[1183] NaH (60 wt % in mineral oil, 7.85 mg, 0.196 mmol) was added to 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-sulfonamide (Intermediate L15) (30 mg, 0.131 mmol) in THF (5 mL) and the reaction mixture was stirred for 1 hour at room temperature. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) (26.1 mg, 0.131 mmol) was added and the reaction mixture was stirred at room temperature for 15 hours. The suspension was filtered and washed with THF (1 mL). The collected solid was triturated with EtOAc (10 mL) and dried in vacuo to afford the title compound (44 mg, 73%) as white solid.

[1184] .sup.1H NMR (DMSO-d.sub.6) δ 8.05 (s, 1H), 7.67 (s, 1H), 7.33 (s, 1H), 6.76 (s, 1H), 5.14-5.11 (m, 2H), 2.75 (t, J=7.4 Hz, 4H), 2.66 (t, J=7.2 Hz, 4H), 1.92-1.89 (m, 4H).

[1185] LCMS m/z 429 (M+H).sup.+ (ES.sup.+).

Example 42

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-sulfonamide

[1186] ##STR00241##

[1187] NaH (60 wt % in mineral oil, 7.85 mg, 0.196 mmol) was added to 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-sulfonamide (Intermediate L16) (30 mg, 0.131 mmol) in THF (5 mL) and the reaction mixture was stirred for 1 hour at room temperature. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) (26.1 mg, 0.131 mmol) was added and the reaction mixture was stirred at room temperature for 15 hours. The reaction was quenched with water (2 mL) and THF was removed by evaporation in vacuo. The aqueous residue was washed with TBME (2×3 mL) and purified by reversed phase chromatography on RP Flash C18 (12 g column, 0-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (7.2 mg, 13%) as a white solid.

[1188] .sup.1H NMR (DMSO-d.sub.6) δ 7.75 (d, J=2.4 Hz, 1H), 7.50 (s, 1H), 6.76 (s, 1H), 6.50 (d, J=2.4 Hz, 1H), 5.14-5.11 (m, 2H), 2.74 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 1.90-1.88 (m, 4H). One exchangeable proton not observed.

[1189] LCMS m/z 429 (M+H).sup.+ (ES.sup.+).

Example 43

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt

[1190] ##STR00242##

[1191] NaO.sup.tBu (2 M in THF, 0.101 mL, 0.201 mmol) was added to 1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide (Intermediate L17) (39 mg, 0.192 mmol) in THF (3 mL). The reaction was stirred for 1 hour at room temperature. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) (38.2 mg, 0.192 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours and filtered, washing with THF (1 mL). The collected solid was triturated with EtOAc (5 mL) and dried in vacuo to afford the title compound (48 mg, 58%) as a white solid.

[1192] .sup.1H NMR (DMSO-d.sub.6) δ 7.75 (s, 1H), 7.46 (s, 1H), 6.76 (s, 1H), 4.38-4.31 (m, 1H), 2.74 (t, J=7.3 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 2.24 (s, 3H), 1.93-1.85 (m, 4H), 1.35 (d, J=6.6 Hz, 6H).

[1193] LCMS m/z 403 (M+H).sup.+ (ES.sup.+).

Example 44

1-(Cyclopropylmethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide, sodium salt

[1194] ##STR00243##

[1195] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate L18) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) to afford the title compound (60 mg, 75%) as a white solid.

[1196] .sup.1H NMR (DMSO-d.sub.6) δ 7.94 (d, J=0.7 Hz, 1H), 7.53 (d, J=0.7 Hz, 1H), 7.34 (s, .sup.1H), 6.76 (s, 1H), 3.92 (d, J=7.1 Hz, 2H), 2.75 (t, J=7.4 Hz, 4H), 2.67 (t, J=7.3 Hz, 4H), 1.90 (p, J=7.4 Hz, 4H), 1.27-1.13 (m, 1H), 0.57-0.45 (m, 2H), 0.38-0.32 (m, 2H).

[1197] LCMS m/z 401 (M+H).sup.+ (ES.sup.+).

Example 45

1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1198] ##STR00244##

[1199] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate L19) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) to afford the title compound (40.1 mg, 28%) as a white solid.

[1200] .sup.1H NMR (DMSO-d.sub.6) δ 7.66 (d, J=2.2 Hz, 1H), 7.52 (s, 1H), 6.77 (s, 1H), 6.36 (d, J=2.2 Hz, 1H), 4.11 (q, J=7.3 Hz, 2H), 2.75 (t, J=7.3 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.90 (p, J=7.4 Hz, 4H), 1.36 (t, J=7.3 Hz, 3H).

[1201] LCMS m/z 375 (M+H).sup.+ (ES.sup.+).

Example 46

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-1,2,4-triazole-3-sulfonamide, sodium salt

[1202] ##STR00245##

[1203] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 1-isopropyl-1H-1,2,4-triazole-3-sulfonamide (Intermediate L20) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) to afford the title compound (83 mg, 76%) as a colourless solid.

[1204] .sup.1H NMR (DMSO-d.sub.6) δ 8.49 (s, 1H), 7.62 (s, 1H), 6.77 (s, 1H), 4.59 (sept, J=6.7 Hz, 1H), 2.75 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.3 Hz, 4H), 1.97-1.81 (m, 4H), 1.44 (d, J=6.7 Hz, 6H).

[1205] LCMS m/z 390.4 (M+H).sup.+ (ES.sup.+).

Example 47

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-1,2,3-triazole-5-sulfonamide

[1206] ##STR00246##

[1207] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 1-isopropyl-1H-1,2,3-triazole-5-sulfonamide (Intermediate L22) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase prep-HPLC method 1 to afford the title compound (15 mg, 14%) as a colourless solid.

[1208] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.89 (s, 1H), 7.82 (s, 1H), 6.84 (s, 1H), 5.38 (sept, J=6.7 Hz, 1H), 2.76 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.91 (p, J=7.4 Hz, 4H), 1.51 (d, J=6.7 Hz, 6H). One exchangeable proton not observed.

[1209] LCMS m/z 390 (M+H).sup.+ (ES.sup.+); 388 (M−H).sup.− (ES.sup.−).

Example 48

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-isopropyl-2H-1,2,3-triazole-4-sulfonamide

[1210] ##STR00247##

[1211] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 2-isopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate L23) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase prep-HPLC method 1 to afford the title compound (15.5 mg, 15%) as a colourless solid.

[1212] .sup.1H NMR (DMSO-d.sub.6) δ 11.25 (s, 1H), 8.20 (s, 1H), 8.06 (s, 1H), 6.92 (s, 1H), 4.91 (sept, J=6.7 Hz, 1H), 2.78 (t, J=7.3 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H), 1.51 (d, J=6.7 Hz, 6H).

[1213] LCMS m/z 390 (M+H).sup.+ (ES.sup.+); 388 (M−H).sup.− (ES.sup.−).

Example 49

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1214] ##STR00248##

[1215] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 5-(2-hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L24) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (27.1 mg, 30%) as a clear colourless solid.

[1216] .sup.1H NMR (DMSO-d.sub.6) δ 10.82 (s, 1H), 8.01 (s, 1H), 6.94 (s, 1H), 6.50 (s, 1H), 5.57 (s, 1H), 5.31 (sept, J=6.6 Hz, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H), 1.51 (s, 6H), 1.39 (d, J=6.6 Hz, 6H).

[1217] LCMS m/z 447.5 (M+H).sup.+ (ES.sup.+).

Example 50

N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1218] ##STR00249##

[1219] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 5-(2-hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L24) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate R16) and purified by reversed phase chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (7.5 mg, 8%) as a clear colourless solid.

[1220] .sup.1H NMR (DMSO-d.sub.6) δ 11.03 (s, 1H), 7.79 (s, 1H), 6.91 (d, J=9.9 Hz, 2H), 6.45 (s, 1H), 5.52 (s, 1H), 5.29 (sept, J=6.6 Hz, 1H), 3.03-2.92 (m, 2H), 1.49 (s, 6H), 1.40 (d, J=6.5 Hz, 6H), 1.05 (app br s, 12H).

[1221] LCMS m/z 469.5 (M+H).sup.+ (ES.sup.+).

Example 51

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(1-methoxycyclobutyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1222] ##STR00250##

[1223] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 5-(1-methoxycyclobutyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L25) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase chromatography on RP Flash C18 (12 g column, 5-100% MeCN/10 mM ammonium bicarbonate) to afford the title compound (31 mg, 28%) as a white solid.

[1224] .sup.1H NMR (DMSO-d.sub.6) δ 7.97 (s, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 3.80 (s, 3H), 2.87 (s, 3H), 2.77 (t, J=7.4, 4H), 2.58 (t, J=7.4, 4H), 2.45-2.27 (m, 4H), 1.91 (p, J=7.5, 41.sup.−), 1.87-1.77 (m, 1H), 1.66-1.51 (m, 1H). One exchangeable proton not observed.

[1225] LCMS m/z 445.4 (M+H).sup.+ (ES.sup.+).

Example 52

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(1-methoxycyclopentyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1226] ##STR00251##

[1227] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 5-(1-methoxycyclopentyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L26) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase chromatography on RP Flash C18 (12 g column, 5-100% MeCN/10 mM ammonium bicarbonate) to afford the title compound (9 mg, 12%) as a cream-coloured solid.

[1228] .sup.1H NMR (DMSO-d.sub.6) δ 7.99 (s, 1H), 6.91 (s, 1H), 6.70 (s, 1H), 3.94 (s, 3H), 2.89 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 2.23-2.14 (m, 2H), 1.98-1.83 (m, 6H), 1.76-1.62 (m, 4H). One exchangeable proton not observed.

[1229] LCMS m/z 459.5 (M+H).sup.+ (ES.sup.+).

Example 53

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(1-methoxyethyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1230] ##STR00252##

[1231] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 5-(1-methoxyethyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate L27) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase prep-HPLC method 1 to afford the title compound (33 mg, 24%) as a white solid.

[1232] .sup.1H NMR (DMSO-d.sub.6) δ 10.81 (s, 1H), 8.01 (s, 1H), 6.93 (s, 1H), 6.69 (s, 1H), 4.65 (q, J=6.5 Hz, 1H), 3.89 (s, 3H), 3.20 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 1.94 (p, J=7.4 Hz, 4H), 1.42 (d, J=6.5 Hz, 3H).

[1233] LCMS m/z 419.4 (M+H).sup.+ (ES.sup.+).

Example 54

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(1-hydroxyethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1234] ##STR00253##

[1235] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 5-(1-hydroxyethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L28) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase chromatography on RP Flash C18 (12 g column, 5-100% MeCN/10 mM ammonium bicarbonate) to afford the title compound (18 mg, 10%) as a white solid.

[1236] .sup.1H NMR (DMSO-d.sub.6) δ 10.84 (br s, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 6.57 (s, 1H), 5.49 (d, J=6.1 Hz, 1H), 4.92-4.79 (m, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.94 (p, J=7.4 Hz, 4H), 1.49-1.34 (m, 9H).

[1237] LMCS m/z 433.4 (M+H).sup.+ (ES.sup.+).

Example 55

4-Fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1238] ##STR00254##

[1239] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 4-fluoro-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L29) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase prep-HPLC method 1 to afford the title compound (23 mg, 34%) as a white solid.

[1240] .sup.1H NMR (DMSO-d.sub.6) δ 11.09 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 6.91 (s, 1H), 4.48 (app. p, J=6.7 Hz, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H), 1.40 (d, J=6.7 Hz, 6H).

[1241] LCMS m/z 407.7, 429.1 (M+H, M+Na).sup.+ (ES.sup.+).

Example 56

1-(1-(Azetidin-1-yl)-2-methylpropan-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

[1242] ##STR00255##

[1243] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 1-(1-(azetidin-1-yl)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate L30) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase prep-HPLC method 1 to afford the title compound (23 mg, 34%) as a white solid.

[1244] .sup.1H NMR (DMSO-d.sub.6) δ 10.71 (s, 1H), 7.95-7.94 (m, 2H), 6.92 (s, 1H), 6.69 (d, J=2.4 Hz, 1H), 2.96 (app br s, 4H), 2.80-2.70 (m, 6H), 2.61 (t, J=7.4 Hz, 4H), 1.94 (p, J=7.5 Hz, 4H), 1.78 (p, J=7.1 Hz, 2H), 1.50 (s, 6H).

[1245] LCMS m/z 458.4 (M+H).sup.+ (ES.sup.+); 456.3 (M−H).sup.− (ES.sup.−).

Example 57

3-((Dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methylbenzenesulfonamide, sodium salt

[1246] ##STR00256##

[1247] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 3-((dimethylamino)methyl)-5-methylbenzenesulfonamide (Intermediate L31) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) to afford the title compound (40 mg, 44%) as a white solid.

[1248] .sup.1H NMR (DMSO-d.sub.6) δ 7.51-7.44 (m, 3H), 7.10 (s, 1H), 6.76 (s, 1H), 3.34 (s, 2H), 2.74 (t, J=.sub.7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 2.31 (s, 3H), 2.14 (s, 6H), 1.94-1.84 (m, 4H).

[1249] LCMS m/z 428.3 (M+H).sup.+(ES.sup.+).

Example 58

1-(2,2-Difluoroethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide, sodium salt

[1250] ##STR00257##

[1251] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example .sub.43) from 1-(2,2-difluoroethyl)-1H-pyrazole-4-sulfonamide (Intermediate L32) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1) to afford the title compound (42 mg, 40%) as a white solid.

[1252] .sup.1H NMR (DMSO-d.sub.6) δ 7.98 (s, 1H), 7.64 (s, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 6.49-6.17 (m, 1H), 4.68-4.51 (m, 2H), 2.75 (t, J=7.4 Hz, 4H), 2.66 (t, J=7.5 Hz, 4H), 1.97-1.82 (m, 4H).

[1253] LCMS m/z 411.6 (M+H).sup.+ (ES.sup.+).

Example 59

1-Cyclobutyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-1H-pyrazole-3-sulfonamide

[1254] ##STR00258##

[1255] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 1-cyclobutyl-1H-pyrazole-3-sulfonamide (Intermediate L33) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase prep-HPLC method 1 to afford the title compound (33 mg, 34%) as a white solid.

[1256] .sup.1H NMR (DMSO-d.sub.6) δ 10.86 (s, 1H), 8.02 (d, J=2.4 Hz, 1H), 6.94 (s, 1H), 6.74 (d, J=2.4 Hz, 1H), 4.95 (p, J=8.4 Hz, 1H), 2.79 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.48-2.35 (m, 4H), 1.94 (p, J=7.4 Hz, 4H), 1.86-1.76 (m, 2H). One exchangeable proton not observed.

[1257] LCMS m/z 401.3 (M+H).sup.+ (ES.sup.+).

Example 60

1-(1-((Dimethylamino)methyl)cyclobutyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

[1258] ##STR00259##

[1259] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 1-(1-((dimethylamino)methyl)cyclobutyl)-1H-pyrazole-3-sulfonamide (Intermediate L.sub.34) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase prep-HPLC method 1 to afford the title compound (3 mg, 4%) as a white solid.

[1260] .sup.1H NMR (DMSO-d.sub.6) δ 7.92 (app s, 2H), 6.91 (s, 1H), 6.70 (app s, 1H), 2.81-2.75 (m, 6H), 2.60 (t, J=7.4 Hz, 4H), 2.49-2.44 (m, 2H), 2.35-2.28 (m, 2H), 1.97-1.92 (m, 4H), 1.91 (s, 6H), 1.89-1.82 (m, 2H). One exchangeable proton not observed.

[1261] LCMS m/z 458.2 (M+H).sup.+(ES.sup.+); 456.3 (M−H).sup.− (ES.sup.−).

Example 61

N-((8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, sodium salt

[1262] ##STR00260##

[1263] Step A: A solution of 8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (Intermediate R17) (80 mg, 0.418 mmol) and (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate L21) (141 mg, 0.418 mmol) in MeCN (5 mL) was stirred at 50° C. for 1.5 hours. The solvent was removed in vacuo and the crude product was purified by reversed phase prep-HPLC method 1 to afford N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (88 mg) as a pale yellow solid.

[1264] LCMS m/z 407.0 (M+H).sup.+(ES.sup.+); 405.2 (M−H).sup.− (ES.sup.−).

[1265] Step B: N-((8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (85 mg, 0.21 mmol) was dissolved in aq NaOH (0.1 M, 2.2 mL, 0.22 mmol) containing 2 drops of THF and freeze-dried to afford the title compound (94 mg, 52%) as a white solid.

[1266] .sup.1H NMR (DMSO-d.sub.6) δ 7.71 (d, J=2.3 Hz, 1H), 7.54 (br s, 1H), 6.38 (d, J=2.3 Hz, 1H), 4.50 (sept, J=6.7 Hz, 1H), 2.78 (t, J=7.5 Hz, 4H), 2.68 (t, J=7.5 Hz, 4H), 1.95 (p, J=7.5 Hz, 4H), 1.40 (d, J=6.7 Hz, 6H).

[1267] LCMS m/z 407.5 (M+H).sup.+ (ES.sup.+); 405.2 (M−H).sup.− (ES.sup.−).

Example 62

5-Fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, sodium salt

[1268] ##STR00261##

[1269] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from of 5-fluoro-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate L35) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase prep-HPLC method 1 to afford 5-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (9.85 mg) as a solid. Aq NaOH (0.1 M, 0.24 mL) was added and the solution was freeze-dried to afford the title compound (10.3 mg, 12%) as a solid.

[1270] .sup.1H NMR (DMSO-d.sub.6) δ 7.89 (s, 1H), 6.89 (s, 1H), 6.40 (s, 1H), 4.67-4.57 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H), 1.40 (d, J=6.7 Hz, 6H).

[1271] LCMS m/z 407.2 (M+H).sup.+ (ES.sup.+).

Example 63

1-(2,2-Difluoroethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1272] ##STR00262##

[1273] Prepared according to the general procedure of N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 61) from ((1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)sulfonyl)(4-(dimethylamino)pyridin-1-ium-1-carbonyl)amide (Intermediate L36) and 1,2,3,5,6,7-hexahydro-s-indacen-4-amine to afford the title compound (13.8 mg, 14%) as a solid.

[1274] .sup.1H NMR (DMSO-d.sub.6) δ 7.92-7.86 (m, 2H), 6.89 (s, 1H), 6.73-6.69 (m, 1H), 6.52-6.23 (m, 1H), 4.77-4.66 (m, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.93 (1), J=7.4 Hz, 4H).

[1275] LCMS m/z 411.2 (M+H).sup.+ (ES.sup.+).

Example 64

1-Isopropyl-N-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1276] ##STR00263##

[1277] Prepared according to the general procedure of N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 61) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate L21) and 3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine to afford the title compound (18 mg, 79%) as a white solid.

[1278] .sup.1H NMR (DMSO-d.sub.6) δ 7.70 (d, J=2.3 Hz, 1H), 7.19 (s, 1H), 6.76 (s, 1H), 6.38 (d, J=2.3 Hz, 1H), 4.56-4.38 (m, 3H), 3.08 (t, J=8.6 Hz, 2H), 2.71 (t, J=7.3 Hz, 2H), 2.61 (t, J=7.4 Hz, 2H), 1.87 (p, J=7.4 Hz, 2H), 1.40 (d, J=6.7 Hz, 6H).

[1279] LCMS m/z 391.3 (M+H).sup.+ (ES.sup.+).

Example 65

N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)-1H-pyrazole-3-sulfonamide, sodium salt

[1280] ##STR00264##

[1281] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 1-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate L37) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)-1H-pyrazole-3-sulfonamide (46.4 mg) as a white solid. The crude product obtained was dissolved in aq NaOH (0.1 M, 0.980 mL, 0.098 mmol) and freeze-dried to afford the title compound (44 mg, 38%) as a white powder.

[1282] .sup.1H NMR (DMSO-d.sub.6) δ 7.68 (d, J=2.4 Hz, 1H), 7.52 (br s, 1H), 6.75 (s, 1H), 6.37 (d, J=2.3 Hz, 1H), 2.82-2.69 (m, 6H), 2.64 (t, J=7.4 Hz, 4H), 2.29-2.17 (m, 4H), 1.88 (p, J=7.4 Hz, 4H), 1.54-1.41 (m, 10H).

[1283] LCMS m/z 472.3 (M+H).sup.+ (ES.sup.+); 470.1 (M−H).sup.− (ES.sup.−).

Example 66

4-((Dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide, sodium salt

[1284] ##STR00265##

[1285] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-3-methyl-1H-pyrazole-4-sulfonamide, sodium salt (Example 43) from 4-((dimethylamino)methyl)benzenesulfonamide (Intermediate L13) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate R1), and purified by reversed phase chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford 4-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide (51.6 mg) as a white powder. The crude product obtained was dissolved in aq NaOH (0.1 M, 1.25 mL, 0.125 mmol) and freeze-dried to afford the title compound (51 mg, 35%) as a white solid.

[1286] .sup.1H NMR (DMSO-d.sub.6) δ 7.76-7.60 (m, 2H), 7.41 (s, 1H), 7.31-7.21 (m, 2H), 6.75 (s, 1H), 3.38 (s, 2H), 2.73 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.13 (s, 6H), 1.87 (p, J=7.4 Hz, 4H).

[1287] LCMS m/z 414.3 (M+H).sup.+ (ES.sup.+); 412.2 (M−H).sup.− (ES.sup.−).

Example 67

1-Cyclopropyl-N-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

[1288] ##STR00266##

[1289] Prepared according to the general procedure of N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Example 61, Step A) from ((1-cyclopropyl-1H-pyrazol-3-yl)sulfonyl)(4-(dimethylamino)pyridin-1-ium-1-carbonyl)amide (Intermediate L38) and 3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-amine to afford the title compound (19 mg, 26%) as a white solid.

[1290] .sup.1H NMR (DMSO-d.sub.6) δ 8.00 (s, 1H), 7.90 (app. t, J=2.0 Hz, 1H), 6.62 (app. t, J=2.0 Hz, 1H), 6.44 (s, 1H), 4.44 (t, J=8.6 Hz, 2H), 3.85-3.78 (m, 1H), 2.94 (t, J=8.6 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.59 (t, J=7.3 Hz, 2H), 1.94 (p, J=7.4 Hz, 2H), 1.07-0.98 (m, 4H). One exchangeable proton not observable.

[1291] LCMS m/z 389.2 (M+H).sup.+ (ES.sup.+).

[1292] The compounds of examples 68-97 were synthesised by methods analogous to those outlined above and below.

TABLE-US-00001 TABLE 1 .sup.1H NMR and MS data Ex Structure .sup.1H NMR MS MW 68 [00267] .sup.1H NMR (DMSO-d.sub.6) δ 7.59 (d, J = 2.3 Hz, 1H), 7.32 (br s, 1H), 7.01 (dd, J = 8.5, 6.6 Hz, 1H), 6.96-6.89 (m, 2H), 6.27 (br s, 1H), 4.39 (m, 1H), 3.07 (m, 2H), 1.32 (d, J = 6.7 Hz, 6H), 0.96 (d, J = 6.8 Hz, 12H). m/z 393.1 (M + H).sup.+ (ES.sup.+) 392.52 N-((2,6-Diisopropylphenyl)carbamoyl)- 1-isopropyl-1H-pyrazole-3- sulfonamide, sodium salt 69 [00268] .sup.1H NMR (DMSO-d.sub.6) δ 10.67 (s, 1H), 8.39 (s, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.28-7.19 (m, 1H), 7.11 (d, J = 7.7 Hz, 2H), 4.58 (sept, J = 6.6 Hz, 1H), 2.90 (sept, J = 6.9 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H), 1.16-0.86 (m, 12H). m/z 393.1 (M + H).sup.+ (ES.sup.+) 392.52 N-((2,6-Diisopropylphenyl)carbamoyl)- 1-isopropyl-1H-pyrazole-4-sulfonamide 70 [00269] .sup.1H NMR (DMSO-d.sub.6) δ 11.19 (s, 1H), 8.02 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 9.9, 3.0 Hz, 1H), 7.45 (dd, J = 8.5, 3.0 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 4.62 (sept, J = 6.6 Hz, 1H), 2.98-2.84 (m, 1H), 1.45 (d, J = 6.7 Hz, 6H), 1.21-0.91 (m, 6H). m/z 437.4 (M + H).sup.+ (ES.sup.+); 435.5 (M − H).sup.− (ES.sup.−) 436.42 N-((4-Fluoro-2-isopropyl-6- (trifluoromethyl)phenyl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide 71 [00270] .sup.1H NMR (DMSO-d.sub.6) δ 11.14 (s, 1H), 8.15 (s, 1H), 7.59 (s, 2H), 6.52 (s, 1H), 5.48 (s, 1H), 4.03 (s, 3H), 3.12-2.93 (m, 2H), 1.48 (s, 6H), 1.08 (d, J = 6.8 Hz, 12H). m/z 448.1 (ES.sup.+) 447.55 N-((4-Cyano-2,6- diisopropylphenyl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1-methyl-1H- pyrazole-3-sulfonamide 72 [00271] .sup.1H NMR (DMSO-d.sub.6) δ 11.19 (s, 1H), 8.14 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.59 (s, 2H), 6.72 (d, J = 2.4 Hz, 1H), 4.69- 4.51 (m, 1H), 3.05-2.87 (m, 2H), 1.44 (d, J = 6.7 Hz, 6H), 1.06 (d, J = 6.8 Hz, 12H). m/z 418.1 (M + H).sup.+ (ES.sup.+) 417.53 N-((4-Cyano-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3- sulfonamide 73 [00272] .sup.1H NMR (DMSO-d.sub.6) δ 11.03 (br s, 1H), 7.97 (br s, 1H), 7.86 (br s, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.5 H, 1H), 7.33 (s, 2H), 6.70 (br s, 1H), 4.61 (sept, J = 6.7 Hz, 1H), 3.00 (sept, J = 6.9 Hz, 2H), 1.45 (d, J = 6.7 Hz, 6H), 1.26-1.00 (m, 12H). m/z 469 (M + H).sup.+ (ES.sup.+); 467 (M − H).sup.− (ES.sup.−), 468.62 N-((3,5-Diisopropyl-[1,1′-biphenyl]-4- yl)carbamoyl)-1-isopropyl-1H-pyrazole- 3-sulfonamide 74 [00273] .sup.1H NMR (DMSO) δ 10.77 (br s, 1H), 7.96 (s, 1H), 6.91 (s, 1H), 6.59 (s, 1H), 5.47 (d, J = 5.6 Hz, 1H), 4.84 (m, 1H), 3.88 (s, 3H), 2.78 (t, J = 7.4 Hz, 4H), 2.62 (t, J = 7.4 Hz, 4H), 1.94 (p, J = 7.5 Hz, 4H), 1.41 (d, J = 6.5 Hz, 3H). m/z 405.4 (M + H).sup.+ (ES.sup.+); 403.3 (M − H).sup.− (ES.sup.−). 404.49 N-((1,2,3,5,6,7-Hexahydro-s-indacen-4- yl)carbamoyl)-5-(1-hydroxyethyl)-1- methyl-1H-pyrazole-3-sulfonamide 75 [00274] .sup.1H NMR (Methanol-d.sub.4) δ 8.27 (s, 1H), 7.91 (s, 1H), 7.51 (s, 2H), 4.71-4.46 (m, 1H), 3.20-2.88 (m, 2H), 1.50 (d, J = 6.7 Hz, 6H), 1.13 (d, J = 6.9 Hz, 12H). Two exchangeable protons not observed. m/z 418.5 (M + H).sup.+ (ES); 416.3 (M − H).sup.− (ES.sup.−). 417.53 N-((4-Cyano-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-4- sulfonamide 76 [00275] .sup.1H NMR (DMSO-d.sub.6) δ 7.75 (br s, 1H), 7.33 (s, 1H), 7.08 (s, 1H), 6.43-6.33 (m, 1H), 6.28 (d, J = 7.7 Hz, 2H), 4.18- 4.15 (m, 2H), 2.43-2.24 (m, 2H), 0.31 (d, J = 6.9 Hz, 12H). One exchangeable proton not observed. m/z 433 (M + H).sup.+ (ES.sup.+). 432.46 N-((2,6-Diisopropylphenyl)carbamoyl)- 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4- sulfonamide 77 [00276] .sup.1H NMR (DMSO-d.sub.6) δ 7.69 (d, J = 2.3 Hz, 1H), 7.38 (br s, 1H), 6.78 (d, J = 10.1 Hz, 2H), 6.36 (br s, 1H), 4.49- 4.46 (m, 1H), 3.15-3.13 (m, 2H), 1.39 (d, J = 6.7 Hz, 6H), 1.02 (d, J = 6.8 Hz, 12H). m/z 411 (M + H).sup.−, (ES.sup.+). 410.51 N-((4-Fluoro-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3- sulfonamide, sodium salt 78 [00277] .sup.1H NMR (DMSO-d.sub.6) δ 7.77 (d, J = 2.4 Hz, 1H), 7.37 (s, 1H), 6.79 (d, J = 10.1 Hz, 2H), 6.50 (d, J = 2.4 Hz, 1H), 5.13-5.10 (m, 2H), 3.14- 3.06 (m, 2H), 1.02 (d, J = 6.8 Hz, 12H). m/z 451 (M + H).sup.+ (ES.sup.+). 450.45 N-((4-Fluoro-2,6-diisopropylphenyl) carbamoyl)-1-(2,2,2-trifluoroethyl)-1H- pyrazole-3-sulfonamide, sodium salt 79 [00278] .sup.1H NMR (DMSO-d.sub.6) δ 11.02 (s, 1H), 8.13 (s, 1H), 7.24 (s, 1H), 6.94 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.16 (s, 3H), 2.79 (t, J = 7.4 Hz, 4H), 2.60 (t, J = 7.4 Hz, 4H), 2.01-1.89 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H). m/z 433.4 (M + H).sup.+ (ES.sup.+). 432.50 Ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)sulfamoyl)-1- methyl-1H-pyrazole-5-carboxylate 80 [00279] .sup.1H NMR (DMSO-d.sub.6) δ 7.69 (s, 1H), 7.39 (s, 1H), 6.75 (s, 1H), 3.69 (s, 3H), 2.74 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 2.22 (s, 3H), 1.93- 1.86 (m, 4H). m/z 375 (M + H).sup.+ (ES.sup.+). 374.46 N-((1,2,3,5,6,7-Hexahydro-s-indacen-4- yl)carbamoyl)-1,3-dimethyl-1H- pyrazole-4-sulfonamide, sodium salt 81 [00280] .sup.1H NMR (DMSO-d.sub.6) δ 10.89 (br s, 1H), 7.82 (s, 1H), 7.26- 7.20 (m, 1H), 7.11 (d, J = 7.6 Hz, 2H), 6.63 (s, 1H), 3.98 (s, 3H), 3.02 (sept, J = 6.9 Hz, 2H), 2.97 (s, 3H), 1.50 (s, 6H), 1.06 (br s, 12H). m/z 437 (M + H).sup.+ (ES.sup.+); 435 (M − H).sup.− (ES.sup.−). 436.57 N-((2,6-Diisopropylphenyl)carbamoyl)- 5-(2-methoxypropan-2-yl)-1-methyl- 1H-pyrazole-3-sulfonamide 82 [00281] .sup.1H NMR (DMSO-d.sub.6) δ 11.05 (s, 1H), 7.83 (s, 1H), 6.92 (d, J = 9.9 Hz, 2H), 6.63 (s, 1H), 3.98 (s, 3H), 3.01 (sept, J = 6.9 Hz, 2H), 2.97 (s, 3H), 1.50 (s, 6H), 1.08−1.02 (br m, 12H). m/z 455 (M + H).sup.+ (ES.sup.+); 453 (M − H).sup.− (ES.sup.−). 454.56 N-((4-Fluoro-2,6-diisopropylphenyl) carbamoyl)-5-(2-methoxypropan-2-yl)- 1-methyl-1H-pyrazole-3-sulfonamide 83 [00282] .sup.1H NMR (DMSO-d.sub.6) δ 11.08 (s, 1H), 7.88 (s, 1H), 7.13 (s, 2H), 6.61 (s, 1H), 3.97 (s, 3H), 3.01 (sept, J = 6.9 Hz, 2H), 2.97 (s, 3H), 1.50 (s, 6H), 1.06 (br s, 12H). m/z 472 (M + H).sup.+ (ES.sup.+); 470 (M − H).sup.− (ES.sup.−). 471.01 N-((4-Chloro-2,6-diisopropylphenyl) carbamoyl)-5-(2-methoxypropan-2-yl)- 1-methyl-1H-pyrazole-3-sulfonamide 84 [00283] .sup.1H NMR (DMSO-d.sub.6) δ 7.93 (s, 1H), 6.91 (s, 1H), 6.60 (s, 1H), 5.42 (t, J = 5.6 Hz, 1H), 4.51 (d, J = 5.5 Hz, 2H), 3.85 (s, 3H), 2.79 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 1.95 (p, J = 7.4 Hz, 4H). One exchangeable proton not observed. m/z 391.3 (M + H).sup.+ (ES.sup.+); 389.3 (M − H).sup.− (ES.sup.−). 390.46 N-((1,2,3,5,6,7-Hexahydro-s-indacen-4- yl)carbamoyl)-5-(hydroxymethyl)-1- methyl-1H-pyrazole-3-sulfonamide 85 [00284] .sup.1H NMR (DMSO-d.sub.6) δ 10.92 (br s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.49 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.87 (dd, J = 8.0, 1.2 Hz, 1H), 6.81 (dd, J = 8.3, 1.2 Hz, 1H), 6.70 (d, J = 1.7 Hz, 1H), 4.95-4.87 (m, 1H), 4.60 (sept, J = 6.4 Hz, 1H), 3.87 (dd, J = 9.9, 4.8 Hz, 1H), 3.78-3.67 (m, 2H), 3.65 (d, J = 10.4 Hz, 1H), 2.94 (sept, J = 7.0 Hz, 1H), 2.18- 2.03 (m, 1H), 1.91-1.82 (m, 1H), 1.45 (d, J = 6.7 Hz, 6H), 1.05 (d, J = 6.9 Hz, 6H). m/z 437 (M + H).sup.+ (ES.sup.+); 435 (M − H).sup.− (ES.sup.−). 436.53 (R)-1-Isopropyl-N-((2-isopropyl-6- ((tetrahydrofuran-3-yl)oxy)phenyl) carbamoyl)-1H-pyrazole-3-sulfonamide 86 [00285] .sup.1H NMR (DMSO-d.sub.6) δ 10.92 (br s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.49 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.87 (dd, J = 8.0, 1.2 Hz, 1H), 6.81 (dd, J = 8.3, 1.2 Hz, 1H), 6.70 (d, J = 1.7 Hz, 1H), 4.95-4.87 (m, 1H), 4.60 (sept, J = 6.4 Hz, 1H), 3.87 (dd, J = 9.9, 4.8 Hz, 1H), 3.78-3.67 (m, 2H), 3.65 (d, J = 10.4 Hz, 1H), 2.94 (sept, J = 7.0 Hz, 1H), 2.18- 2.03 (m, 1H), 1.91-1.82 (m, 1H), 1.45 (d, J = 6.7 Hz, 6H), 1.05 (d, J = 6.9 Hz, 6H). m/z 437 (M + H).sup.+ (ES.sup.+); 435 (M − H).sup.− (ES.sup.−). 436.53 (S)-1-Isopropyl-N-((2-isopropyl-6- ((tetrahydrofuran-3-yl)oxy)phenyl) carbamoyl)-1H-pyrazole-3-sulfonamide 87 [00286] .sup.1H NMR (DMSO-d.sub.6) δ 7.55 (s, 1H), 6.79 (s, 1H), 4.51 (sept, J = 6.3 Hz, 1H), 2.76 (t, J = 7.4 Hz, 4H), 2.71 (t, J = 7.4 Hz, 4H), 1.92 (p, J = 7.4 Hz, 4H), 1.19 (d, J = 6.3 Hz, 6H). m/z 337.0 (M − H).sup.− (ES.sup.−). 338.42 Isopropyl (1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoylsulfamate, sodium salt 88 [00287] .sup.1H NMR (DMSO-d.sub.6) δ 8.13 (d, J = 5.3 Hz, 1H), 7.84 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.92 (dd, J = 5.3, 1.4 Hz, 1H), 6.74 (d, J = 1.4 Hz, 1H), 6.55 (t, J =5.4 Hz, 1H), 4.41 (d, J = 5.3 Hz, 2H), 3.86 (s, 3H), 2.92 (t, J = 7.4 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.00 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. m/z 366.2 (M + H).sup.+ (ES.sup.+); 364.4 (M − H).sup.− (ES.sup.−). 365.40 1((1H-Tetrazol-5-yl)methyl)-3-(5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)urea 89 [00288] .sup.1H NMR (DMSO-d.sub.6) δ 12.92 (br s, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.41-7.33 (m, 1H), 7.25 (s, 1H), 7.14 (dd, J = 8.0, 6.9 Hz, 1H), 5.32 (S, 2H), 1.36 (s, 6H). One exchangeable proton not observed. m/z 364.0 (M + H).sup.+ (ES.sup.+). 363.39 N-((4-(2-Hydroxypropan-2-yl)furan-2- yl)sulfonyl)-2-(1H-indazol-1- yl)acetamide 90 [00289] .sup.1H NMR (DMSO-d.sub.6) δ 7.81 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.67-7.62 (m, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.26 (s, 1H), 5.10 (s, 1H), 4.15 (s, 2H), 1.36 (s, 6H). One exchangeable proton not observed. m/z 387.1 (M + Na).sup.+ (ES.sup.+). 364.37 2-(Benzo[d]isoxazol-3-yl)-N-((4-(2- hydroxypropan-2-yl)furan-2- yl)sulfonyl)acetamide 91 [00290] m/z 464.2 (M + Na).sup.+ (ES.sup.+); 440.2 (M − H).sup.− (ES.sup.−); [R.sub.T = 1.44 min]. 441.03 2-(3-Chloro-5-(trifluoromethoxy) phenyl)-N-((4-(2-hydroxypropan-2- yl)furan-2-yl)sulfonyl)acetamide 92 [00291] m/z 448.2 (M + Na).sup.+ (ES.sup.+); 424.2 (M − H).sup.− (ES.sup.−); [R.sub.T = 1.41 min]. 425.81 2-(3-Chloro-5-(trifluoromethyl) phenyl)-N-((4-(2-hydroxypropan-2- yl)furan-2-yl)sulfonyl)acetamide 93 [00292] m/z 472.1 (M + Na).sup.+ (ES.sup.+); [R.sub.T = 1.33 min]. 416.29 N-((4-(2-Hydroxypropan-2-yl)furan-2- yl)sulfonyl)-2-(3-iodophenyl)acetamide 94 [00293] m/z 438.1/44 0.1 (M + Na).sup.+ (ES.sup.+); [R.sub.T = 1.33 min]. 416.29 2-(3-Bromo-5-methylphenyl)-N-((4-(2- hydroxypropan-2-yl)furan-2- yl)sulfonyl)acetamide 95 [00294] .sup.1H NMR (DMSO-d.sub.6) δ 11.29 (s, 1H), 8.21 (d, 5.2 Hz, 1H), 7.85 (d, J = 1.0 Hz, 1H), 7.25 (dd, J = 10.5, 2.8 Hz, 1H), 7.08 (d, J = 1.0 Hz, 1H), 6.93 (dd, J = 8.9, 2.8 Hz, 1H), 6.89 (dd, J = 5.2, 1.5 Hz, 1H), 6.72 (s, 1H), 3.87 (s, 3H), 3.33 (s, 2H), 3.06-2.98 (m, 1H), 1.19 (d, J = 6.7 Hz, 6H). 370.6 (M + H).sup.+ (ES.sup.+). 369.39 2-(4-Fluoro-2-isopropyl-6-(2- methoxypyridin-4-yl)phenyl)-N- (oxazol-2-yl)acetamide 96 [00295] .sup.1H NMR (MeOD-d.sub.4) δ 8.42 (br, s, 1H), 7.85-7.98 (m, 4H), 7.51-7.60 (m, 2H), 6.69 (d, 2H), 3.62 (s, 2H), 2.98- 3.15 (m, 2H), 1.12-0.88 (m, 12H). m/z 428.2 (M + H).sup.+ (ES.sup.+). 427.53 2-(4-Fluoro-2,6-diisopropylphenyl)-1- (2-naphthylsulfonylamino)-1-ethanone 97 [00296] .sup.1H NMR (DMSO-d.sub.6) δ 8.15 (d, J = 5.5 Hz, 1H), 7.44 (s, 1H), 7.04 (s, 1H), 6.70 (dd, J = 5.2, 1.4 Hz, 1H), 6.52 (s, 1H), 6.24 (t, J = 6.0 Hz, 1H), 5.06-4.98 (m, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.72 (d, J = 5.9 Hz, 2H), 2.88 (t, J = 7.4 Hz, 2H), 2.82-2.68 (m, 4H), 2.36-2.29 (m, 2H), 2.28 (s, 3H), 2.08-1.94 (m, 7H), 1.78- 1.68 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H). m/z 467.3 (M + H).sup.+ (ES.sup.+). 466.57 Ethyl 2-(3-(6-methyl-5-(2-((1- methylpiperidin-4-yl)oxy)pyridin-4-yl)- 2,3-dihydro-1H-inden-4- yl)ureido)acetate

Example 98

2-(3,5-bis(Trifluoromethyl)phenyl)-N-((4-(2-hydroxy-propan-2-yl)furan-2-yl)sulfonyl)acetamide

[1293] ##STR00297##

[1294] To a solution of 2-(3,5-bis(trifluoromethyl)phenyl)acetic acid (0.1 mmol) in DMF (0.33 mL) was added a solution of 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (0.021 g, 0.100 mmol), DMAP (0.024 g, 0.200 mmol) and EDC (0.038 g, 0.200 mmol) in DMF (1 mL). The resultant mixture was shaken in a 96-well plate at room temperature for 16 hours. The crude product was purified by reversed phase prep-HPLC method 4 to afford the title compound (0.9 mg, 2%) as a white solid.

[1295] LCMS m/z 482.2 (M+Na).sup.+ (ES.sup.+).

EXAMPLES

Biological Studies

[1296] NLRP3 and Pyroptosis

[1297] 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.

[1298] THP-1 Cells: Culture and Preparation

[1299] 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.

[1300] THP-1 Cells Pyroptosis Assay

[1301] The following method step-by-step assay was followed for compound screening. [1302] 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 μg/ml LPS in 400 of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) [1303] 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 [1304] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1305] 4. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells [1306] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1307] 6. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant [1308] 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 [1309] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [1310] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[1311] 96-Well Plate Map

TABLE-US-00002 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) Low Drug free control Compound 8-point half-log dilution

[1312] The results of the pyroptosis assay performed are summarised in Table 2 below as THP IC.sub.50.

[1313] Human Whole Blood IL-1β Release Assay

[1314] 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.

[1315] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [1316] 1. Nate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [1317] 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 [1318] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1319] 4. Add 10 μl nigericin (Sigma #N7143) (10 μM FAC) to all wells [1320] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1321] 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) [1322] 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [1323] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[1324] The results of the human whole blood assay are summarised in Table 2 below as HWB IC.sub.50.

TABLE-US-00003 TABLE 2 NLRP3 inhibitory activity (≤0.25 μM = ‘++++++’, ≤0.5 μM = ‘+++++’, ≤1 μM = ‘++++’, ≤5 μM = ‘+++’, ≤10 μM = ‘++’, >10 μM = ‘+’, not determined = ‘ND’). Example No THP IC.sub.50 HWB IC.sub.50 1 ++ ND 2 +++++ + 3 +++ + 4 ++ ND 5 ++ ND 6 +++ ++ 7 ++ ND 8 ++++ +++ 9 ++ ND 10 ++ ND 11 ++ ND 12 ++++++ ++++ 13 +++ + 14 ++++ ++ 15 +++ + 16 ++++++ ++ 17 +++++ +++ 18 +++ ND 19 +++++ ++++ 20 ++++++ +++ 21 ++ ++ 22 ++++++ +++ 23 +++ ND 24 +++ + 25 ++ ND 26 +++ ND 27 +++ ND 28 +++ ++ 29 ++ ND 30 +++ ND 31 +++ ++ 32 +++ ND 33 +++ +++ 34 +++++ ++ 35 ++++++ ++ 36 ++++++ ++ 37 +++++ ND 38 ++++++ ND 39 ++++++ ++++ 40 +++++ +++ 41 +++++ ++ 42 ++++++ +++ 43 +++++ ND 44 ++++++ ND 45 ++++++ +++ 46 +++++ ++++ 47 ++++++ +++ 48 ++++++ +++ 49 ++++++ ++++ 50 +++++ ND 51 ++++++ +++++ 52 ++++++ ++++ 53 ++++++ ++++ 54 ++++++ ++++ 55 ++++++ ++++ 56 ++++++ +++++ 57 ++++++ +++ 58 ++++++ +++ 59 ++++++ +++ 60 ++++++ ++++++ 61 ++++++ ++++ 62 ++++++ + 63 ++++++ +++ 64 +++ ND 65 ++++++ +++++ 66 ++++++ +++++ 67 ++++++ +++ 68 +++ ND 69 ++++ +++ 70 ++ ND 71 ++++ +++ 72 +++ ++ 73 ++ ND 74 ++++ ND 75 +++ ND 76 ++ ND 77 +++ ++ 78 +++ ND 79 ++++ ND 80 ++++ ND 81 +++++ +++++ 82 +++++ ++++ 83 ++++++ +++ 84 +++++ ++++ 85 ++ ND 86 +++ ND 87 +++ ND 88 ++ ND 89 +++ ND 90 +++ ND 91 +++ ND 92 ++ ND 93 ++ ND 94 +++ ND 95 ++ ND 96 +++ ND 97 +++ ND 98 +++ ND

[1325] PK Protocol

[1326] Pharmacokinetic parameters were determined in male Sprague Dawley rats (Charles River, UK, 250-300 g; or Vital River Laboratory Animal Technology Co Ltd, Beijing, China, 7-9 weeks old). Animals were individually housed during the study and maintained under a 12 h light/dark cycle. Animals had free access to food and water, except that orally dosed animals were food deprived overnight prior to the study.

[1327] For intravenous administration, compounds were formulated as a solution in DMSO:PBS [10:90] in 2 mL/kg dosing volume and administered via tail vein. For oral administration, compounds were formulated as a solution in DMSO:water [10:90] in 5 mL/kg dosing volume and administered orally.

[1328] Serial blood samples (about 200-230 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). 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) 51 1 4871.9 1.0 0.29 3.4 20 1 21569.6 4.7 0.25 0.8 46 1 10016.4 4.0 0.45 1.7 83 1 1127.4 3.9 2.23 14.8 39 3 3840.2 4.0 0.9 13.1

TABLE-US-00005 TABLE 4 PK data (oral administration) (ND = not determined) Ex- AUC Cl/F Bioavail- ample 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) (%) 45 3 7901.1 61633.7 2 2.5 0.8 ND 83 1.3 467.9 2751.2 3.17 3.7 8.5 >100 39 3 1368.3 3921.2 0.83 2.2 13.0 >100

[1329] 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.

[1330] 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.

[1331] 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.