NOVEL SULFONAMIDE CARBOXAMIDE COMPOUNDS

Abstract

The present invention relates to sulfonylureas and sulfonylthioureas comprising a 5-membered heteroaryl group substituted with an amide-containing group. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP.sub.3.

Claims

1. A compound of formula (I): ##STR00233## Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is selected from O or S; R.sup.1 is a 5-membered heteroaryl group substituted with at least one group R.sup.X, wherein R.sup.X is any group comprising an amide group, wherein the 5-membered heteroaryl group may optionally be further substituted; and R.sup.2 is a cyclic group substituted at the α-position, wherein R.sup.2 may optionally be further substituted; provided that the compound is not: ##STR00234## ##STR00235## ##STR00236## ##STR00237##

2. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein R.sup.X is monovalent, and optionally wherein —R.sup.X is any saturated 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 with one or more groups selected from halo, —CN, —OH, —NH.sub.2, oxo (═O) and ═NH, wherein the hydrocarbyl group includes at least one amide group in its carbon skeleton, and wherein the hydrocarbyl group may optionally include one, two or three further heteroatoms N and/or O in its carbon skeleton.

3. (canceled)

4. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein the 5-membered heteroaryl group of R.sup.1 is monocyclic.

5. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein R.sup.X is divalent, and optionally wherein —R.sup.X— is any saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbylene group may optionally be substituted with one or more groups selected from halo, —CN, —OH, —NH.sub.2, oxo (═O) and ═NH, wherein the hydrocarbylene group includes at least one amide group in its carbon skeleton, and wherein the hydrocarbylene group may optionally include one or more further heteroatoms N, O or S in its carbon skeleton.

6. (canceled)

7. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein R.sup.X contains only atoms selected from the group consisting of carbon, hydrogen, nitrogen, oxygen and halogen atoms.

8. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein: (i) R.sup.X contains from 4 to 11 atoms other than hydrogen or halogen; and/or (ii) R.sup.1 contains from 9 to 16 atoms other than hydrogen or halogen.

9. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein (i) the 5-membered heteroaryl group of R.sup.1 contains at least one nitrogen or sulfur atom in the 5-membered ring structure; or (ii) the 5-membered heteroaryl group of R.sup.1 contains at least one nitrogen atom in the 5-membered ring structure; or (iii) the 5-membered heteroaryl group of R.sup.1 contains only carbon and nitrogen atoms in the 5-membered ring structure.

10-12. (canceled)

13. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein (i) Q is O; and/or (ii) the 5-membered heteroaryl group of R.sup.1 is further substituted with one, two or three substituents independently selected from halo; —CN; —NO.sub.2; —N.sub.3; —R.sup.β; —OH; —OR.sup.β; —R.sup.α-halo; —R.sup.α—CN; —R.sup.α—NO.sub.2; —R.sup.α—N.sub.3; —R.sup.α—R.sup.β; —R.sup.α—OH; —R.sup.α—OR; —SH; —SR.sup.β; —SOR.sup.β; —SO.sub.2H; —SO.sub.2R.sup.β; —SO.sub.2NH.sub.2; —SO.sub.2NHR.sup.β; —SO.sub.2N(R.sup.β).sub.2; —R α-SH; —R.sup.α—SR.sup.β; —R.sup.α—SOR.sup.β; —R.sup.α—SO.sub.2H; —R.sup.α—SO.sub.2R.sup.β; —R.sup.α—SO.sub.2NH.sub.2; —R.sup.α—SO.sub.2NHR.sup.β; —R.sup.α—SO.sub.2 N(R.sup.β).sub.2; —NH.sub.2; —NHR.sup.β; —N(R.sup.β).sub.2; —R.sup.α—NH.sub.2; —R.sup.α—NHR.sup.β; —R.sup.α—N(R.sup.β).sub.2; —CHO; —CORP; —COOH; —COOR.sup.β; —OCOR.sup.β; —R.sup.α—CHO; —R.sup.α—COR.sup.β; —R.sup.α—COOH; —R.sup.α—COOR.sup.β; or —R.sup.α—OCOR.sup.β; wherein each —R.sup.α— is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its backbone, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group may optionally be replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo and/or —R groups; and wherein each —R.sup.β is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group, and wherein any —R.sup.β may optionally be substituted with one or more C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl, —O(C.sub.1-C.sub.4 alkyl), —O(C.sub.1-C.sub.4 haloalkyl), —O(C.sub.3-C.sub.7 cycloalkyl), halo, —OH, —NH.sub.2, —CN, —C≡CH, oxo (═O), or 4- to 6-membered heterocyclic group.

14. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein R.sup.2 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the α-position, and wherein R.sup.2 may optionally be further substituted, and optionally wherein: (i) R.sup.2 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the α and α′ positions, and wherein R.sup.2 may optionally be further substituted; or (ii) R.sup.2 is a fused aryl or a fused heteroaryl group, wherein a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α,β positions and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α′,β′ positions, and wherein R.sup.2 may optionally be further substituted.

15-16. (canceled)

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

18. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein R.sup.2 is a cyclic group substituted at the α and α′ positions, wherein R.sup.2 may optionally be further substituted, and wherein optionally each substituent at the α and α′ positions comprises a carbon atom.

19-20. (canceled)

21. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein the compound is selected from the group consisting of: ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258##

22. (canceled)

23. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, and a pharmaceutically acceptable excipient, optionally wherein the pharmaceutical composition is a topical pharmaceutical composition.

24. (canceled)

25. 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 a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, to the subject, thereby treating or preventing the disease, disorder or condition, optionally wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

26. (canceled)

27. The method as claimed in claim 25, wherein the disease, disorder or condition is selected from: (i) inflammation; (ii) an auto-immune disease; (iii) cancer; (iv) an infection; (v) a central nervous system disease; (vi) a metabolic disease; (vii) a cardiovascular disease; (viii) a respiratory disease; (ix) a liver disease; (x) a renal disease; (xi) an ocular disease; (xii) a skin disease; (xiii) a lymphatic condition; (xiv) a psychological disorder; (xv) graft versus host disease; (xvi) allodynia; and (xvii) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

28. The method as claimed in claim 27, wherein the disease, disorder or condition is selected from: (i) a cardiovascular disease; (ii) a liver disease; (iii) a renal disease; (iv) a psychological disorder; (v) a lymphatic condition; and/or (vi) any disease, disorder or condition in which an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

29. The method as claimed in claim 25, 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).

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

31. 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 a 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.

32. The method as claimed in claim 25, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

Description

EXAMPLES—COMPOUND SYNTHESIS

[0605] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0606] 2-MeTHF 2-methyltetrahydrofuran [0607] Ac.sub.2O acetic anhydride [0608] AcOH acetic acid [0609] aq aqueous [0610] Boc tert-butyloxycarbonyl [0611] br broad [0612] Cbz carboxybenzyl [0613] CDI 1,1-carbonyl-diimidazole [0614] conc concentrated [0615] d doublet [0616] DABCO 1,4-diazabicyclo[2.2.2]octane [0617] DCE 1,2-dichloroethane, also called ethylene dichloride [0618] DCM dichloromethane [0619] DIPEA N,N-diisopropylethylamine, also called Hünig's base [0620] DMA dimethylacetamide [0621] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0622] DME dimethoxyethane [0623] DMF N,N-dimethylformamide [0624] DMSO dimethyl sulfoxide [0625] eq or equiv equivalent [0626] (ES+) electrospray ionization, positive mode [0627] Et ethyl [0628] EtOAc ethyl acetate [0629] EtOH ethanol [0630] h hour(s) [0631] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0632] HPLC high performance liquid chromatography [0633] LC liquid chromatography [0634] m multiplet [0635] m-CPBA 3-chloroperoxybenzoic acid [0636] Me methyl [0637] MeCN acetonitrile [0638] MeOH methanol [0639] (M+H)+protonated molecular ion [0640] MHz megahertz [0641] min minute(s) [0642] MS mass spectrometry [0643] Ms mesyl, also called methanesulfonyl [0644] MsCl mesyl chloride, also called methanesulfonyl chloride [0645] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0646] m/z mass-to-charge ratio [0647] NaO.sup.tBu sodium tert-butoxide [0648] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0649] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0650] NMP N-methylpyrrolidine [0651] NMR nuclear magnetic resonance (spectroscopy) [0652] Pd(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o) [0653] Pd(dppf)Cl.sub.2 [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [0654] PE petroleum ether [0655] Ph phenyl [0656] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0657] prep-HPLC preparative high performance liquid chromatography [0658] prep-TLC preparative thin layer chromatography [0659] PTSA p-toluenesulfonic acid [0660] q quartet [0661] RP reversed phase [0662] RT room temperature [0663] s singlet [0664] Sept septuplet [0665] sat saturated [0666] SCX solid supported cation exchange (resin) [0667] t triplet [0668] T3P propylphosphonic anhydride [0669] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0670] TEA triethylamine [0671] TFA 2,2,2-trifluoroacetic acid [0672] THF tetrahydrofuran [0673] TLC thin layer chromatography [0674] wt % weight percent or percent by weight

Experimental Methods

[0675] Nuclear Magnetic Resonance

[0676] 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: [0677] a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe, [0678] a Bruker 400 MHz spectrometers using ICON-NMR, under TopSpin program control, [0679] a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™, [0680] 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 [0681] an Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

[0682] LC-MS

[0683] 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.3HO in water (v/v); B: acetonitrile. Column: Kinetex EVO C18 2.1×30 mm, 5 μm.

[0684] Reversed Phase HPLC Conditions for the LCMS Analytical Methods

[0685] 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.

[0686] 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.

[0687] Reversed Phase HPLC Conditions for the UPLC Analytical Methods

[0688] Methods 2a and 2b: Waters BEH C18 (2.1×30 mm, 1.7 μm) at 40° C.; flow rate 0.77 mL min.sup.−1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 2a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 2b) over 3 min employing UV detection at 254 nm. Gradient information: 0.11 min, held at 95% water-5% acetonitrile, flow rate 0.77 mL min.sup.−1; 0.11-2.15 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 2.15-2.49 min, held at 5% water-95% acetonitrile, flow rate 0.77 mL min.sup.−1; 2.49-2.56 min, returned to 95% water-5% acetonitrile; 2.56-3.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 0.77 mL min.sup.−1.

[0689] Preparative Reversed Phase HPLC General Methods

[0690] Method 1 (acidic preparation): Waters X-Select CSH column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a H.sub.2O-MeCN gradient containing 0.1% v/v formic acid over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 20% MeCN; 0.2-5.5 min, ramped from 20% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0691] Method 2 (basic preparation): Waters X-Bridge Prep column C18.5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 10% MeCN; 0.2-5.5 min, ramped from 10% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0692] Method 3: Phenomenex Gemini column, 10 m (150×25 mm), flow rate=25 mL/min eluting with a water-acetonitrile gradient containing 0.04% NH.sub.3 at pH 10 over 9 minutes using UV detection at 220 and 254 nm. Gradient information: 0-9 minutes, ramped from 8% to 35% acetonitrile; 9-9.2 minutes, ramped from 35% to 100% acetonitrile; 9.2-15.2 minutes, held at 100% acetonitrile.

[0693] Method 4: Revelis C18 reversed-phase 12 g cartridge [carbon loading 18%; surface area 568 m.sup.2/g; pore diameter 65 Angstrom; pH (5% slurry) 5.1; average particle size 40 μm], flow rate=30 mL/min eluting with a water-methanol gradient over 35 minutes using UV detection at 215, 235, 254 and 280 nm. Gradient information: 0-5 minutes, held at 0% methanol; 5-30 minutes, ramped from 0% to 70% methanol; 30-30.1 minutes, ramped from 70% to 100% methanol; 30.1-35 minutes, held at 100% methanol.

Synthesis of Intermediates

Intermediate P1: N,N-Dimethyl-2-(3-sulfamoyl-1H-pyrazol-1-yl)acetamide

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

[0694] ##STR00065##

[0695] A solution of BuLi (100 mL, 250 mmol, 2.5M 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 allowed to warm to room temperature, the solvent evaporated and the residue triturated with TBME (300 mL) and filtered. The solid was washed with TBME and isohexane and dried to afford the crude title compound (54.89 g, 99%).

[0696] .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).

[0697] 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

[0698] ##STR00066##

[0699] 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), filtered and evaporated to ˜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 then partitioned between DCM (300 mL) and water (250 mL). The organic layer was washed with water (250 mL), aq 1M HCl (2×250 mL), water (250 mL), dried (MgSO.sub.4), filtered, and evaporated to afford the crude title compound (41.02 g, 97%) as a brown oil.

[0700] LCMS; m/z 494.2 (M+Na).sup.+ (ES.sup.+).

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

[0701] ##STR00067##

[0702] A mixture of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (41 g, 87 mmol) and aq 1M 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 1M HCl (200 mL). The organic layer was washed with 10% brine (200 mL), dried (MgSO.sub.4), filtered and evaporated. The residue was triturated with TBME, filtered and dried to afford the title compound (24.87 g, 69%) as an off white solid.

[0703] .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). Exchangeable proton not visible.

[0704] LCMS; m/z 388 (M+H).sup.+ (ES.sup.+); 386 (M−H).sup.− (ES.sup.−).

Step D: 2-(3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-H-pyrazol-1-yl)-N,N-dimethylacetamide

[0705] ##STR00068##

[0706] Under nitrogen, a mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (500 mg, 1.290 mmol) and K.sub.2CO.sub.3 (350 mg, 2.53 mmol) was suspended in dry acetonitrile (1 mL). 2-Chloro-N,N-dimethylacetamide (0.133 mL, 1.290 mmol) was added in a single portion and the cloudy mixture was heated to 65° C. (bath temperature) for 3 hours. The mixture was diluted with water (5 mL) and extracted with DCM (3×25 mL). The organic phase was dried by passing through a hydrophobic frit 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 (420 mg, 65%) as a pale yellow oil.

[0707] .sup.1H NMR (CDCl.sub.3) δ 7.65 (d, J=2.4 Hz, 1H), 7.09-6.99 (m, 4H), 6.85-6.76 (m, 4H), 6.72 (d, J=2.4 Hz, 1H), 5.08 (s, 2H), 4.32 (s, 4H), 3.80 (s, 6H), 3.10 (s, 3H), 3.04 (s, 3H). LCMS; m/z 473 (M+H).sup.+ (ES.sup.+).

Step E: N,N-Dimethyl-2-(3-sulfamoyl-1H-pyrazol-1-yl)acetamide

[0708] ##STR00069##

[0709] 2-(3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide (440 mg, 0.931 mmol) was dissolved in DCM (1 mL) and water (0.5 mL) and TFA (2 mL, 26.0 mmol) added. The reaction mixture was stirred at room temperature for 15 hours. The mixture was concentrated in vacuo and the crude product purified by chromatography (Companion apparatus, RP Flash C18, 12 g column, 0-10% acetonitrile/10 mM ammonium bicarbonate) to afford the title compound (195 mg, 88%) as a white solid.

[0710] .sup.1H NMR (DMSO-d.sub.6) δ 7.76 (d, J=2.4 Hz, 1H), 7.35 (s, 2H), 6.59 (d, J=2.4 Hz, 1H), 5.20 (s, 2H), 3.04 (s, 3H), 2.86 (s, 3H).

Intermediate P2: N-Methyl-2-(3-sulfamoyl-1H-pyrazol-1-yl)acetamide

Step A: 2-(3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-H-pyrazol-1-yl)-N-methylacetamide

[0711] ##STR00070##

[0712] Prepared according to the general procedure of 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-chloro-N-methylacetamide to afford the title compound (449 mg, 72%) as a colourless solid.

[0713] .sup.1H NMR (CDCl.sub.3) δ 7.54 (d, J=2.4 Hz, 1H), 7.09-7.02 (m, 4H), 6.81-6.76 (m, 4H), 6.71 (d, J=2.4 Hz, 1H), 5.91 (s, 1H), 4.83 (s, 2H), 4.32 (s, 4H), 3.79 (s, 6H), 2.75 (d, J=4.6 Hz, 3H).

[0714] LCMS; m/z 480 (M+Na).sup.+ (ES.sup.+), 457 (M−H).sup.+ (ES.sup.−).

Step B: N-Methyl-2-(3-sulfamoyl-1H-pyrazol-1-yl)acetamide

[0715] ##STR00071##

[0716] Prepared according to the general procedure of N,N-dimethyl-2-(3-sulfamoyl-1H-pyrazol-1-yl)acetamide (Intermediate P1, Step E) from 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-N-methylacetamide to afford the title compound (146 mg, 70%) as a colourless crystalline solid.

[0717] .sup.1H NMR (DMSO-d.sub.6) δ 8.22-8.11 (br s, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.41 (s, 2H), 6.59 (d, J=2.4 Hz, 1H), 4.85 (s, 2H), 2.64 (d, J=4.6 Hz, 3H).

Intermediate P3: 1-(1-Acetylazetidin-3-yl)-1H-pyrazole-3-sulfonamide

Step A: tert-Butyl 3-(3-nitro-H-pyrazol-1-yl)azetidine-1-carboxylate

[0718] ##STR00072##

[0719] Under nitrogen, a mixture of 3-nitro-1H-pyrazole (3 g, 26.5 mmol) and K.sub.2CO.sub.3 (11.00 g, 80 mmol) was suspended in dry DMF (75 mL). tert-Butyl 3-iodoazetidine-1-carboxylate (5.52 mL, 31.8 mmol) was added in a single portion and the cloudy mixture was heated to 100° C. for 4 hours. The mixture was diluted with water (5 mL) and extracted with DCM (3×50 mL). The organic phase was dried by passing through a hydrophobic frit 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 (5.3 g, 74%) as a colourless solid.

[0720] .sup.1H NMR (DMSO-d.sub.6) δ 8.20 (d, J=2.6 Hz, 1H), 7.11 (d, J=2.6 Hz, 1H), 5.43-5.28 (m, 1H), 4.35 (t, J=8.6 Hz, 2H), 4.22-4.03 (m, 2H), 1.42 (s, 9H).

[0721] LCMS; m/z 269 (M+H).sup.+ (ES.sup.+).

Step B: 1-(Azetidin-3-yl)-3-nitro-1H-pyrazole, HCl

[0722] ##STR00073##

[0723] 4M Hydrogen chloride in dioxane (24.70 mL, 99 mmol) was added to a solution of tert-butyl 3-(3-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (5-3 g, 19.76 mmol) in 1,4-dioxane (20 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated to afford the title compound (4.1 g, 96%) as an off-white solid. LCMS; m/z 169 (M+H).sup.+ (ES.sup.+).

Step C: 1-(3-(3-Nitro-1H-pyrazol-1-yl)azetidin-1-yl)ethanone

[0724] ##STR00074##

[0725] A suspension of 1-(azetidin-3-yl)-3-nitro-1H-pyrazole hydrochloride (2.59 g, 12.66 mmol) in DCM (36 mL) was treated with triethylamine (5.26 mL, 38.0 mmol) and stirred at room temperature for 10 minutes. The mixture was then cooled on ice to 0° C. and acetyl chloride (1.084 mL, 15.19 mmol) was added dropwise at 0° C. The reaction mixture was stirred for 10 minutes at 0° C., then the reaction mixture was left to warm to room temperature with stirring over 18 hours. The solvent was removed under reduced pressure and the residue was suspended in acetonitrile and then filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g column, 0-20% MeOH/DCM) to afford the title compound (1.02 g, 35%) as a yellow solid.

[0726] .sup.1H NMR (DMSO-d.sub.6) δ 8.22 (d, J=2.6 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 5.46-5.34 (m, 1H), 4.66-4.56 (m, 1H), 4.46-4.37 (m, 1H), 4.36-4.27 (m, 1H), 4.11 (dd, J=10.3, 5.2 Hz, 1H), 1.83 (s, 3H).

[0727] LCMS; m/z 211 (M+H).sup.+ (ES.sup.+).

Step D: 1-(3-(3-Amino-1H-pyrazol-1-yl)azetidin-1-yl)ethanone

[0728] ##STR00075##

[0729] 1-(3-(3-Nitro-1H-pyrazol-1-yl)azetidin-1-yl)ethanone (1.02 g, 4.46 mmol) and 10% palladium on carbon (wet Type 87 L) (0.024 g) were suspended in MeOH (10 mL) and EtOAc (10 mL). The reaction mixture was stirred at room temperature under 2 bar of H.sub.2 for 17 hours. The reaction mixture was filtered through a pad of Celite® and the filter cake was washed with EtOAc (2×10 mL). The filtrate was concentrated to dryness to give the title compound (0.95 g, 92%) as a viscous yellow oil.

[0730] .sup.1H NMR (DMSO-d.sub.6) δ 7.42 (d, J=2.3 Hz, 1H), 5.41 (d, J=2.3 Hz, 1H), 4.94 (ddd, J=8.0, 5.3, 2.7 Hz, 1H), 4.80 (s, 2H), 4.43 (ddd, J=9.0, 8.0, 1.1 Hz, 1H), 4.29 (dd, J=8.6, 5.4 Hz, 1H), 4.15 (ddd, J=9.4, 8.1, 1.1 Hz, 1H), 4.07-3.93 (m, 1H), 1.78 (s, 3H).

[0731] LCMS; m/z 181 (M+H).sup.+ (ES.sup.+).

Step E: 1-(1-Acetylazetidin-3-yl)-1H-pyrazole-3-sulfonyl Chloride

[0732] ##STR00076##

[0733] A mixture of concentrated HCl (1.5 mL) in water (1 mL) and acetonitrile (5.0 mL) was cooled to −10° C. and treated with a solution of sodium nitrite (0.338 g, 4.90 mmol) in water (0.6 mL) dropwise maintaining the internal temperature below 0° C. The solution was stirred for 10 minutes and then treated with a solution of 1-(3-(3-amino-1H-pyrazol-1-yl)azetidin-1-yl)ethanone (0.95 g, 4.09 mmol) in acetonitrile (5.1 mL) (which was pre-cooled to 0° C.) at 0° C. The resulting reaction mixture was stirred at 0° C. for 50 minutes. Cold AcOH (2 mL), CuCl.sub.2.2H.sub.2O (0.275 g, 2.043 mmol) and CuCl (0.02 g, 0.204 mmol) were sequentially added to the reaction mixture and the reaction mixture was purged with SO.sub.2 gas for 20 minutes at 0° C. The reaction was stirred for a further 45 minutes, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The organic phase was washed with water (25 mL) and saturated brine (25 mL), dried over Na.sub.2SO.sub.4 filtered and concentrated in vacuo to afford a brown oil. The crude product was purified by chromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford the title compound (528 mg, 32%) as a yellow oil.

[0734] .sup.1H NMR (CDCl.sub.3 δ 7.69 (d, J=2.5 Hz, 1H), 6.96 (d, J=2.5 Hz, 1H), 5.25 (p, J=6.7 Hz, 1H), 4.74-4.27 (m, 4H), 1.96 (s, 3H).

Step F: 1-(1-Acetylazetidin-3-yl)-1H-pyrazole-3-sulfonamide

[0735] ##STR00077##

[0736] 1-(1-Acetylazetidin-3-yl)-1H-pyrazole-3-sulfonyl chloride (0.52 g, 1.301 mmol) in THF (8 mL) was treated with 0.5 M ammonia in dioxane (7.8 mL, 3.90 mmol) and the reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated and the crude product was purified by chromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford the title compound (136 mg, 42%) as a white powder.

[0737] .sup.1H NMR (DMSO-d.sub.6) δ 8.06 (d, J=2.4 Hz, 1H), 7.50 (s, 2H), 6.64 (d, J=2.4 Hz, 1H), 5.34 (ddd, J=8.1, 5.3, 2.9 Hz, 1H), 4.75-4.43 (m, 1H), 4.50-4.12 (m, 2H), 4.09 (dd, J=10.0, 5.3 Hz, 1H), 1.82 (s, 3H).

[0738] LCMS; m/z 245 (M+H).sup.+ (ES.sup.+).

Intermediate P4: 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide

Step A: 2-Amino-5-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0739] ##STR00078##

[0740] Zinc (167 mg, 2.55 mmol) was added portionwise to 5-methyl-2-nitro-6,7-dihydropyrazolo [1,5-a]pyrazin-4(5H)-one (1.4 g, 7.14 mmol) in AcOH (1.0 mL) and THF (1.5 mL). The reaction mixture was left to stir at room temperature for 2 days. The reaction mixture was filtered through a pad of Celite®, washed with DCM (2×15 mL) and the filtrate concentrated under reduced pressure to give a yellow solid. The solid was suspended in DCM (5 mL), filtered and the filtrate was evaporated to dryness to give the title compound (2.2 g, 74%) as a yellow solid.

[0741] .sup.1H NMR (DMSO-d.sub.6) δ 5.80 (s, 1H), 4.83 (s, 2H), 4.10-3.93 (m, 2H), 3.72-3.55 (m, 2H), 2.97 (s, 3H).

[0742] LCMS; m/z 167 (M+H).sup.+ (ES.sup.+).

Step B: 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonyl Chloride

[0743] ##STR00079##

[0744] A mixture of aqueous HCl (2.2 mL) in water (8 mL) and acetonitrile (8 mL) was cooled to −10° C. and treated with a solution of NaNO.sub.2 (0.50 g, 7.25 mmol) in water (0.9 mL) dropwise maintaining the internal temperature below 0° C. The solution was stirred for 10 minutes and then treated with a solution of 2-amino-5-methyl-6,7-dihydropyrazolo [1,5-a]pyrazin-4(5H)-one (0.997 g, 6 mmol) in acetonitrile (8 mL) (which was pre-cooled to 0° C.) at 0° C. The resulting reaction mixture was stirred at 0° C. for 50 minutes. Cold AcOH (4.8 mL), CuCl.sub.2 dihydrate (0.30 g, 2.23 mmol) and CuCl (0.03 g, 0.30 mmol) were sequentially added to the reaction mixture and the reaction mixture was purged with SO.sub.2 gas for 20 minutes at 0° C. The reaction was stirred for a further 45 minutes, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The organic phase was washed with water (25 mL) and saturated brine (25 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford a brown oil. The brown oil was purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (577 mg, 30%) as a yellow crystalline solid.

[0745] .sup.1H NMR (CDCl.sub.3) δ 7.39 (s, 1H), 4.63-4.45 (m, 2H), 3.95-3.83 (m, 2H), 3.19 (s, 3H).

Step C: 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide

[0746] ##STR00080##

[0747] 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonylchloride (577 mg, 1.826 mmol) in THF (4 mL) was treated with 0.5 M ammonia in 1,4-dioxane (11.00 mL, 5.50 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated to dryness. The residue was suspended in water (10 mL) and filtered. The yellow powder obtained was then washed with DCM (2×5 mL) and dried under vacuum to afford the title compound (332 mg, 77%) as a white powder.

[0748] .sup.1H NMR (DMSO-d.sub.6) δ 7.57 (s, 2H), 6.93 (s, 1H), 4.59-4.34 (m, 2H), 3.90-3.71 (m, 2H), 3.01 (s, 3H).

[0749] LCMS; m/z 231 (M+H).sup.+ (ES.sup.+).

Intermediate P5: N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

Step A: 1-Methyl-3-sulfamoyl-1H-pyrazole-5-carboxylic Acid, Sodium Salt

[0750] ##STR00081##

[0751] To a suspension of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (3 g, 12.86 mmol) in ethanol (60 mL) was added a solution of sodium hydroxide (2.0 M, 13.5 mL) and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was filtered off, washed with ethanol and dried to afford the title compound (2.92 g, 99%) as a white solid.

[0752] .sup.1H NMR (D.sub.2O) δ 6.79 (s, 1H) and 4.01 (s, 3H).

Step B: N,N,1-Trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide

[0753] ##STR00082##

[0754] To a mixture of 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylic acid, sodium salt (2.38 g, 10.48 mmol) was added T3P (50% in ethyl acetate, 12.47 ml, 20.95 mmol) and N,N-diisopropylethylamine (Hunig's Base, 3.66 ml, 20.95 mmol) in tetrahydrofuran (50 mL). A solution of 2.0 M dimethylamine in THF (15.71 ml, 31.4 mmol) was added and the reaction stirred for 20 hours before being quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (3×20 ml). The combined extracts were dried (magnesium sulfate), filtered and evaporated in vacuo to afford a yellow gum. The crude product was triturated in dichloromethane (20 mL) and filtered to obtain the title compound (900 mg) as a white solid. The mother layers were evaporated, dissolved in dichloromethane/methanol and purified by chromatography (Companion apparatus, 40 g column, 0-10% methanol/dichloromethane with product eluting at ˜5% methanol) to afford a further batch of the title compound (457 mg) as a white solid. The solids were combined to afford the title compound (1.36 g, 55%).

[0755] .sup.1H NMR (DMSO-d.sub.6) δ 7.50 (s, 2H), 6.82 (s, 1H), 3.90 (s, 3H), 3.03 (s, 3H) and 3.01 (s, 3H).

[0756] LCMS m/z 233.0 (M+H).sup.+ (ES.sup.+).

Intermediate P6: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid

[0757] ##STR00083##

[0758] Triphosgene (170 mg, 0.573 mmol) was added to a mixture of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (165 mg, 0.952 mmol) and triethylamine (0.36 mL, 2.58 mmol) in THF (8 mL) and stirred for 15 hours. The reaction mixture was evaporated in vacuo and azeotroped with toluene (3×1 mL). THF (8 mL) was added and the reaction mixture was filtered. The filtrate was added to a mixture of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (200 mg, 0.857 mmol) and sodium hydride (86 mg, 2.150 mmol) in THF (8 mL) and stirred for 20 hours. The reaction was quenched with aqueous Na.sub.2CO.sub.3 (3.5 mL, 1.295 mmol), and evaporated in vacuo to remove the THF. The residual aqueous was washed with MTBE (2×5 mL). The solid that precipitated from the aqueous was filtered off and dried to afford ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium (100 mg) as a solid. The filtrate was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (180 mg) as a white solid. The solids were combined and dissolved in MeOH (3 mL). Aq. NaOH (0.25 mL, 0.500 mmol) was added and the reaction mixture was stirred for 20 hours. The MeOH was evaporated in vacuo. The remaining aqueous was adjusted to pH 8 with NaH.sub.2PO.sub.4 and purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (140 mg, 39%) as a white solid.

[0759] .sup.1H NMR (DMSO-d.sub.6) δ 7.65 (s, 2H), 6.31 (s, 1H), 6.15 (s, 1H), 3.41 (s, 3H), 2.05 (t, J=7.4 Hz, 4H), 1.90 (t, J=7.3 Hz, 4H), 1.24 (quin, J=7.4 Hz, 4H). One exchangeable proton not observed.

[0760] LCMS; m/z 405.0 (M+H).sup.+ (ES.sup.+).

Intermediate P7: 1-Methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide

[0761] ##STR00084##

[0762] Prepared according to the general procedure for N,N,1-trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P5, Step B) from 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylic acid, sodium salt (Intermediate P5, Step A) and pyrrolidine to afford the title compound (204 mg, 54%) as a cream solid.

[0763] LCMS; m/z 259.3 (M+H).sup.+ (ES.sup.+).

Intermediate P8: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt

Step A: Ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, Sodium Salt

[0764] ##STR00085##

[0765] 2 M Sodium tert-butoxide in THF (1.005 mL, 2.009 mmol) was added to a solution of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (0.5 g, 1.914 mmol) in THF (15 mL) and stirred at room temperature for 1 hour to give a white suspension. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.419 g, 2.105 mmol) in THF (5 mL) was added and stirred at room temperature overnight. The resultant colourless precipitate was collected by filtration, washing with THF (4 mL), and dried in vacuo to afford the title compound (930 mg, 91%) as a colourless solid. .sup.1H NMR (DMSO-d.sub.6) δ 7.51 (s, 1H), 6.96 (s, 1H), 6.77 (s, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 2.74 (t, J=7.4 Hz, 4H), 2.66 (t, J=7.3 Hz, 4H), 1.90 (p, J=7.4 Hz, 4H), 1.30 (t, J=7.1 Hz, 3H).

[0766] LCMS; m/z 433.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt

[0767] ##STR00086##

[0768] Ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt (3.15 g, 6.24 mmol) was dissolved in MeOH (20 mL), 2 M aqueous NaOH (3.12 mL, 6.24 mmol) was added and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (2.80 g, 99%) as a colourless solid.

[0769] .sup.1H NMR (DMSO-d.sub.6) δ 7.57 (s, 1H), 6.76 (s, 1H), 6.44 (s, 1H), 4.02 (s, 3H), 2.74 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.89 (p, J=7.4 Hz, 4H).

[0770] LCMS; m/z 405.4 (M+H).sup.+ (ES.sup.+).

Intermediate P9: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt

Step A: Ethyl 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, Sodium Salt

[0771] ##STR00087##

[0772] Ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (2 g, 7.65 mmol) was dissolved in THF (80 mL, 986 mmol). Sodium hydride (0.367 g, 9.18 mmol) was added and stirred at room temperature for 30 minutes to give a white suspension. Then 2-isocyanato-1,3-diisopropylbenzene (Intermediate A9) (1.712 g, 8.42 mmol) in THF (20 mL) was added and stirred at room temperature overnight. The resultant colourless precipitate was collected by filtration, washing with THF (2×20 mL), and dried in vacuo to afford the title compound (2.16 g, 60%) as a colourless solid.

[0773] .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 1H), 7.15-7.05 (m, 1H), 7.05-6.95 (m, 2H), 6.93 (s, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 3.20-3.02 (m, 2H), 1.28 (t, J=7.1 Hz, 3H), 1.03 (d, J=6.9 Hz, 12H).

[0774] LCMS; m/z 437.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt

[0775] ##STR00088##

[0776] Prepared according to the general procedure for 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) from ethyl 3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt to afford the title compound (2.0 g, 99%) as a colourless solid.

[0777] .sup.1H NMR (DMSO-d.sub.6) δ 7.44 (s, 1H), 7.13-7.05 (m, 1H), 7.05-6.94 (m, 2H), 6.42 (s, 1H), 4.00 (s, 3H), 3.16-3.03 (m, 2H), 1.01 (d, J=6.8 Hz, 12H).

[0778] LCMS; m/z 409.4 (M+H).sup.+ (ES.sup.+).

Intermediate P10: 3-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt

Step A: Ethyl 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, Sodium Salt

[0779] ##STR00089##

[0780] Prepared according to the general procedure for ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt (Intermediate P8, Step A) from ethyl 1-methyl-3-sulfamoyl-H-pyrazole-5-carboxylate and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (1.7 g, 92%) as a colourless solid.

[0781] .sup.1H NMR (DMSO-d.sub.6) δ 7.32 (s, 1H), 6.93 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 3.21-2.94 (m, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.03 (d, J=6.8 Hz, 12H).

[0782] LCMS; m/z 455.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt

[0783] ##STR00090##

[0784] Prepared according to the general procedure for 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) from ethyl 3-(N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt to afford the title compound (1.65 g, 98%) as a colourless solid.

[0785] .sup.1H NMR (DMSO-d.sub.6) δ 7.41 (s, 1H), 6.77 (d, J=10.1 Hz, 2H), 6.45 (s, 1H), 4.01 (s, 3H), 3.15-3.02 (m, 2H), 1.10-0.93 (m, 12H).

[0786] LCMS; m/z 427.4 (M+H).sup.+ (ES.sup.+).

Intermediate P11: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt

Step A: Ethyl 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, Sodium Salt

[0787] ##STR00091##

[0788] Prepared according to the general procedure for ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, Sodium Salt (Intermediate P8, Step A) from ethyl 1-methyl-3-sulfamoyl-H-pyrazole-5-carboxylate and 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A12) to afford the title compound (1.32 g, 92%) as a colourless solid.

[0789] .sup.1H NMR (DMSO-d.sub.6); δ 7.41 (s, 1H), 7.01 (s, 2H), 6.92 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 3.13 (br s, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.04 (d, J=6.8 Hz, 12H).

[0790] LCMS; m/z 471.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt

[0791] ##STR00092##

[0792] Prepared according to the general procedure for 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) from ethyl 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt to afford the title compound (1.0 g, 77%) as a colourless solid.

[0793] .sup.1H NMR (DMSO-d.sub.6) δ 7.49 (s, 1H), 7.00 (s, 2H), 6.42 (s, 1H), 4.01 (s, 3H), 3.09 (br s, 2H), 1.02 (d, J=6.8 Hz, 12H).

[0794] LCMS; m/z 443.4 (M+H).sup.+ (ES.sup.+).

Intermediate P12: 5-(Azetidine-1-carbonyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

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

[0795] ##STR00093##

[0796] Ethyl 3-(chlorosulfonyl)-1H-pyrazole-5-carboxylate (4.9 g, 15-19 mmol) in DCM (52 mL) was added dropwise to bis(4-methoxybenzyl)amine (4.34 g, 15-19 mmol), DCM (100 mL) and triethylamine (2.54 mL, 18.23 mmol). The reaction was left to stir at room temperature for 18 hours and then poured onto water (50 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated to dryness to give a pale yellow oil which was purified by chromatography on silica gel (120 g column, 0-70% EtOAc in isohexane) to afford the title compound (5-7 g, 81%) as a white solid.

[0797] .sup.1H NMR (DMSO-d.sub.6) δ 14.87 (s, 1H), 7.28-6.98 (m, 5H), 6.98-6.47 (m, 4H), 4.35 (q, J=7.1 Hz, 2H), 4.24 (br s, 4H), 3.71 (s, 6H), 1.33 (t, J=7.1 Hz, 3H).

[0798] LCMS; m/z 482.1 (M+Na).sup.+ (ES.sup.+).

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

[0799] ##STR00094##

[0800] Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazole-5-carboxylate (1 g, 2.176 mmol), K.sub.2CO.sub.3 (0.391 g, 2.83 mmol) and 2-iodopropane (0.26 mL, 2.61 mmol) were stirred in DMF (10 mL) under a nitrogen atmosphere for 18 hours. The reaction was poured onto brine (100 mL) and EtOAc (50 mL). The aqueous layer was discarded and the organic layer washed with brine (2×100 mL), dried (MgSO.sub.4), filtered and concentrated to dryness to give a yellow oil which was purified by chromatography on silica gel (80 g column, 0-40% EtOAc/isohexane) to afford the title compound (1.0 g, 85%) as a clear colourless oil which solidified on standing.

[0801] .sup.1H NMR (DMSO-d.sub.6) δ 7.22-6.93 (m, 5H), 6.93-6.68 (m, 4H), 5.45 (sept, J=6.6 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 4.25 (s, 4H), 3.71 (s, 6H), 1.42 (d, J=6.6 Hz, 6H), 1.32 (t, J=7.1 Hz, 3H).

[0802] LCMS; m/z 524.2 (M+Na).sup.+ (ES.sup.+).

Step C: 3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazole-5-carboxylic Acid, Sodium Salt

[0803] ##STR00095##

[0804] Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazole-5-carboxylate (1 g, 1.994 mmol) was suspended in EtOH (10 mL) and 2 M aqueous sodium hydroxide (1.994 ml, 3.99 mmol). The reaction was left to stir at room temperature for 17 hours, then evaporated to dryness under reduced pressure to afford the title compound as a colourless foam which was used without further purification.

[0805] LCMS; m/z 496.1 (M+Na).sup.+ (ES.sup.+).

Step D: 5-(Azetidine-1-carbonyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0806] ##STR00096##

[0807] T3P (50 wt % in EtOAc) (2.28 mL, 3.83 mmol) was added to a mixture of sodium 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazole-5-carboxylate (0.99 g, 1.913 mmol) and azetidine hydrochloride (0.215 g, 2.296 mmol) in THF (10 mL). DIPEA (0.67 mL, 3.84 mmol) was added and the reaction stirred at room temperature for 5 hours. Additional T3P (50 wt % in EtOAc) (2.28 mL, 3.83 mmol), DIPEA (0.67 mL, 3.84 mmol) and azetidine hydrochloride (0.215 g, 2.296 mmol) were added and the reaction was stirred at room temperature for a further 2 days. The reaction mixture was diluted with EtOAc (20 mL) and washed with 2 M aqueous NaOH (2×20 mL) followed by 1 M aqueous HCl (20 mL). The organic layer was dried (MgSO.sub.4), filtered and concentrated to dryness to give crude product still containing starting acid. The mixture was subjected to the reaction procedure above, stirred for 2 days, then diluted with EtOAc (20 mL) and washed with water (2×30 mL) followed by 1 M aqueous HCl (20 mL). The organic layer was dried (MgSO.sub.4), filtered and concentrated to dryness to afford the title compound (786 mg, 75%) as an orange oil which was used without further purification in the next step.

[0808] .sup.1H NMR (CDCl.sub.3) δ 7.17-6.99 (m, 4H), 6.85-6.73 (m, 4H), 6.70 (s, 1H), 5.46 (sept, J=6.6 Hz, 1H), 4.37-4.24 (m, 6H), 4.20 (t, J=7.8 Hz, 2H), 3.78 (s, 6H), 2.50-2.29 (m, 2H), 1.47 (d, J=6.6 Hz, 6H).

[0809] LCMS; m/z 513.2 (M+H).sup.+ (ES.sup.+).

Step E: 5-(Azetidine-1-carbonyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[0810] ##STR00097##

[0811] 5-(Azetidine-1-carbonyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.79 g, 1.54 mmol) was dissolved in DCM:TFA (5:1.12 mL) and stirred for 18 hours at room temperature. The solvent was removed under reduced pressure and the purple residue obtained was purified by chromatography on silica gel (24 g column, 0-5% MeOH/DCM) to afford the title compound (201 mg, 47%) as a colourless foam. .sup.1H NMR (DMSO-d.sub.6) δ 7.51 (s, 2H), 6.85 (s, 1H), 5.28 (sept, J=6.6 Hz, 1H), 4.30 (t, J=7.7 Hz, 2H), 4.04 (t, J=7.8 Hz, 2H), 2.27 (p, J=7.8 Hz, 2H), 1.40 (d, J=6.6 Hz, 6H). LCMS; m/z 273.1 (M+H).sup.+ (ES.sup.+).

Intermediate Pin: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide

[0812] ##STR00098##

[0813] A solution of N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P5) (459 mg, 1.976 mmol) in MeCN (2.3 mL) was treated with N,N-dimethylpyridin-4-amine (483 mg, 3.95 mmol) and the reaction mixture was stirred at room temperature until the sulfonamide had dissolved. Diphenyl carbonate (466 mg, 2.174 mmol) was added and the reaction mixture was left for 16 hours at room temperature. The resulting precipitate was separated by filtration, washed with MeCN and dried to afford the title compound (578 mg, 77%) which was used in the next step without further purification.

[0814] .sup.1H NMR (DMSO-d.sub.6) δ 8.77-8.73 (m, 2H), 7.02-6.98 (m, 2H), 6.83 (s, 1H), 3.85 (s, 3H), 3.26 (s, 6H), 3.05 (s, 3H), 3.00 (s, 3H).

Intermediate P14: 1-(1-Acetylpiperidin-4-yl)-1H-pyrazole-3-sulfonamide

Step A: 1-(4-(3-Nitro-1H-pyrazol-1-yl)piperidin-1-yl)ethanone

[0815] ##STR00099##

[0816] Triethylamine (3.59 ml, 25.8 mmol) was added to 4-(3-nitro-1H-pyrazol-1-yl) piperidine, HCl (2.00 g, 8.60 mmol) in DCM (30 mL), and the reaction was stirred at room temperature for 5 minutes. Then acetyl chloride (0.744 ml, 10.32 mmol) was added dropwise at 0° C. The reaction was stirred for 20 minutes at 0° C. and then allowed to warm to room temperature and stirred for 16 hours. The mixture was then diluted with water (20 mL). The phases were separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were washed with brine, dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound as a yellow solid (1.85 g, 89%).

[0817] .sup.1H NMR (DMSO-d.sub.6) δ 8.13 (d, J=2.6 Hz, 1H), 7.07 (d, J=2.6 Hz, 1H), 4.60 (tt, J=11.5, 4.1 Hz, 1H), 4.52-4.43 (m, 1H), 3.98-3.89 (m, 1H), 3.23-3.15 (m, 1H), 2.76-2.64 (m, 1H), 2.14-2.04 (m, 2H), 2.04 (s, 3H), 1.97-1.85 (m, 1H), 1.75 (qd, J=12.3, 4.6 Hz, 1H). LCMS; m/z 239.2 (M+H).sup.+ (ES.sup.+).

Step B: 1-(4-(3-Amino-1H-pyrazol-1-yl)piperidin-1-yl)ethanone

[0818] ##STR00100##

[0819] A solution of 1-(4-(3-nitro-1H-pyrazol-1-yl)piperidin-1-yl)ethanone (1.75 g, 7.35 mmol) in ethanol (36.7 mL) was treated with saturated aq NH.sub.4Cl (24.48 mL, 7.35 mmol), followed by iron powder (2.05 g, 36.7 mmol) at room temperature. The mixture was then stirred at 75° C. for 1 hour. After cooling, the reaction was filtered through a pad of Celite®, washing with EtOAc (2×20 mL). The organic solvents were evaporated in vacuo. The aqueous solution obtained was then extracted with EtOAc (2×40 mL) and the combined organic layers dried (MgSO.sub.4), filtered and concentrated in vacuo to give the title product as a green solid (250 mg). The aqueous layer was concentrated to dryness, suspended in EtOAc:MeOH (9:1, 50 mL) and the insoluble material was filtered off. The filtrate was concentrated in vacuo to afford further product which was combined with the extracted portion previously obtained to afford the title compound as a green-brown solid (731 mg, 45%).

[0820] .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (d, J=2.3 Hz, 1H), 5.38 (d, J=2.2 Hz, 1H), 4.64 (br s, 2H), 4.49-4.28 (m, 1H), 4.15-4.02 (m, 1H), 3.93-3.80 (m, 1H), 3.21-3.08 (m, 1H), 2.64 (td, J=12.8, 2.8 Hz, 1H), 2.01 (s, 3H), 1.98-1.85 (m, 2H), 1.75 (qd, J=12.3, 4.3 Hz, 1H), 1.62 (qd, J=12.3, 4.4 Hz, 1H).

[0821] LCMS; m/z 209.1 (M+H).sup.+ (ES.sup.+).

Step C: 1-(1-Acetylpiperidin-4-yl)-1H-pyrazole-3-sulfonamide

[0822] ##STR00101##

[0823] A solution of NaNO.sub.2 (273 mg, 3.95 mmol) in water (0.5 mL) was added dropwise to a solution of HCl (aq 37%,1.2 mL) in water (0.8 mL) and MeCN (4.1 mL) at −10° C., maintaining the internal temperature below 0° C. The solution was stirred for 10 minutes and then a solution of 1-(4-(3-amino-H-pyrazol-1-yl)piperidin-1-yl)ethanone (730 mg, 3.29 mmol) in MeCN (4.1 mL) was added dropwise at 0° C. over 15 minutes. The resulting reaction mixture was stirred at 0° C. for 45 minutes. AcOH (1.7 mL), CuCl.sub.2 (222 mg, 1.65 mmol) and CuCl (16.3 mg, 0.165 mmol) were sequentially added and the reaction mixture was purged with SO.sub.2 gas for 20 minutes at 0° C. The reaction mixture was stirred for a further 50 minutes and then diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-10% 0.7 N NH.sub.3 in MeOH/DCM) to afford the intermediate 1-(1-acetylpiperidin-4-yl)-1H-pyrazole-3-sulfonyl chloride as a clear yellow oil (217 mg), which was dissolved in THF (1 mL) and treated with ammonia (0.5M in dioxane, 3.37 mL, 1.684 mmol). The reaction mixture was stirred at room temperature for 22 hours and then concentrated in vacuo, quenched with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated in vacuo. The residue was dissolved in EtOAc (5 mL) and precipitated by addition of isohexane (10 mL). The solid was collected by filtration, washed with isohexane (2×3 mL) and dried under vacuum to afford the title compound as a white solid (81 mg, 37%).

[0824] .sup.1H NMR (DMSO-d.sub.6) δ 7.95 (d, J=2.4 Hz, 1H), 7.40 (s, 2H), 6.59 (d, J=2.4 Hz, 1H), 4.62-4.35 (m, 2H), 3.97-3.83 (m, 1H), 3.24-3.18 (m, 1H), 2.77-2.62 (m, 1H), 2.09-1.99 (m, 4H), 1.88 (qd, J=12.2, 4.4 Hz, 1H), 1.73 (qd, J=12.3, 4.5 Hz, 1H), 0.89-0.79 (m, 1H).

[0825] LCMS; m/z 273.0 (M+H).sup.+ (ES.sup.+).

Intermediate P15: N-((1-Isopropyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide

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

[0826] ##STR00102##

[0827] 1-Isopropyl-1H-pyrazole-3-sulfonyl chloride (10.0 g, 47.9 mmol) was added portionwise to a solution of bis(4-methoxybenzyl)amine (12.5 g, 48.6 mmol) and Et.sub.3N (13 mL, 93 mmol) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 30 minutes, warmed to room temperature and stirred for 2 hours. The mixture was washed with water (200 mL), aqueous 1M HCl (200 mL) and water (200 mL), dried (MgSO.sub.4), filtered and evaporated to give a yellow oil. The yellow oil was purified by chromatography on silica gel (330 g column, 0-70% EtOAc/isohexane) to afford the title compound (16.6 g, 80%) as a white solid.

[0828] .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).

[0829] LCMS; m/z 452.2 (M+Na).sup.+ (ES.sup.+).

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

[0830] ##STR00103##

[0831] A solution of n-BuLi (2.5 M in hexanes, 2 mL, 5.00 mmol) was added dropwise to a stirred solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (2 g, 4.66 mmol) in THF (26 mL) at −78° C. The reaction was stirred for 1 hour. Then a solution of morpholine-4-carbaldehyde (1.6 g, 13.90 mmol) in THF (4 mL) was added dropwise, whilst maintaining the temperature below −65′C. The reaction mixture was left at −78° C. for 1 hour and then quenched with saturated NH.sub.4Cl solution (25 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with saturated brine (50 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford a yellow oil. The crude product was purified by chromatography on SiO.sub.2 (120 g column, 0-100% EtOAc/isohexane) to afford the title compound (1.43 g, 66%) as a white solid.

[0832] .sup.1H NMR (DMSO-d.sub.6) δ 9.91 (s, 1H), 7.43 (s, 1H), 7.10-7.03 (m, 4H), 6.86-6.79 (m, 4H), 5.34 (sept, J=6.6 Hz, 1H), 4.26 (s, 4H), 3.72 (s, 6H), 1.43 (d, J=6.5 Hz, 6H). LCMS m/z 480.3 (M+Na).sup.+ (ES.sup.+).

Step C: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-5-((methylamino)methyl)-1H-pyrazole-3-sulfonamide, Acetic Acid Salt

[0833] ##STR00104##

[0834] Acetic acid (10 μL, 0.175 mmol) was added to a stirred suspension of 5-formyl-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (400 mg, 0.874 mmol), methylamine (2 M in THF) (874 μL, 1.748 mmol) and sodium triacetoxy-borohydride (278 mg, 1.311 mmol) in THF (14 mL). The reaction mixture was left to stir at room temperature for 16 hours. Water (1 mL) was added and volatiles were evaporated. The crude product was purified by chromatography on SiO.sub.2 (24 g column, 0-10% MeOH/DCM) to afford the title compound (130 mg, 24%) as a colourless oil. .sup.1H NMR (DMSO-d.sub.6) δ 7.05-6.98 (m, 4H), 6.85-6.79 (m, 4H), 6.57 (s, 1H), 4.77 (sept, J=6.5 Hz, 1H), 4.19 (s, 4H), 3.74 (s, 2H), 3.72 (s, 6H), 3.37 (bs, 1H), 2.27 (s, 3H), 1.90 (s, 3H), 1.39 (d, J=6.5 Hz, 6H). OH not observed.

[0835] LCMS; m/z 473.5 (M+H).sup.+ (ES.sup.+).

Step D: N-((3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide

[0836] ##STR00105##

[0837] To a solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-5-((methylamino)methyl)-1H-pyrazole-3-sulfonamide, acetic acid salt (130 mg, 0.248 mmol) in DCM (1 mL) was added pyridine (45 μL, 0-556 mmol) and the mixture was cooled to 0° C. Trifluoroacetic anhydride (53 μL, 0.375 mmol) was added dropwise and the resultant mixture was stirred at 0° C. for 15 minutes, before warming to room temperature for 16 hours. Additional pyridine (45 μL, 0.556 mmol) and trifluoroacetic anhydride (53 μL, 0.375 mmol) were added and the mixture was stir for another 16 hours. The mixture was quenched with saturated sodium bicarbonate (5 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×10 mL) and EtOAc (10 mL) and the combined organic phases were dried with magnesium sulfate. The solvent was removed under reduced pressure. The crude product was purified by chromatography on SiO.sub.2 (12 g column, 0-10% MeOH/DCM) to afford the title compound (88 mg, 57%) as a brown oil.

[0838] .sup.1H NMR (DMSO-d.sub.6); rotamers: δ 7.05-6.99 (m, 4H), 6.85-6.79 (m, 4H), 6.63 (s, 1H), 4.75-4.66 (m, 1H), 4.63 (s, 2H), 4.21 (s, 4H), 3.73 (s, 6H), 3.32 (s, 3H), 2.07 (s, 3H), 1.35 (d, J=6.5 Hz, 6H).

[0839] LCMS; m/z 537.1 (M+Na).sup.+ (ES.sup.+).

Step E: N-((1-Isopropyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide

[0840] ##STR00106##

[0841] N-((3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide (88 mg, 0.140 mmol) was dissolved in DCM (0.5 mL) and TFA (1.5 mL) was added. The solution was stirred for 16 hours. The reaction mixture was concentrated in vacuo, suspended in toluene (5 mL) and concentrated again. The crude product was purified by chromatography on RP Flash C18 (basic) to afford the title compound (30 mg, 78%) as a white solid.

[0842] .sup.1H NMR (DMSO-d.sub.6) δ 7.37 (bs, 2H), 6.51 (s, 1H), 4.73-4.66 (m, 1H), 4.61 (s, 2H), 2.95 (s, 3H), 2.06 (s, 3H), 1.35 (d, J=6.5 Hz, 6H).

[0843] LCMS m/z 275.2 (M+H).sup.+ (ES.sup.+).

Intermediate P16: N,N-Bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

Step A: 1-Methyl-1H-pyrazole-3-sulfonyl Chloride

[0844] ##STR00107##

[0845] A solution of 1-methyl-1H-pyrazol-3-amine (25 g, 257.42 mmol, 1 eq) in MeCN (600 mL) at 0° C. was treated with concentrated HCl (60 mL) and H.sub.2O (60 mL). Then an aqueous solution of NaNO.sub.2 (21-31 g, 308.90 mmol, 1.2 eq) in H.sub.2O (60 mL) was added slowly. The resulting mixture was stirred at 0° C. for 40 minutes. AcOH (60 mL), CuCl.sub.2 (17-31 g, 128.71 mmol, 0.5 eq) and CuCl (1.27 g, 12.87 mmol, 307.78 μL, 0.05 eq) were added, then SO.sub.2 gas (15 psi) was bubbled into the mixture for 15 minutes at 0° C. The reaction mixture was concentrated in vacuo to remove most of the MeCN. Then the reaction mixture was treated with H.sub.2O (2.5 L) and extracted with EtOAc (2×1.2 L). The combined organic layers were washed with brine (3×2 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=15:1 to 5:1) to give the title compound (19 g, 41%) as a yellow oil.

[0846] .sup.1H NMR (CDCl.sub.3): δ 7.52 (d, 1H), 6.89 (d, 1H) and 4.07 (s, 3H).

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

[0847] ##STR00108##

[0848] To a solution of bis(4-methoxybenzyl)amine (99.83 g, 387.96 mmol, 0.91 eq) in THF (1 L) was added TEA (86.28 g, 852.65 mmol, 118.68 mL, 2 eq), followed by 1-methyl-1H-pyrazole-3-sulfonyl chloride (77 g, 42633 mmol, 1 eq). Then the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated in vacuo to remove most of the THF. The reaction mixture was quenched by addition of aqueous HCl (1 M, 500 mL) and then extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (2×600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of petroleum ether and ethyl acetate (70 mL, v:v=5:1) to give the title compound (138 g, 81%) as a white solid.

[0849] .sup.1H NMR (CDCl.sub.3): δ 7.40 (d, 1H), 7.08 (d, 4H), 6.78 (d, 4H), 6.65-6.63 (m, 1H), 4.32 (s, 4H), 3.98 (s, 3H) and 3.79 (s, 6H).

[0850] 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

[0851] ##STR00109##

[0852] 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 cooled to −70° C. Then n-BuLi (2.5 M, 104.61 mL, 1.05 eq) was added dropwise. The reaction mixture was stirred at −70° C. for 1 hour, then CO.sub.2 (15 psi) was bubbled into the mixture for 15 minutes. The reaction mixture was stirred at −70° C. for another 1 hour. The reaction mixture was quenched with H.sub.2O (1.2 L) and adjusted with aqueous HCl (1 M) to pH=3. Then the mixture was extracted with EtOAc (2×1). The combined organic layers were washed with brine (2×1 L), dried over 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, v:v=1:1) to give the title compound (94 g, 84% yield, 99% purity on LCMS) as a white solid.

[0853] .sup.1H NMR (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).

[0854] LCMS: m/z 468.2 (M+Na).sup.+ (ES.sup.+).

Step D: 3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0855] ##STR00110##

[0856] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (8 g, 17.96 mmol, 1 eq) in DMF (100 mL) was added with HATU (10.24 g, 26.94 mmol, 1.5 eq), DIPEA (6.96 g, 53.87 mmol, 3 eq) and bis(2-methoxyethyl)amine (2.87 g, 21.55 mmol, 1.2 eq). The reaction mixture was stirred at 25° C. for 1 hour. Then the reaction mixture was diluted with EtOAc (50 mL), washed with saturated aqueous NH.sub.4C solution (3×50 mL) and brine (3×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.05% NH.sub.3.H.sub.2O-MeCN) to give the title compound (8 g, 79%) as a red oil.

[0857] .sup.1H NMR (CD.sub.3OD): δ 7.05 (d, 4H), 6.81-6.77 (m, 5H), 4.29 (s, 4H), 3.90 (s, 3H), 3.79-3.72 (m, 8H), 3.68-3.57 (m, 4H), 3.48-3.46 (m, 2H), 3.38 (s, 3H) and 3.27 (s, 3H). LCMS: m/z 561.3 (M+H).sup.+ (ES.sup.+).

Step E: N,N-Bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

[0858] ##STR00111##

[0859] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (8 g, 14.27 mmol, 1 eq) in DCM (50 mL) was added TFA (56 g, 491.13 mmol, 34.42 eq). The reaction mixture was stirred at 25° C. for 12 hours and then concentrated in vacuo. The residue was triturated with a mixture of EtOAc and PE (50 mL, v:v=3:2) to give the title compound (4.0 g, 88%) as a white solid.

[0860] .sup.1H NMR (DMSO-d.sub.6): δ 7.50 (s, 2H), 6.74 (s, 1H), 3.84 (s, 3H), 3.63 (t, 4H), 3.43-3.40 (m, 4H), 3.28 (s, 3H) and 3.18 (s, 3H).

Intermediate P17: 1-(1-(Dimethylamino)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide

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

[0861] ##STR00112##

[0862] A solution of n-BuLi (100 mL, 250 mmol, 2.5M 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 allowed to warm to room temperature, the solvent evaporated and the residue triturated with TBME (300 mL) and filtered. The solid was washed with TBME and isohexane and dried to afford the crude title compound (54.89 g, 99%).

[0863] .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).

[0864] 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

[0865] ##STR00113##

[0866] 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), filtered and evaporated to ˜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 then partitioned between DCM (300 mL) and water (250 mL). The organic layer was washed with water (250 mL), aq 1M HCl (2×250 mL), water (250 mL), dried (MgSO.sub.4), filtered, and evaporated to afford the crude title compound (41.02 g, 97%) as a brown oil.

[0867] LCMS; m/z 494.2 (M+Na).sup.+ (ES.sup.+).

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

[0868] ##STR00114##

[0869] A mixture of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (41 g, 87 mmol) and aq 1M 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 1M HCl (200 mL). The organic layer was washed with 10% brine (200 mL dried (MgSO.sub.4), filtered and evaporated. The residue was triturated with TBME, filtered and dried to afford the title compound (24.87 g, 69%) as an off-white solid.

[0870] .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). Exchangeable proton not visible.

[0871] LCMS; m/z 388 (M+H).sup.+ (ES.sup.+); 386 (M−H).sup.− (ES.sup.−).

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

[0872] ##STR00115##

[0873] N,N-Bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (2.00 g, 5.16 mmol) and potassium carbonate (2.140 g, 15-49 mmol) were suspended in dry DMF (30 mL). Methyl 2-bromo-2-methylpropanoate (1.002 mL, 7.74 mmol) was added and the mixture was heated to 80° C. overnight. The reaction mixture was cooled to room temperature, diluted with water (20 mL), poured into brine (200 mL) and extracted with TBME (2×50 mL). The combined organic layers were dried (MgSO.sub.4), filtered and evaporated to dryness to give a yellow oil. The crude product was purified by chromatography on silica gel (80 g column, 0-70% EtOAc/isohexane) to afford the title compound (2.45 g, 94%) as a clear colourless oil.

[0874] .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).

[0875] LCMS; m/z 511 (M+Na).sup.+ (ES.sup.+).

Step E: 2-(3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-H-pyrazol-1-yl)-2-methylpropanoic Acid

[0876] ##STR00116##

[0877] 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 2M NaOH (5 mL, 10.00 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. 1M HCl (100 mL), the organic layer washed with brine (50 mL), dried (MgSO.sub.4), filtered and evaporated to afford the title compound (2.38 g, 95%) as a gum that solidified on standing.

[0878] .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). Exchangeable proton not visible.

[0879] LCMS; m/z 472 (M−H).sup.− (ES.sup.−).

Step F: 2-(3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-H-pyrazol-1-yl)-N,N,2-trimethylpropanamide

[0880] ##STR00117##

[0881] A mixture of 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid (2.1 g, 4.43 mmol), N,N-diisopropylethylamine (3.1 mL, 17.75 mmol) and HATU (1.9 g, 5.00 mmol) in DMF (30 mL) was stirred at 0-5° C. for 10 minutes, and then dimethylamine hydrochloride (0.723 g, 8.87 mmol) was added. The mixture was warmed to room temperature, stirred for 20 hours, and then partitioned between TBME (200 mL) and aq 1M HCl (200 mL). The organic layer was washed with water (100 mL), dried (MgSO.sub.4), filtered, evaporated to dryness, and then purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/heptane) to afford the title compound (2.2 g, 98%) as a clear gum.

[0882] .sup.1H NMR (CDCl.sub.3, rotamers) δ 7.48 (d, J=2.4 Hz, 1H), 7.14-7.10 (m, 4H), 6.82-6.78 (m, 5H), 4.33 (s, 4H), 3.81 (s, 6H), 2.97 (br s, 3H), 2.37 (br s, 3H), 1.82 (s, 6H).

[0883] LCMS; m/z 501 (M+H).sup.+ (ES.sup.+).

Step G: N,N,2-Trimethyl-2-(3-sulfamoyl-1H-pyrazol-1-yl)propanamide

[0884] ##STR00118##

[0885] A mixture of 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-H-pyrazol-1-yl)-N,N,2-trimethylpropanamide (0.8 g, 1.598 mmol) and TFA (6 mL) was stirred for 4 hours. The reaction mixture was concentrated and the crude product was purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford the title compound (360 mg, 86%) as a colourless solid.

[0886] .sup.1H NMR (DMSO-d.sub.6, rotamers) δ 8.02 (d, J=2.5 Hz, 1H), 7.47 (s, 2H), 6.68 (d, J=2.4 Hz, 1H), 2.82 (br s, 3H), 2.30 (br s, 3H), 1.71 (s, 6H).

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

[0887] ##STR00119##

[0888] To a solution of phosgene (4.45 mL, 20% weight in toluene, 8.4 mmol) in EtOAc (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 EtOAc (45 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 3 hours and upon cooling was filtered and concentrated in vacuo to afford the title compound as a brown oil (756 mg, 100%). The crude product was used directly in the next step without further purification.

[0889] .sup.1H NMR (CDCl.sub.3) δ 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m, 4H).

Intermediate A2: 5-Fluoro-2-isocyanato-,3-diisopropylbenzene

[0890] ##STR00120##

[0891] 4-Fluoro-2,6-diisopropylaniline (1 g, 5.12 mmol) and triethylamine (0.785 mL, 5.63 mmol) were dissolved in THF (10 mL) and cooled to 0° C. Triphosgene (0.760 g, 2.56 mmol) was added to the mixture portionwise and the reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated in vacuo. Isohexane (so mL) was added and the suspension filtered through silica (3 g). The filtrate was dried under reduced pressure to afford the title compound (900 mg, 75%) as a colourless oil. .sup.1H NMR (DMSO-d.sub.6) δ 6.8 (d, J=9.4 Hz, 2H), 3.27-3.12 (m, 2H), 1.23 (d, J=6.8 Hz, 12H).

Intermediate A3: 4-Fluoro-2-isopropyl-6-(pyridin-3-yl)aniline

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

[0892] ##STR00121##

[0893] N-Bromosuccinimide (5.64 g, 31.7 mmol) was added portionwise to 4-fluoro-2-isopropylaniline (4.62 g, 30.2 mmol) in DCM (72 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour and then left to warm to room temperature over 21 hours. The reaction mixture was washed with a solution of aqueous sodium hydroxide (2 M, 2×50 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give a brown residue. The crude product was then filtered through a plug of silica (50 g) and washed through with 50% DCM in iso-hexane (500 mL). The red filtrate was concentrated to dryness and the crude product was purified by chromatography on silica gel (120 g column, 0-% DCM/iso-hexane) to afford the title compound (4.99 g, 70%) as a red oil.

[0894] .sup.1H NMR (CDCl.sub.3) δ 7.07 (dd, 1H), 6.86 (dd, 1H), 4.14 (s, 2H), 2.93 (sept, 1H) and 1.25 (d, 6H). NH.sub.2 not observed.

[0895] LCMS; m/z 232.2/234.3 (M+H).sup.+ (ES.sup.+).

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

[0896] ##STR00122##

[0897] To a stirred, nitrogen-degassed mixture of 2-bromo-4-fluoro-6-isopropylaniline (1.00 g, 4.27 mmol) was added pyridin-3-ylboronic acid (0.577 g, 4.69 mmol), Pd(dppf)Cl.sub.2 (0.156 g, 0.213 mmol) and potassium carbonate (1.769 g, 12.80 mmol) in a 10:1 mixture of 1,4-dioxane:water (33 mL). The reaction mixture was then heated to 80° C. under a nitrogen atmosphere for 2 days, left to cool to room temperature, filtered through a pad of Celite® (10 g) and the filter cake washed with EtOAc (2×30 mL). The filtrate was poured onto water (50 mL) and the organic layer collected. The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to dryness. The crude product was purified by chromatography on silica gel (80 g column, 0-60% EtOAc/iso-hexane) to afford the title compound (273 mg, 27%) as a brown gum.

[0898] .sup.1H NMR (CDCl.sub.3) δ 8.70 (dd, 1H), 8.63 (dd, 1H), 7.82 (ddd, 1H), 7.48-7.34 (m, 1H), 6.94 (dd, 1H), 6.70 (dd, 1H), 2.93 (sept, 1H), 3.98-2.44 (br s, 2H) and 1.29 (d, 6H). LCMS; m/z 231.1 (M+H).sup.+ (ES.sup.+).

[0899] The following intermediates were synthesised following the general procedure for Intermediate A3:

TABLE-US-00001 Intermediate Structure Analytical data A4 [00123] .sup.1H NMR (CDCl.sub.3) δ 7.68 (d, 1H), 7.58 (d, 1H), 6.86 (dd, 1H), 6.78 (dd, 1H), 3.99 (s, 3H), 3.74 (br s, 2H), 2.94 (sept, 1H) and 1.29 (d, 6H). (85 mg, 22%) A5 [00124] .sup.1H NMR (CDCl.sub.3) δ 9.23 (s, 1H), 8.86 (s, 2H), 6.98 (dd, 1H), 6.69 (dd, 1H), 3.55 (br s, 2H), 2.92 (sept, 1H) and 1.29 (d, 6H). (126 mg, 60%)

Intermediate A6: 4-Fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl) aniline

Step A: 2-Bromo-4-fluoro-6-(prop-1-en-2-yl)aniline

[0900] ##STR00125##

[0901] Nitrogen gas was bubbled through a mixture of 2,6-dibromo-4-fluoroaniline (5 g, 18-59 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (4.2 mL, 22.34 mmol) and potassium triphosphate (7.9 g, 37.2 mmol) in dioxane (50 mL) and water (8 mL) for 15 minutes. Then (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate [XPhos G3 Pd cat (500 mg, 0.591 mmol)] was added. The mixture was heated at 90° C. for 8 hours and then partitioned between hexane (200 mL) and water (100 mL). The organic layer was dried (magnesium sulfate), filtered, evaporated in vacuo and the residue purified by chromatography on silica gel (120 g column, 0-2% EtOAc/iso-hexane) to afford the title compound (1.95 g, 43%) as an oil.

[0902] .sup.1H NMR (CDCl.sub.3) δ 7.13 (dd, 1H), 6.77 (dd, 1H), 5.37-5.35 (m, 1H), 5.12-5.10 (m, 1H), 3.52 (br s, 2H) and 2.08-2.06 (m, 3H).

[0903] LCMS; m/z 230.2 (M+H).sup.+ (ES.sup.+).

Step B: 2-(3,6-Dihydro-2H-pyran-4-yl)-4-fluoro-6-(prop-1-en-2-yl)aniline

[0904] ##STR00126##

[0905] 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (457 mg, 2.176 mmol), tetrakis(triphenylphosphine)palladium(o) (251 mg, 0.218 mmol), sodium carbonate (923 mg, 8.70 mmol) and water (4 mL) were added to a sealed vial containing a solution of 2-bromo-4-fluoro-6-(prop-1-en-2-yl)aniline (500 mg, 2.173 mmol) in DMF (22 mL). The reaction mixture was heated under nitrogen at 100° C. overnight and then allowed to cool. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), dried (sodium sulfate) and concentrated in vacuo. The crude product was purified by chromatography on silica (40 g column, 0-20% EtOAc/iso-hexanes) to afford the title compound (355 mg, 65%) as a brownish oil. .sup.1H NMR (CDCl.sub.3) δ 6.71 (dd, 1H), 6.67 (dd, 1H), 5.88 (m, 1H), 5.35-5.31 (m, 1H), 5.09 (m, 1H), 4.32 (m, 2H), 3.95 (t, J=5.4 Hz, 2H), 3.82 (br s, 2H), 2.42 (m, 2H) and 2.09-2.07 (m, 3H).

Step C: 4-Fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)aniline

[0906] ##STR00127##

[0907] A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-6-(prop-1-en-2-yl)aniline (355 mg, 1.522 mmol) and 5% palladium on carbon (156 mg, 0.03 mmol; type 87L (58.5% moisture)) in EtOAc (3.8 mL) was hydrogenated at 5 bar for 1 hour. The mixture was filtered through Celite® and evaporated to afford the title compound (340 mg, 91%). .sup.1H NMR (CDCl.sub.3) δ 6.80 (dd, 1H), 6.75 (dd, 1H), 4.16-4.14 (m, 1H), 4.13-4.10 (m, 1H), 3.65-3.51 (m, 4H), 3.01-2.89 (m, 1H), 2.85-2.74 (m, 1H), 1.86-1.78 (m, 4H) and 1.28 (d, 6H).

[0908] LCMS; m/z 238.1 (M+H).sup.+ (ES.sup.+).

Intermediate A7: 2-Isopropyl-5-(1-methyl-1H-pyrazol-4-yl)aniline

[0909] ##STR00128##

[0910] To a sealed vial was added 5-bromo-2-isopropylaniline (250 mg, 1.168 mmol) in DMF (11 mL), followed by the addition of (1-methyl-H-pyrazol-4-yl)boronic acid (147 mg, 1.168 mmol), Pd(PPh.sub.3).sub.4 (135 mg, 0.117 mmol) and aqueous 2 M Na.sub.2CO.sub.3 (2.335 mL, 4.67 mmol). The reaction mixture is heated under Argon at 100° C. overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated, and then purified by chromatography on silica gel (40 g column, 0-60% EtOAc/iso-hexane) to afford the title compound (90 mg, 36%) as a white solid.

[0911] .sup.1H NMR (CDCl.sub.3) δ 7.70 (d, J=0.9 Hz, 1H), 7.54 (s, 1H), 7.13 (d, J=7.9 Hz, 1H), 6.90 (dd, J=7.9, 1.8 Hz, 1H), 6.80 (d, J=1.8 Hz, 1H), 3.93 (s, 3H), 3.69 (bs, 2H), 2.90 (sept, J=6.8 Hz, 1H), 1.27 (d, J=6.8 Hz, 6H).

Intermediate A8: 2-Isopropyl-5-(pyrimidin-5-yl)aniline

[0912] ##STR00129##

[0913] Prepared according to the general procedure for 2-isopropyl-5-(1-methyl-H-pyrazol-4-yl)aniline (Intermediate A7) from 5-bromo-2-isopropylaniline and pyrimidin-5-ylboronic acid to afford the title compound (130 mg, 51%) as a white solid.

[0914] .sup.1H NMR (CDCl.sub.3) δ 9.16 (s, 1H), 8.91 (s, 2H), 7.28 (d, J=7.9 Hz, 1H), 6.98 (dd, J=8.0, 1.9 Hz, 1H), 6.87 (d, J=1.9 Hz, 1H), 3.84 (bs, 2H), 2.95 (sept, J=6.8 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H).

Intermediate A9: 2-Isocyanato-1,3-diisopropylbenzene

[0915] ##STR00130##

[0916] 2,6-Diisopropylaniline (3.07 g, 17-14 mmol) was dissolved in dry THF (40 mL) and Et.sub.3N (3 mL, 21.52 mmol) was added. A solution of triphosgene (4.26 g, 14.35 mmol) in dry THF (12 mL) was added over 5 minutes, resulting in the formation of a thick colourless precipitate. The reaction mixture was stirred at room temperature overnight. The THF was removed in vacuo and toluene (50 mL) was added. The mixture was filtered through a short silica plug eluting with toluene (150 mL). The filtrate was concentrated in vacuo to afford the title compound (2.76 g, 92%) as a colourless oil. .sup.1H NMR (CDCl.sub.3) δ 7.20-7.10 (m, 3H), 3.22 (hept, J=6.9 Hz, 2H), 1.26 (d, J=6.8 Hz, 12H).

Intermediate A: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine

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

[0917] ##STR00131##

[0918] To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (36.21 g, 215.51 mmol, 1.05 eq) and K.sub.2CO.sub.3 (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H.sub.2O (40 mL) was added Pd(dppf)Cl.sub.2 (7-51 g, 10.26 mmol, 0.05 eq) under N.sub.2 atmosphere. Then the reaction mixture was stirred at 80° C. for 5 hours. The reaction mixture was quenched by addition of H.sub.2O (600 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (2×600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 100:1) to give the title compound (27 g, 77% yield, 89% purity on LCMS) as a yellow oil.

[0919] .sup.1H NMR (CDCl.sub.3): δ 6.81-6.76 (m, 2H), 6.66-6.62 (m, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 3.69 (br s, 2H) and 1.25 (s, 3H).

[0920] LCMS: m/z 152.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Fluoro-2-isopropylaniline

[0921] ##STR00132##

[0922] To a solution of 4-fluoro-2-(prop-1-en-2-yl)aniline (21 g, 138.91 mmol, 1 eq) in MeOH (300 mL) was added Pd/C (2.1 g, 178.59 mmol, 10 wt % loading on activated carbon) under N.sub.2 atmosphere. The reaction mixture was degassed in vacuo and purged with H.sub.2 several times. The reaction mixture was stirred at 25° C. for 12 hours under H.sub.2 (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (20 g, crude) as a yellow oil.

[0923] .sup.1H NMR (CDCl.sub.3): δ 6.86 (dd, 1H), 6.75-6.72 (m, 1H), 6.63-6.61 (m, 1H), 3.50 (br s, 2H), 2.95-2.84 (m, 1H) and 1.25 (d, 6H).

[0924] LCMS: m/z 154.2 (M+H).sup.+ (ES.sup.+).

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

[0925] ##STR00133##

[0926] To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 mL) was added NBS (23.24 g, 130.55 mmol, 1 eq) at 25° C. The reaction mixture was stirred at 25° C. for 10 minutes. Then the reaction mixture was poured into H.sub.2O (300 mL) and extracted with EtOAc (2×250 mL). The organic phases were washed with brine (2×400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting only by using petroleum ether) to give the title compound (30 g, 99%) as a black brown oil.

[0927] .sup.1H NMR (CDCl.sub.3): δ 6.99 (dd, 1H), 6.78 (dd, 1H), 3.91 (br s, 2H), 2.88-2.71 (m, 1H) and 1.17 (d, 6H).

[0928] LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

Step D: 4-Bromo-2-isopropoxypyridine

[0929] ##STR00134##

[0930] To a solution of 4-bromo-2-chloropyridine (20 g, 103.93 mmol, 1 eq) in THF (400 mL) was added NaH (6.24 g, 155.89 mmol, 60% purity, 1.5 eq) at 0° C. Then the mixture was stirred for 0.5 hour. Propan-2-ol (6.87 g, 114.32 mmol, 8.75 mL, 1.1 eq) was added and the resulting mixture was warmed to 50° C. and stirred for 12 hours. The reaction mixture was quenched with H.sub.2O (1 L) at 25° C. and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (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=50:1 to 40:1) to give the title compound (22 g, 98%) as a light yellow oil.

[0931] .sup.1H NMR (CDCl.sub.3): δ 7.96 (d, 1H), 6.98 (dd, 1H), 6.89 (d, 1H), 5.44-5.24 (m, 1H) and 1.34 (d, 6H).

Step E: 2-Isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0932] ##STR00135##

[0933] To a solution of 4-bromo-2-isopropoxypyridine (19 g, 87.93 mmol, 1 eq) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (22.33 g, 87.93 mmol, 1 eq) in 1,4-dioxane (300 mL) was added KOAc (25.89 g, 263.80 mmol, 3 eq) followed by Pd(dppf)Cl.sub.2 (1.93 g, 2.64 mmol, 0.03 eq) under nitrogen. Then the reaction mixture was heated to 80° C. and stirred for 12 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=50:1 to 20:1) to give the title compound (22 g, 95%) as a light yellow oil. .sup.1H NMR (CDCl.sub.3): δ 8.16 (d, 1H), 7.13 (d, 1H), 7.08 (s, 1H), 5.32-5.24 (m, 1H), 1.34 (s, 12H) and 1.27 (s, 6H).

[0934] LCMS: m/z 264.2 (M+H).sup.+ (ES.sup.+).

Step F: 4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylaniline

[0935] ##STR00136##

[0936] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (10.94 g, 47.12 mmol, 1 eq) and 2-isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (12.4 g, 47.12 mmol, 1 eq) in 1,4-dioxane (200 mL) and H.sub.2O (20 mL) was added Pd(dppf)Cl.sub.2 (1.72 g, 2.36 mmol, 0.05 eq) followed by K.sub.2CO.sub.3 (19.54 g, 141-37 mmol, 3 eq) at 25° C. Then the reaction mixture was heated to 80° C. and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=50:1 to 20:1) to give the title compound (10.3 g, 69% yield, 91% purity on LCMS) as a brown oil.

[0937] .sup.1H NMR (CDCl.sub.3): δ 8.21 (d, 1H), 6.94-6.91 (m, 2H), 6.76 (s, 1H), 6.72 (dd, 1H), 5.38-5.29 (m, 1H), 3.64 (br s, 2H), 2.98-2.89 (m, 1H), 1.38 (d, 6H) and 1.30-1.27 (m, 6H). LCMS: m/z 289.2 (M+H).sup.+ (ES.sup.+).

Step G: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine

[0938] ##STR00137##

[0939] To a solution of 4-fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylaniline (4 g, 13.87 mmol, 1 eq) in THF (80 mL) was added TEA (2.81 g, 27.74 mmol, 3.86 mL, 2 eq). The mixture was cooled to 0° C. and then triphosgene (1.65 g, 5.55 mmol, 0.4 eq) was added to the mixture. The resulting mixture was heated to 70° C. and stirred for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=100:1 to 30:1) to give the title compound (1.9 g, 44% yield) as a yellow oil, which was used directly in the next step.

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

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

[0940] ##STR00138##

[0941] To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol, 62.50 mL, 1 eq) in concentrated H.sub.2SO.sub.4 (30 mL) was added a mixture of HNO.sub.3 (50 mL, 69 wt % in water) and concentrated H.sub.2SO.sub.4 (50 mL) dropwise at 0° C. over a period of 3.5 hours. The reaction mixture was stirred at 0° C. for 0.5 hour. Then the reaction mixture was poured into ice water (600 mL) and extracted with ethyl acetate (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). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (55 g, 66%) as a colourless oil.

[0942] .sup.1H NMR (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

[0943] ##STR00139##

[0944] To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g, contained another regio-isomer) in MeOH (500 mL) was added Pd/C (5 g, 10 wt % loading on activated carbon) under N.sub.2 atmosphere. The suspension was degassed under vacuum and purged with H.sub.2 several times. The reaction mixture was stirred under H.sub.2 (50 psi) at 20° C. for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:4) to give the title compound (19.82 g, 43% yield, 96.39% purity on LCMS) as a brown oil.

[0945] .sup.1H NMR (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).

[0946] LCMS: m/z 134.2 (M+H).sup.+ (ES.sup.+).

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

[0947] ##STR00140##

[0948] To a solution of 2,3-dihydro-1H-inden-4-amine (19.8 g, 148.66 mmol, 1 eq) and TEA (19.56 g, 193.26 mmol, 1.3 eq) in DCM (300 mL) was added dropwise Ac.sub.2O (17.45 g, 170.96 mmol, 1.15 eq) over 6 minutes at 0° C. Then the reaction mixture was warmed to 16° C. and stirred for 1.4 hours. The mixture was poured into water (500 mL) and extracted with DCM (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, 96.69% purity on LCMS) as a white solid.

[0949] .sup.1H NMR (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).

[0950] LCMS: m/z 176.2 (M+H).sup.+ (ES.sup.+)

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

[0951] ##STR00141##

[0952] N-(2,3-dihydro-1H-inden-4-yl)acetamide (34.6 g, 197.46 mmol, 1 eq), p-toluenesulfonic acid (18.70 g, 108.60 mmol, 0.55 eq) and Pd(OAc).sub.2 (2.22 g, 9.87 mmol, 0.05 eq) were suspended in toluene (400 mL) and stirred at 20° C. for 0.5 hour under air atmosphere. NBS (38.66 g, 217.20 mmol, 1.1 eq) was added. Then the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic phases were washed with brine (2×500 mL), dried over anhydrous NaSO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10: 1 to 2:1) to give the title compound (13.9 g, 27% yield, 98.1% purity on LCMS) as a white solid.

[0953] .sup.1H NMR (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).

[0954] LCMS: m/z 254.1 (M+H).sup.+ (ES.sup.+).

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

[0955] ##STR00142##

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

[0956] .sup.1H NMR (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).

[0957] LCMS: m/z 212.0 (M+H).sup.+ (ES.sup.+).

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

[0958] ##STR00143##

[0959] A solution of (2-methoxypyridin-4-yl)boronic acid (25.11 g, 164.15 mmol, 1.2 eq), 5-bromo-2,3-dihydro-1H-inden-4-amine (34 g, 136.80 mmol, 1 eq, HCl salt) and K.sub.2CO.sub.3 (60.50 g, 437.74 mmol, 3.2 eq) in dioxane (500 mL) and H.sub.2O (100 mL) was degassed with nitrogen for 15 minutes before Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (6 g, 7.35 mmol, 0.053 eq) was added. The reaction mixture was heated to 80° C. for 12 hours. The mixture was poured into water (500 mL) and extracted with ethyl acetate (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 silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 10:1) to give the title compound (27.4 g, 79% yield, 95% purity on LCMS) as a white solid.

[0960] .sup.1H NMR (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).

[0961] LCMS: m/z 241.2 (M+H).sup.+ (ES.sup.+).

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

[0962] ##STR00144##

[0963] To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50-35 mmol, 1.1 eq) in THF (275 mL) was added bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) in portions at 0° C. Then the reaction mixture was stirred at 16° C. for 0.5 hour. The reaction mixture was filtered and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacuo to give the title compound (9.04 g, 74%) as a light yellow solid.

[0964] .sup.1H NMR (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 A12: 5-Chloro-2-isocyanato-1,3-diisopropylbenzene

[0965] ##STR00145##

[0966] To a solution of 4-chloro-2,6-diisopropylaniline (0.105 g, 0.496 mmol) in toluene (1 mL) was added a phosgene solution (0.65 mL, 20 wt % in toluene, 1.22 mmol) and the reaction mixture was refluxed for 1 hour. Upon cooling, the mixture was concentrated in vacuo to afford the title compound as an orange oil (0.111 g, 94%).

[0967] .sup.1H NMR (CDCl.sub.3) δ 7.07 (d, 2H), 3.17 (h, 2H),1.24 (d, 12H).

PREPARATION OF EXAMPLES

Example 1: 2-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide, Sodium Salt

[0968] ##STR00146##

[0969] N,N-dimethyl-2-(3-sulfamoyl-H-pyrazol-1-yl)acetamide (Intermediate P1) (67 mg, 0.287 mmol) was dissolved in dry THF (2 mL) and sodium tert-butoxide (2 M in THF) (0.151 mL, 0.301 mmol) was added. After stirring for 1 hour, a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (60 mg, 0.301 mmol) in THF (1 mL) was added. The reaction mixture was stirred overnight at room temperature. EtOAc (6 mL) was added and the suspension stirred for 1 hour. The resultant colourless precipitate was collected by filtration, washed with EtOAc, and dried in vacuo to afford the title compound (15 mg, 11%) as a white solid.

[0970] .sup.1H NMR (DMSO-d.sub.6) δ 7.55-7.54 (m, 2H), 6.77 (s, 1H), 6.42 (d, J=2.2 Hz, 1H), 5.08 (s, 2H), 3.03 (s, 3H), 2.86 (s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.67 (t, J=7.3 Hz, 4H), 1.95-1.87 (m, 4H).

[0971] LCMS; m/z 432 (M+H).sup.+ (ES.sup.+).

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

[0972] ##STR00147##

[0973] N-Methyl-2-(3-sulfamoyl-1H-pyrazol-1-yl)acetamide (Intermediate P2) (58 mg, 0.251 mmol) was dissolved in dry THF (2 mL) and sodium tert-butoxide (2 M in THF) (0.125 mL, 0.251 mmol) was added. After stirring for 1 hour, a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A11 (so mg, 0.251 mmol) in THF (1 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in DMSO (2 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (29.6 mg, 27%) a colourless powder.

[0974] .sup.1H NMR (DMSO-d.sub.6) δ 8.06 (s, 1H), 7.84 (s, 1H), 7.81 (d, J=1.5 Hz, 1H), 6.88 (s, 1H), 6.64 (d, J=1.7 Hz, 1H), 4.84 (s, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 2.60 (d, J=4.6 Hz, 3H), 2.05-1.82 (m, 4H). One exchangeable proton not visible. LCMS; m/z 418 (M+H).sup.+ (ES.sup.+), 416 (M−H).sup.− (ES.sup.−).

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

[0975] ##STR00148##

[0976] Prepared according to the general procedure of 2-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1H-pyrazol-1-yl)-N-methylacetamide (Example 2) from 1-(1-acetylazetidin-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P3) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (8 mg, 11%) as a white solid.

[0977] .sup.1H NMR (DMSO-d.sub.6) δ 7.95 (s, 1H), 7.73 (s, 1H), 6.85 (s, 1H), 6.61 (s, 1H), 5.35-5.22 (m, 1H), 4.63-4.54 (m, 1H), 4.41-4.22 (m, 2H), 4.09 (dd, J=10.1, 5.5 Hz, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.3 Hz, 4H), 1.99-1.87 (m, 4H), 1.81 (s, 3H). One exchangeable proton not visible.

[0978] LCMS; m/z 444 (M+H).sup.+ (ES.sup.+).

Example 4: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide, Sodium Salt

[0979] ##STR00149##

[0980] 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide (Intermediate P4) (59.8 mg, 0.26 mmol) was dissolved in THF:DMF (1:1) (4 mL) and sodium tert-butoxide (2M in THF) (0.136 ml, 0.273 mmol) was added. After stirring for 1 hour, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (54.3 mg, 0.273 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. Ethyl acetate (6 mL) was added and the suspension stirred for hours. The resultant precipitate was collected by filtration, washed with ethyl acetate (2 mL), triturated with ethyl acetate (5 mL) for 1 hour, filtered, and dried under reduced pressure to afford the title compound (73 mg, 60%) as a white solid.

[0981] .sup.1H NMR (DMSO-d.sub.6) δ 7.47 (s, 1H), 6.79-6.74 (m, 2H), 4.38-4.32 (m, 2H), 3.80-3.72 (m, 2H), 3.00 (s, 3H), 2.79-2.71 (m, 4H), 2.67 (t, J=7.2 Hz, 4H), 1.95-1.86 (m, 4H).

[0982] LCMS; m/z 430 (M+H).sup.+ (ES.sup.+).

Example 5: 1-(1-Acetylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, Sodium Salt

[0983] ##STR00150##

[0984] 1-(1-Acetylpiperidin-4-yl)-1H-pyrazole-3-sulfonamide (Intermediate P14) (42.8 mg, 0.157 mmol) was dissolved in THF (10 mL) by heating to 60° C. Sodium tert-butoxide (2M in THF, 0.083 ml, 0.165 mmol) was added and the mixture was allowed to cool to room temperature and stirred for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (31.3 mg, 0.157 mmol) was added and the mixture was stirred at room temperature for 15 hours. The suspension was filtered, washing with THF (1 mL). The solid was triturated with EtOAc (5 mL) and filtered. The solid was further triturated with MeCN (5 mL), filtered and dried under vacuum to afford the title compound as a white solid (35 mg, 43%).

[0985] .sup.1H NMR (DMSO-d.sub.6) δ 7.72 (d, J=2.3 Hz, 1H), 7.55 (s, 1H), 6.76 (s, 1H), 6.38 (d, J=2.3 Hz, 1H), 4.54-4.25 (m, 2H), 3.99-3.80 (m, 1H), 3.22-3.07 (m, 1H), 2.74 (t, J=7.4 Hz, 4H), 2.71-2.58 (m, 5H), 2.03 (s, 3H), 2.00-1.65 (m, 8H).

[0986] LCMS; m/z 472 (M+H).sup.+ (ES.sup.+).

Example 6: N-(3-(Dimethylamino)propyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[0987] ##STR00151##

[0988] N1,N1,N3-Trimethylpropane-1,3-diamine (28 μl, 0.19 mmol), sodium bicarbonate (16 mg, 0.19 mmol) and HATU (72 mg, 0.19 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred at room temperature for 2 days. The reaction was quenched with water (1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound as a white solid (34 mg, 43%).

[0989] .sup.1H NMR (DMSO-d.sub.6) (rotamers) δ 7.77 (s, 1H), 6.83 (s, 1H), 6.80 & 6.72 (2×s, 1H), 3.85 &3.81 (2×s, 3H),3.47 & 3.30 (t, J=6.9 & 7.3 Hz, 2H),3.01 & 2.96 (2×s, 3H),2.84 & 2.76 (t, J=7.7 Hz, 2H), 2.76 (t, J=7.4 Hz, 4H), 2.64 (t, J=6.1 Hz, 4H), 2.60 & 2.32 (2×s, 6H), 1.89 (quin, J=7.2 Hz, 4H), 1.90 & 1.77 (2×m, 2H). NH not observed.

[0990] LCMS; m/z 503.5 (M+H).sup.+ (ES.sup.+); 501.3 (M−H).sup.− (ES.sup.−).

Example 7: N-Cyclobutyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[0991] ##STR00152##

[0992] Prepared according to the general procedure of N-(3-(dimethylamino)propyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 6) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) and N-methylcyclobutanamine, HCl salt to afford the title compound (40 mg, 54%) as a white solid.

[0993] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.74 (s, 1H), 7.39 (br s, 1H), 6.83 (s, 1H), 6.80-6.32 (m, 1H), 5.00-4.14 (m, 1H), 3.83 (s, 3H), 2.98 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H),2.36-2.12 (m, 2H), 2.13-1.85 (m, 6H), 1.81-1.24 (m, 2H).

[0994] LCMS; m/z 472.5 (M+H).sup.+ (ES.sup.+); 470.3 (M−H).sup.− (ES.sup.−).

Example 8: N-Cyclobutyl-3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[0995] ##STR00153##

[0996] HATU (68.5 mg, 0.180 mmol) was added to a solution of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) (67.9 mg, 0.150 mmol) and N-methylcyclobutanamine, HCl (20.07 mg, 0.165 mmol) in DMF (1 mL). Triethylamine (23.01 μL, 0.165 mmol) was added and the mixture stirred for 20 hours. Water (1 mL) was slowly added and the suspension stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was purified by chromatography on RP Flash C18 (13 g column, 0-50% MeCN/10 mM ammonium bicarbonate) and triturated with TBME (2 mL) for 1 hour to afford the title compound (30 mg, 40%) as a white solid.

[0997] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.09 (s, 1H), 7.90 (s, 1H), 7.28-7.20 (m, 1H), 7.12 (d, J=7.7 Hz, 2H), 7.03-6.86 (2×m, 1H), 4.78-4.24 (2×m, 1H), 3.91 (s, 3H), 3.02-2.91 (m, 5H), 2.27-1.91 (m, 4H), 1.72-1.36 (m, 2H), 1.17-0.94 (m, 12H).

[0998] LCMS; m/z 476 (M+H).sup.+ (ES.sup.+).

Example 9: N-(2-Cyanoethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[0999] ##STR00154##

[1000] HATU (77 mg, 0.201 mmol) was added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (75.2 mg, 0.168 mmol) and 3-(methylamino)propanenitrile (18.83 μL, 0.201 mmol) in DMF (1 mL) and the mixture stirred at room temperature for hours. Water (1 mL) was slowly added and the suspension stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (25 mg, 31%) as a white solid.

[1001] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.96 (s, 1H), 8.09 (s, 1H), 7.06 (s, 1H), 6.95 (s, 1H), 3.95-3.92 (2×s, 3H), 3.80-3.65 (m, 2H), 3.07-2.87 (2×s, 3H), 2.88 (t, J=6.6 Hz, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.5 Hz, 4H), 1.99-1.92 (m, 4H).

[1002] LCMS: m/z 471 (M+H).sup.+ (ES.sup.+).

Example 10: N-(2-(Dimethylamino)ethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1003] ##STR00155##

[1004] N1,N1,N2-Trimethylethane-1,2-diamine (29 μL, 0.223 mmol) and HATU (83 mg, 0.219 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (34 mg, 44%) as a white solid.

[1005] .sup.1H NMR (DMSO-d.sub.6), rotamers; 610.36 (s, 1H), 7.87 & 7.80 (2×s, 1H), 6.91-6.80 (m, 2H), 3.88 & 3.83 (2×s, 3H), 3.70-3.62 & 3.48-3.40 (2×m, 2H), 3.04 & 2.96 (2×s, 3H), 2.86 & 2.40 (2×m, 2H), 2.77 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 2.01-1.85 (m, 7H). CH.sub.3 not visible.

[1006] LCMS; m/z 489.4 (M+H).sup.+ (ES.sup.+); 487.3 (M−H).sup.− (ES.sup.−).

Example 11: N-Cyclopentyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1007] ##STR00156##

[1008] N-Methylcyclopentanamine (0.012 mL, 0.102 mmol) and HATU (39 mg, 0.103 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (60 mg, 0.134 mmol) in DMF (1 mL) and stirred for 20 hours. TBME (5 mL) was added and the resulting solid filtered off. The filtrate was treated with NaHCO.sub.3 (5-7 mg, 0.068 mmol) and the solution purified by reversed phase chromatography (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the crude product as a white solid. This material (33 mg) was dissolved in MeOH (3 mL), 0.1 M aqueous NaHCO.sub.3 (0.68 mL, 0.068 mmol) and water (1 mL), sonicated for 10 minutes, evaporated in vacuo and dried to afford the title compound (29 mg, 83%) as a white solid.

[1009] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.51 (s, 1H), 6.76 (s, 1H), 6.53 (br s, 1H), 4.31-414 (m, 1H), 3.78 (s, 3H), 2.86 (s, 3H), 2.74 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.5 Hz, 4H), 1.89 (p, J=7.5 Hz, 4H), 1.82-1.47 (m, 8H).

[1010] LCMS; m/z 486.5 (M+H).sup.+ (ES.sup.+); 484.3 (M−H).sup.− (ES.sup.−).

Example 12: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(2-(N-methylacetamido)ethyl)-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1011] ##STR00157##

[1012] Prepared according to the general procedure of N-(3-(dimethylamino)propyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 6) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt (Intermediate P8) and N-methyl-N-(2-(methylamino)ethyl)acetamide to afford the title compound (38 mg, 47%) as a white solid.

[1013] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.98 (br s, 1H), 7.90 (br s, 1H), 6.94-6.74 (m, 2H), 3.92-3.77 (m, 3H), 3.65-3.37 (m, 4H), 3.08-2.51 (m, 14H), 2.04-1.76 (m, 7H). LCMS; m/z 517.4 (M+H).sup.+ (ES.sup.+); 515.3 (M−H).sup.− (ES.sup.−).

Example 13: N-(2-Acetamidoethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1014] ##STR00158##

[1015] Prepared according to the general procedure of N-(3-(dimethylamino)propyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 6) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt (Intermediate P8) and N-(2-(methylamino)ethyl)acetamide, HCl to afford the title compound (26 mg, 32%) as a white solid.

[1016] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.94 (br s, 1H), 8.32-7.69 (m, 2H), 6.94-6.74 (m, 2H), 3.92-3.78 (m, 3H), 3.54-3.36 (m, 2H), 3.31-3.12 (m, 2H), 3.08-2.93 (m, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.92 (p, J=7.5 Hz, 4H), 1.81-1.62 (m, 3H).

[1017] LCMS; m/z 503.5 (M+H).sup.+ (ES.sup.+); 501.3 (M−H).sup.− (ES.sup.−).

Example 14: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide, Sodium Salt

[1018] ##STR00159##

[1019] HATU (49.3 mg, 0.130 mmol) was added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (67.3 mg, 0.150 mmol) and N-methyltetrahydro-2H-pyran-4-amine (14.93 mg, 0.130 mmol) in DMF (1 mL) and the reaction mixture was stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide. The solid was dissolved in THF (2 mL) and 2 M sodium tert-butoxide in THF (54.0 μL, 0.108 mmol) was added. The suspension was stirred at room temperature for 2 hours and filtered. The collected solid was washed with EtOAc (2 mL) and dried under reduced pressure for 6 hours to afford the title compound (46 mg, 80%) as a white solid.

[1020] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.47 (s, 1H), 6.77 (s, 1H), 6.58 (s, 1H), 4.53-4.49 (m, 0.6H), 3.94-3.90 (m, 2.4H), 3.80 (s, 3H), 3.43-3.41 (m, 1H), 3.16-3.12 (m, 1H), 2.89 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.66 (t, J=7.6 Hz, 4H), 1.93-1.80 (m, 6H), 1.59-1.55 (m, 2H).

[1021] LCMS; m/z 502 (M+H).sup.+ (ES.sup.+).

Example 15: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N-bis(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1022] ##STR00160##

[1023] HATU (67.9 mg, 0.178 mmol) was added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (66.7 mg, 0.149 mmol) and 2,2′-azanediylbis(ethan-1-ol) (17.11 μL, 0.178 mmol) in DMF (1 mL) and the reaction mixture was stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (32 mg, 42%) as a white solid.

[1024] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.60 (d, J=10.0 Hz, 1H), 7.24 (br s, 1H), 6.80 (s, 1H), 6.69 (s, 1H), 4.95-4.77 (m, 2H), 3.78 (s, 3H), 3.78-3.52 (m, 8H), 2.76 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.6 Hz, 4H), 1.95-1.88 (m, 4H).

[1025] LCMS; m/z 492 (M+H).sup.+ (ES.sup.+).

Example 16: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1026] ##STR00161##

[1027] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,N-bis(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 15) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P8) and 2-((2-methoxyethyl)amino)ethan-1-ol to afford the title compound as a white solid (7 mg, 9%).

[1028] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.61 (s, 1H), 7.11 (br s, 1H), 6.81 (s, 1H), 6.60 (s, 1H), 4.89-4.82 (m, 1H), 3.78 (s, 3H), 3.67-3.36 (m, 8H), 3.28-3.15 (2×2s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.95-1.88 (m, 4H).

[1029] LCMS; m/z 506 (M+H).sup.+ (ES.sup.+).

Example 17: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(oxetan-3-yl)-1H-pyrazole-5-carboxamide

[1030] ##STR00162##

[1031] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,N-bis(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 15) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P8) and N-methyloxetan-3-amine to afford the title compound (27 mg, 36%) as a white solid.

[1032] .sup.1H NMR (DMSO-d.sub.6) rotamers: δ 10.95 (br s, 1H), 8.09 (s, 1H), 7.11 (s, 0.5H), 6.95 (s, 1H), 6.89 (s, 0.5H), 5.25-5.22 (m, 0.5H), 5.06-5.03 (m, 0.5H), 4.69-4.60 (m, 4H), 3.92 (s, 3H), 3.19-3.06 (m, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.5 Hz, 4H), 2.00-1.92 (m, 4H).

[1033] LCMS; m/z 474 (M+H).sup.+ (ES.sup.+).

Example 18: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1034] ##STR00163##

[1035] 3-(Methylamino)propan-1-ol (19 μL, 0.195 mmol), NaHCO.sub.3 (16 mg, 0.190 mmol) and HATU (72 mg, 0.189 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 2 days. The reaction was quenched with water (1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (37 mg, 48%) as a white solid.

[1036] .sup.1H NMR (DMSO-d6), rotamers; δ 7.81 (s, 1H), 7.61-6.99 (br s, 1H), 6.85 (s, 1H), 6.82-6.71 (m, 1H), 4.48 (br s, 1H), 3.94-3.78 (m, 3H), 3.59-3.13 (m, 4H), 3.07-2.90 (m, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 1.92 (p, J=7.4 Hz, 4H), 1.79-1.57 (m, 2H).

[1037] LCMS; m/z 476.4 (M+H).sup.+ (ES.sup.+); 474.4 (M−H).sup.− (ES.sup.−).

Example 19: N-(2,3-Dihydroxypropyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1038] ##STR00164##

[1039] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 18) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P8) and 3-(methylamino)propane-1,2-diol to afford the title compound (43 mg, 54%) as a white solid.

[1040] .sup.1H NMR (DMSO-d6), rotamers; δ 7.83-7.64 (m, 1H), 7.61-7.01 (m, 1H), 6.87-6.80 (m, 1H), 6.78-6.71 (m, 1H), 5.13-4.99 (m, 1H), 4.96-4.84 (m, 1H), 4.62 (s, 1H), 3.90-3.73 (m, 3H), 3.71-3.09 (m, 5H), 3.07 (s, 1H), 2.98 (s, 1H), 2.76 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 2.07-1.79 (m, 4H).

[1041] LCMS; m/z 492.4 (M+H).sup.+ (ES.sup.+); 490.2 (M−H).sup.− (ES.sup.−).

Example 20: N-Ethyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1042] ##STR00165##

[1043] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 18) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P8) and 2-(ethylamino)ethan-1-ol to afford the title compound (39 mg, 52%) as a white solid.

[1044] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 8.16-6.99 (br s, 1H), 7.82 & 7.80 (2×s, 1H), 6.86 (s, 1H), 6.79 & 6.74 (2×s, 1H), 4.93 & 4.82 (2×m, 1H), 3.82 (s, 3H), 3.65-3.33 (m, 6H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.3 Hz, 4H), 1.93 (quin, J=7.4 Hz, 4H), 1.15 & 1.08 (2×t, J=7.1 Hz, 3H).

[1045] LCMS; m/z 476.5 (M+H).sup.+ (ES.sup.+); 474.3 (M−H).sup.− (ES.sup.−).

Example 21: N-((2,6-Diisopropylphenyl)carbamoyl)-1-methyl-5-(morpholine-4-carbonyl)-1H-pyrazole-3-sulfonamide

[1046] ##STR00166##

[1047] Morpholine (19 μL, 0.220 mmol) and HATU (82 mg, 0.217 mmol) were successively added to a solution of 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) (70 mg, 0.155 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (41 mg, 53%) as a white solid.

[1048] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.11 (br s, 1H), 7.79 (s, 1H), 7.22 (t, J=7.7 Hz, 1H), 7.10 (d, J=7.7 Hz, 2H), 6.91 (s, 1H), 3.93 (s, 3H), 3.72-3.39 (m, 8H), 2.98 (sept, J=6.9 Hz, 2H), 1.05 (d, J=6.8 Hz, 12H).

[1049] LCMS; m/z 478.4 (M+H).sup.+ (ES.sup.+); 476.4 (M−H).sup.− (ES.sup.−).

Example 22: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1050] ##STR00167##

[1051] HATU (66.5 mg, 0.175 mmol) was added to a solution of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) (65.9 mg, 0.146 mmol) and 2-methoxy-N-methylethanamine (19.00 μL, 0.175 mmol) in DMF (1 mL) and the mixture stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred at room temperature for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (18 mg, 25%) as a white solid.

[1052] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.11 (s, 1H), 8.00-7.72 (m, 1H), 7.28-7.20 (m, 1H), 7.15-7.09 (m, 2H), 7.02-6.86 (m, 1H), 3.93 (s, 1H), 3.86 (s, 2H), 3.66-3.57 (m, 1H), 3.57-3.45 (m, 2H), 3.44-3.37 (m, 1H), 3.27 (s, 1H), 3.16 (s, 2H), 3.03-2.87 (m, 4H), 1.17-0.77 (m, 12H).

[1053] LCMS; m/z 480 (M+H).sup.+ (ES.sup.+).

Example 23:3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1054] ##STR00168##

[1055] Prepared according to the general procedure of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 22) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) and bis(2-methoxyethyl)amine to afford the title compound (22 mg, 23%) as a white solid.

[1056] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.11 (s, 1H), 7.91 (s, 1H), 7.31-7.18 (m, 1H), 7.13 (s, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 3.86 (s, 3H), 3.66-3.58 (m, 2H), 3.56-3.47 (m, 4H), 3.43-3.35 (m, 2H), 3.27 (s, 3H), 3.14 (s, 3H), 2.94 (sept, J=6.8 Hz, 2H), 1.18-0.87 (m, 12H).

[1057] LCMS; m/z 524 (M+H).sup.+ (ES.sup.+).

Example 24: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(4-hydroxypiperidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, Partial Ammonium Salt

[1058] ##STR00169##

[1059] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 18) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P8) and piperidin-4-ol to afford the title compound (44 mg, 57%) as a white solid.

[1060] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.88 (s, 1H), 7.48-6.92 (m, 1H), 6.88 (s, 1H), 6.78 (s, 1H), 4.83 (d, J=3.9 Hz, 1H), 3.96 (m, 1H), 3.87 (s, 3H), 3.77 (m, 1H), 3.63 (m, 1H), 3.32 (m, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.94 (quin, J=7.5 Hz, 4H), 1.77 (m, 2H), 1.39 m, 2H).

[1061] LCMS; m/z 488.4 (M+H).sup.+ (ES.sup.+); 486.3 (M−H).sup.− (ES.sup.−).

Example 25: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxypyrrolidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, Partial Ammonium Salt

[1062] ##STR00170##

[1063] 3-Methoxypyrrolidine (19 mg, 0.188 mmol) and HATU (72 mg, 0.189 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 20 hours. The solution was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (25 mg, 32%) as a white solid.

[1064] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.82 (s, 1H), 7.08 (s, 1H), 6.96 (d, J=2.6 Hz, 1H), 6.86 (s, 1H), 4.07-3.90 (m, 4H), 3.75-3.67 (m, 1H), 3.64-3.39 (m, 4H), 3.26 (s, 1H), 3.19 (s, 1H), 2.76 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.06-1.84 (m, 6H). LCMS; m/z 488.43 (M+H).sup.+ (ES.sup.+); 486.35 (M−H).sup.− (ES.sup.−).

Example 26: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1065] ##STR00171##

[1066] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxypyrrolidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, partial ammonium salt (Example 25) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P8) and bis(2-methoxyethyl)amine to afford the title compound (36 mg, 44%) as a white solid.

[1067] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.79 (s, 1H), 7.10 (br s, 1H), 6.85 (s, 1H), 6.73 (s, 1H), 3.80 (s, 3H), 3.63 (t, J=5.8 Hz, 2H), 3.58-3.49 (m 4H), 3.39 (t, J=5.0 Hz, 2H), 3.28 (s, 3H), 3.14 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.3 Hz, 4H), 1.92 (quin, J=7.5 Hz, 4H).

[1068] LCMS; m/z 520.44 (M+H).sup.+ (ES.sup.+); 518.30 (M−H).sup.− (ES.sup.−).

Example 27:3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1069] ##STR00172##

[1070] 2-Methoxy-N-methylethanamine (19 μL, 0.173 mmol), HATU (71 mg, 0.187 mmol) and Hunig's base (65 μL, 0.372 mmol) were successively added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate P6) (50 mg, 0.124 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (1 mL) and purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford crude product. 18 mg of the crude product were partitioned between TBME (1 mL) and 0.1 M aqueous NaHCO.sub.3 (340 μL, 0.034 mmol). The layers were separated and the aqueous layer washed with further TBME (2×1 mL). The aqueous layer was evaporated in vacuo and dried to afford the title compound (17 mg, 27%) as a white solid.

[1071] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.52 (s, 1H), 6.77 (s, 1H), 6.6 & 6.55 (2×s, 1H), 3.81 & 3.76 (2×s, 3H), 3.61 (m, 1H), 3.56 (m, 2H), 3.4 (m, 1H), 3.28 & 3.16 (2×s, 3H), 3.05 & 2.97 (2×s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.5 Hz, 4H), 1.89 (quin, J=7.5 Hz, 4H).

[1072] LCMS; m/z 476.4 (M+H).sup.+ (ES.sup.+); 474.3 (M−H).sup.− (ES.sup.−).

Example 28: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-(morpholine-4-carbonyl)-1H-pyrazole-3-sulfonamide, Sodium Salt

[1073] ##STR00173##

[1074] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 27) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P8) and morpholine to afford the title compound (12 mg, 16%) as a white solid.

[1075] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.54 (s, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 3.84 (s, 3H), 3.76-3.43 (m, 8H), 2.75 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.3 Hz, 4H), 1.90 (quin, J=7.5 Hz, 4H).

[1076] LCMS; m/z 474.4 (M+H).sup.+ (ES.sup.+); 472.3 (M−H).sup.− (ES.sup.−).

Example 29: N-((3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide

[1077] ##STR00174##

[1078] Sodium tert-butoxide (2 M in THF) (0.057 mL, 0.115 mmol) was added to a solution of N-((1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide (Intermediate P15) (30 mg, 0.109 mmol) in THF (2.2 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (24 mg, 0.120 mmol) was added and stirred at room temperature overnight. The suspension was filtered and the collected solid washed with EtOAc (2 mL). The solid was dissolved in DMSO (2 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (20 mg, 38%) as a white solid.

[1079] .sup.1H NMR (DMSO-d.sub.6) δ 10.77 (br s, 1H), 7.93 (s, 1H), 6.88 (s, 1H), 6.62 (s, 1H), 4.75-4.61 (m, 1H), 4.59 (s, 2H), 2.90 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.56 (t, J=7.3 Hz, 4H), 2.02 (s, 3H), 1.90 (p, J=7.6 Hz, 4H), 1.31 (d, J=6.5 Hz, 6H).

[1080] LCMS; m/z 474.5 (M+H).sup.+ (ES.sup.+)

Example 30: 5-(Azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, Sodium Salt

[1081] ##STR00175##

[1082] 5-(Azetidine-1-carbonyl)-1-isopropyl-H-pyrazole-3-sulfonamide (Intermediate P12) (50 mg, 0.184 mmol) was dissolved in THF (2 mL), and 2M sodium tert-butoxide in THF (0.101 mL, 0.202 mmol) was added. After 1 hour, 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) (44.7 mg, 0.202 mmol) followed by THF (2 mL) was added and the mixture stirred at room temperature for 16 hours. Additional isocyanate (20 mg) and 2 M sodium tert-butoxide in THF (0.05 mL) were added and the reaction was left to stir for a further 4 hours. The emulsion obtained was filtered and dried under vacuum at 40° C. for 4 days to afford the title compound (46 mg, 48%) as a white solid.

[1083] .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.65 (s, 1H), 5.26 (sept, J=6.7 Hz, 1H), 4.25 (t, J=7.7 Hz, 2H), 4.02 (t, J=7.8 Hz, 2H), 3.22-2.93 (m, 2H), 2.26 (app. pent, J=7.7 Hz, 2H), 1.37 (d, J=6.6 Hz, 6H), 1.03 (d, J=6.8 Hz, 12H).

[1084] LCMS; m/z 494.4 (M+H).sup.+ (ES.sup.+); 492.3 (M−H).sup.− (ES.sup.−).

Example 31: 5-(Azetidine-1-carbonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, partial Ammonium Salt

[1085] ##STR00176##

[1086] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Example 30) from 5-(azetidine-1-carbonyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P12) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1). The crude product was purified by chromatography on RP Flash C18 (basic) to afford the title compound (47 mg, 52%) as a white solid.

[1087] .sup.1H NMR (DMSO-d.sub.6) δ 7.77 (s, 1H), 6.92-6.68 (m, 2H), 5.28 (sept, J=6.5 Hz, 1H), 4.27 (t, J=7.7 Hz, 2H), 4.03 (t, J=7.7 Hz, 2H), 2.76 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.3 Hz, 4H), 2.31-2.19 (m, 2H), 1.90 (p, J=7.4 Hz, 4H), 1.38 (d, J=6.6 Hz, 6H).

[1088] LCMS; m/z 472.5 (M+H).sup.+ (ES.sup.+); 470.3 (M−H).sup.− (ES.sup.−).

Example 32: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1089] ##STR00177##

[1090] HATU (68.8 mg, 0.181 mmol) was added to a solution of 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P11) (73.4 mg, 0.151 mmol) and methylamine (83 μL, 0.166 mmol) in DMF (1 mL). TEA (21 μL, 0.151 mmol) was added and the mixture stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the mixture stirred for 1 hour, filtered, and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered, the solid washed with water (0.5 mL) and MTBE (1 mL), and then purified by chromatography on RP Flash C18 (13 g column, 0-50% MeCN/10 mM ammonium bicarbonate). The product was triturated with MTBE (2 mL) for 1 hour, filtered and dried under vacuum for 15 hours to afford the title compound (7 mg, 10%) as a white solid.

[1091] .sup.1H NMR (DMSO-d.sub.6) δ 11.21 (s, 1H), 8.64 (s, 1H), 7.89 (s, 1H), 7.31 (s, 1H), 7.12 (s, 2H), 4.13 (s, 3H), 3.00-2.90 (m, 2H), 2.74 (d, J=4.5 Hz, 3H), 1.05-1.01 (m, 12H).

[1092] LCMS; m/z 456.4 and 458.4 (M+H).sup.+ (ES.sup.+).

Example 33: 3-(N-((4-Fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1093] ##STR00178##

[1094] A mixture of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P13) (70 mg, 0.184 mmol) and 4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)aniline (Intermediate A6) (40 mg, 0.167 mmol) in MeCN (1 mL) was stirred at 50° C. for 1 hour. The crude product was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the desired carboxamide as a white solid (21 mg). To a solution of the carboxamide (21 mg) in THF (0.5 mL), a solution of 2.0 M NaO.sup.tBu in THF (1.0 eq) was added. The mixture was stirred for 1 hour, the solvent evaporated and the solid triturated with THF/MTBE. The precipitate was collected by filtration, washing with ether, and dried in vacuo to afford the title compound (5 mg, 6%) as a white solid.

[1095] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.39 (s, 1H), 6.81 (td, J=10.6, 2.9 Hz, 2H), 6.61 (s, 1H), 3.90-3.81 (m, 5H), 3.28-3.11 (m, 3H), 3.04-2.97 (m, 7H), 1.57-1.43 (m, 4H), 1.04 (d, J=6.8 Hz, 6H).

[1096] LCMS; m/z 496.5 (M+H).sup.+ (ES.sup.+); 494.3 (M−H).sup.− (ES.sup.−).

Example 34: 3-(N-((2-Isopropyl-5-(pyrimidin-5-yl)phenyl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1097] ##STR00179##

[1098] Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 33) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P13) and 2-isopropyl-5-(pyrimidin-5-yl)aniline (Intermediate A8) to afford the title compound (27 mg, 23%) as a white solid.

[1099] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 9.15 (s, 1H), 9.01 (s, 2H), 8.14 (s, 1H), 7.77 (s, 1H), 7.31 (s, 2H), 6.63 (s, 1H), 3.82 (s, 3H), 3.19 (sept, J=6.8 Hz, 1H), 3.03 (s, 3H), 2.98 (s, 3H), 1.17 (d, J=6.8 Hz, 6H).

[1100] LCMS; m/z 472.4 (M+H).sup.+ (ES.sup.+); 470.4 (M−H).sup.− (ES.sup.−).

Example 35: 3-(N-((4-Fluoro-2-isopropyl-6-(1-methyl-H-pyrazol-4-yl) phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1101] ##STR00180##

[1102] Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 33) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P13) and 4-fluoro-2-isopropyl-6-(1-methyl-H-pyrazol-4-yl)aniline (Intermediate A4) to afford the title compound (40 mg, 20%) as a white solid.

[1103] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.95 (s, 1H), 7.76 (s, 1H), 7.25 (s, 1H), 7.10 (dd, J=9.9, 3.0 Hz, 1H), 6.86 (dd, J=9.8, 2.9 Hz, 1H), 6.58 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.20 (m, 1H), 2.99 (s, 6H), 1.06 (d, J=6.8 Hz, 6H).

[1104] LCMS; m/z 492.4 (M+H).sup.+ (ES.sup.+); 490.3 (M−H).sup.− (ES.sup.−).

Example 16: 3-(N-((2-Isopropyl-5-(1-methyl-1H-pyrazol-4-yl)phenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1105] ##STR00181##

[1106] Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 33) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P13) and 2-isopropyl-5-(1-methyl-1H-pyrazol-4-yl)aniline (Intermediate A7) to afford the title compound (6 mg, 5%) as a white solid.

[1107] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.94 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.10-7.05 (m, 1H), 6.61 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.09 (sept, J=6.8 Hz, 1H), 3.03 (s, 3H), 2.98 (s, 3H), 1.14 (d, J=6.8 Hz, 6H).

[1108] LCMS; m/z 474.5 (M+H).sup.+ (ES.sup.+); 472.3 (M−H).sup.− (ES.sup.−).

Example 37: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N-(cyanomethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1109] ##STR00182##

[1110] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P11) and 2-(methylamino)acetonitrile, HCl to afford the title compound (26 mg, 42%).

[1111] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.25 (s, 1H), 7.99 (s, 1H), 7.14 (s, 3H), 4.58 (s, 2H), 3.97 (s, 3H), 3.12 (s, 3H), 2.98-2.85 (m, 2H), 1.05 (br s, 12H).

[1112] LCMS; m/z 495.5 and 497.5 (M+H).sup.+ (ES.sup.+).

Example 38:3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N-isopropyl-1-methyl-1H-pyrazole-5-carboxamide

[1113] ##STR00183##

[1114] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) and isopropylamine to afford the title compound (28 mg, 45%) as a white solid.

[1115] .sup.1H NMR (DMSO-d.sub.6) δ 11.06 (s, 1H), 8.49 (d, J=7.8 Hz, 1H), 7.85 (s, 1H), 7.47 (s, 1H), 7.27-7.20 (m, 1H), 7.11 (d, J=7.6 Hz, 2H), 4.15 (s, 3H), 4.09-3.99 (m, 1H), 2.90-2.86 (m, 2H), 1.13 (d, J=6.6 Hz, 6H), 1.05-1.03 (m, 12H).

[1116] LCMS; m/z 450 (M+H).sup.+ (ES.sup.+).

Example 39: N-((2,6-Diisopropylphenyl)carbamoyl)-5-(3-fluoroazetidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

[1117] ##STR00184##

[1118] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) and 3-fluoroazetidine, HCl. The sodium salt was generated by dissolving the free acid (19 mg, 0.041 mmol) in THF (1 mL) and adding 2 M solution of sodium tert-butoxide (20.50 μL, 0.041 mmol) in THF. The suspension was stirred for 2 hours and filtered. The collected solid was washed with EtOAc (2 mL) and dried under reduced pressure for 6 hours to afford the title compound (6 mg, 8%) as a white solid.

[1119] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.32 (s, 1H), 7.11-7.10 (m, 1H), 7.01 (d, J=7.3 Hz, 2H), 6.71 (s, 1H), 5.51-5.33 (m, 1H), 4.63-4.59 (m, 1H), 4.40-4.32 (m, 2H), 4.11-4.01 (m, 1H), 3.98 (s, 3H), 3.16-3.12 (m, 2H), 1.04 (d, J=6.8 Hz, 12H).

[1120] LCMS; m/z 466 (M+H).sup.+ (ES.sup.+).

Example 40: N-(Cyanomethyl)-3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1121] ##STR00185##

[1122] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) and 2-(methylamino)acetonitrile, HCl to afford the title compound (25 mg, 33%) as a white solid.

[1123] .sup.1H NMR (DMSO-d.sub.6) δ 7.59 (s, 1H), 7.20-7.12 (m, 1H), 7.06 (d, J=7.6 Hz, 2H), 6.91 (s, 1H), 4.57 (s, 2H), 3.91 (s, 3H), 3.13 (s, 3H), 3.08-3.05 (m, 2H), 1.05 (d, J=6.9 Hz, 12H). Acidic NH not observed

[1124] LCMS; m/z 461 (M+H).sup.+ (ES.sup.+).

Example 41: 3-(N-((4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1125] ##STR00186##

[1126] Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 33) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P13) and 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A3) to afford the title compound (23 mg, 9%) as a white solid.

[1127] .sup.1H NMR (DMSO-d.sub.6, 70° C.) δ 8.55 (m, 1H), 8.45 (dd, J=4.8, 1.7 Hz, 1H), 7.77 (dt, J=7.8, 2.0 Hz, 1H), 7.25 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 7.06 (dd, J=10.2, 3.0 Hz, 1H), 6.91 (dd, J=9.1, 3.0 Hz, 1H), 6.44 (s, 1H), 3.84 (s, 3H), 3.26 (sept, J=6.9 Hz, 1H), 3.04 (s, 6H), 1.13 (d, J=6.9 Hz, 6H). NH not observed.

[1128] LCMS; m/z 489.4 (M+H).sup.+ (ES.sup.+).

Example 42: 3-(N-((4-Fluoro-2-isopropyl-6-(pyrimidin-5-yl)phenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1129] ##STR00187##

[1130] Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 33) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P13) and 4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)aniline (Intermediate A5) to afford the title compound (44 mg, 16%) as a white solid.

[1131] .sup.1H NMR (DMSO-d.sub.6, 70° C.) δ 9.03 (s, 1H), 8.76 (s, 2H), 7.30 (bs, 1H), 7.11 (dd, J=10.2, 3.0 Hz, 1H), 7.03 (dd, J=9.0, 3.0 Hz, 1H), 6.43 (s, 1H), 3.85 (s, 3H), 3.26 (sept, J=6.8 Hz, 1H), 3.04 (s, 6H), 1.14 (d, J=6.8 Hz, 6H).

[1132] LCMS; m/z 490.4 (M+H).sup.+ (ES.sup.+).

Example 43: N-Cyclopropyl-3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1133] ##STR00188##

[1134] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) and N-methylcyclopropanamine, HCl to afford the title compound (45 mg, 55%) as a white solid.

[1135] .sup.1H NMR (DMSO-d.sub.6), rotamers; 611.04 (s, 1H), 7.96-7.86 (2×s, 1H), 7.26-7.23 (m, 1H), 7.16-7.11 (m, 3H), 3.95 (s, 3H), 3.09-2.84 (m, 6H), 1.18-1.14 (m, 12H), 0.55-0.52 (m, 4H).

[1136] LCMS; m/z 462 (M+H).sup.+ (ES.sup.+).

Example 44: 3-(N-((2,5-Diisopropylphenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1137] ##STR00189##

[1138] Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 33) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P13) and 2,5-diisopropylaniline to afford the title compound (8 mg, 6%) as a white solid.

[1139] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.51-7.47 (m, 2H), 7.05 (d, J=8.0 Hz, 1H), 6.80 (dd, J=8.0, 2.0 Hz, 1H), 6.62 (s, 1H), 3.83 (s, 3H), 3.04 (m, 4H), 2.99 (s, 3H), 2.75 (sept, J=6.9 Hz, 1H), 1.15 (d, J=6.9 Hz, 6H), 1.10 (d, J=6.8 Hz, 6H).

[1140] LCMS; m/z 436.5 (M+H).sup.+ (ES.sup.+).

Example 45: 5-(Azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

[1141] ##STR00190##

[1142] Azetidine hydrochloride (17 mg, 0.182 mmol), NaHCO.sub.3 (30 mg, 0.357 mmol) and HATU (68 mg, 0.179 mmol) were successively added to a solution of 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P10) (70 mg, 0.149 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (1 mL) and purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the free acid (59 mg, 84%) as a white solid. The sodium salt was generated by dissolving the free acid (55 mg, 0.12 mmol) in THF (3 mL) and adding a 2 M solution of sodium tert-butoxide (63 μL, 0.126 mmol) in THF. The suspension was stirred for 30 minutes and filtered. The collected solid was washed with EtOAc (2 mL), slurried in MeCN (3 mL), filtered and dried under vacuum to afford the title compound (29 mg, 40%) as a white solid.

[1143] .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.67 (s, 1H), 4.29 (t, J=7.7 Hz, 2H), 4.03 (t, J=7.7 Hz, 2H), 3.98 (s, 3H), 3.11 (m, 2H), 2.27 (p, J=7.7 Hz, 2H), 1.02 (d, J=7.7 Hz, 12H).

[1144] LCMS; m/z 466.4 (M+H).sup.+ (ES.sup.+); 464.3 (M−H).sup.− (ES.sup.−).

Example 46: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-isopropyl-1-methyl-1H-pyrazole-5-carboxamide

[1145] ##STR00191##

[1146] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt (Intermediate P8) and isopropylamine to afford the title compound (14 mg, 24%) as a white solid.

[1147] .sup.1H NMR (DMSO-d.sub.6) δ 10.94 (s, 1H), 8.50 (d, J=7.8 Hz, 1H), 8.02 (s, 1H), 7.46 (s, 1H), 6.94 (s, 1H), 4.13 (s, 3H), 4.09-3.98 (m, 1H), 2.79 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.98-1.91 (m, 4H), 1.14 (d, J=6.6 Hz, 6H).

[1148] LCMS; m/z 446 (M+H).sup.+ (ES.sup.+).

Example 47: 3-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N-isopropyl-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1149] ##STR00192##

[1150] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 45) from 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P10) and N-methylpropan-2-amine to afford the title compound (33 mg, 45%) as a white solid. .sup.1H NMR (DMSO-d.sub.6), rotamers; 611.18 (bs, 1H), 7.82 (s, 1H), 6.92 & 6.80 (2×s, 1H), 6.90 (d, J=10.0 Hz, 2H), 4.67 & 3.96 (2×m, 1H), 3.89 & 3.87 (2×s, 3H), 2.99 (m, 2H), 2.85 & 2.82 (2×s, 3H), 1.14 (d, J=6.7 Hz, 6H), 1.04 (bs, 12H).

[1151] LCMS; m/z 482.4 (M+H).sup.+ (ES.sup.+); 480.3 (M−H).sup.− (ES.sup.−).

Example 48: N,N-Diethyl-3-(N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1152] ##STR00193##

[1153] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 45) from 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P10) and diethylamine to afford the title compound (26 mg, 34%) as a white solid.

[1154] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.35 (s, 1H), 6.79 (d, J=10.0 Hz, 2H), 6.51 (s, 1H), 3.77 (s, 3H), 3.50-3.28 (m, 4H), 3.14 (m, 2H), 1.12 (bs, 6H), 1.03 (d, J=6.8 Hz, 12H). LCMS; m/z 482.4 (M+H).sup.+ (ES.sup.+); 480.4 (M−H).sup.− (ES.sup.−).

Example 49: N-Ethyl-3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1155] ##STR00194##

[1156] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 45) from 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P10) and N-methylethanamine to afford the title compound (24 mg, 33%) as a white solid.

[1157] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.34 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.58 & 6.52 (2×s, 1H), 3.80 (s, 3H), 3.52-3.35 (m, 2H), 3.14 (m, 2H), 3.0 & 2.96 (2×s, 3H), 1.12 (t, J=7.1 Hz, 3H), 1.03 (d, J=6.9 Hz, 12H).

[1158] LCMS; m/z 468.4 (M+H).sup.+ (ES.sup.+); 466.3 (M−H).sup.− (ES.sup.−).

Example 50: 3-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1159] ##STR00195##

[1160] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 45) from 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P10) and methylamine to afford the title compound (26 mg, 39%) as a white solid.

[1161] .sup.1H NMR (DMSO-d.sub.6) δ 11.16 (bs, 1H), 8.62 (q, J=4.6 Hz, 1H), 7.76 (s, 1H), 7.28 (s, 1H), 6.89 (d, J=10.0 Hz, 2H), 4.12 (s, 3H), 2.95 (sept, J=6.4 Hz, 2H),2.74 (d, J=4.6 Hz, 3H), 1.02 (bs, 12H).

[1162] LCMS; m/z 440.4 (M+H).sup.+ (ES.sup.+); 438.4 (M−H).sup.− (ES.sup.−).

Example 51:5-(Azetidine-1-carbonyl)-N-((2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1163] ##STR00196##

[1164] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) and azetidine, HCl to afford the title compound (6 mg, 8%) as a white solid.

[1165] .sup.1H NMR (DMSO-d.sub.6) δ 7.38 (s, 1H), 7.11 (dd, J=8.4, 6.8 Hz, 1H), 7.06-6.99 (m, 2H), 6.71 (s, 1H), 4.29 (t, J=7.7 Hz, 2H), 4.07-3.97 (m, 5H), 3.12-3.08 (m, 2H), 2.31-2.22 (m, 2H), 1.04 (d, J=6.8 Hz, 12H). Acidic NH not observed.

[1166] LCMS; m/z 448 (M+H).sup.+ (ES.sup.+).

Example 52: N-Cyclopropyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1167] ##STR00197##

[1168] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) and N-methylcyclopropanamine, HCl to afford the title compound (28 mg, 34%) as a white solid.

[1169] .sup.1H NMR (DMSO-d.sub.6) δ 10.90 (br s, 1H), 8.06 (s, 1H), 7.16 (br s, 1H), 6.95 (s, 1H), 3.94 (s, 3H), 2.99 (s, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 1.99-1.91 (m, 4H), 0.60-0.50 (m, 4H). One exchangeable proton not observed.

[1170] LCMS; m/z 458 (M+H).sup.+ (ES.sup.+).

Example 53: N-(Cyanomethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1171] ##STR00198##

[1172] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 45) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) and N 2-(methylamino)acetonitrile, HCl to afford the title compound (33 mg, 46%) as a white solid.

[1173] .sup.1H NMR (DMSO-d.sub.6) δ 7.75 (s, 1H), 6.91 (s, 1H), 6.84 (s, 1H), 4.58 (s, 2H), 3.90 (s, 3H), 3.14 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 1.92 (quin, J=7.4 Hz, 4H).

[1174] LCMS; m/z 457.4 (M+H).sup.+ (ES.sup.+); 455.3 (M−H).sup.− (ES.sup.−).

Example 54: 5-(Azetidine-1-carbonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1175] ##STR00199##

[1176] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 45) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) and azetidine, HCl to afford the title compound (40 mg, 55%), as a white solid.

[1177] .sup.1H NMR (DMSO-d.sub.6) δ 10.93 (bs, 1H), 8.09 (s, 1H), 7.06 (s, 1H), 6.95 (s, 1H), 4.34 (t, J=7.7 Hz, 2H), 4.08 (s, 3H), 4.05 (t, J=7.7 Hz, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.3 Hz, 4H), 2.33-2.20 (m, 2H), 1.95 (quin, J=7.4 Hz, 4H).

[1178] LCMS; m/z 444.5 (M+H).sup.+ (ES.sup.+); 442.3 (M−H).sup.− (ES.sup.−).

Example 5:3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1179] ##STR00200##

[1180] Methylamine in THF (108 μL, 0.217 mmol) and HATU (82 mg, 0.217 mmol) were successively added to a solution of 3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) (70 mg, 0.155 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (26 mg, 40%) as a white solid.

[1181] .sup.1H NMR (DMSO-d.sub.6) δ 11.07 (bs, 1H), 8.62 (d, J=5.1 Hz, 1H), 7.74 (s, 1H), 7.28 (s, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.09 (d, J=7.7 Hz, 2H), 4.13 (s, 3H), 2.96 (m, 2H), 2.73 (d, J=4.5 Hz, 3H), 1.06-1.00 (m, 12H).

[1182] LCMS; m/z 422.4 (M+H).sup.+ (ES.sup.+); 420.4 (M−H).sup.− (ES.sup.−).

Example 56:3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N-ethyl-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1183] ##STR00201##

[1184] Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 55) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) and N-methylethanamine to afford the title (10 mg, 14%) as a white solid.

[1185] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.09 (bs, 1H), 7.81 (s, 1H), 7.23 (t, J=7.7 Hz, 1H), 7.11 (d, J=7.6 Hz, 2H), 6.96 & 6.87 (2×s, 1H), 3.92 & 3.90 (2×s, 3H), 3.46 & 3.31 (2×q, J=7.1 Hz, 2H),2.98 (brs, 5H), 1.16-1.0 (m, 15H).

[1186] LCMS; m/z 450.5 (M+H).sup.+ (ES.sup.+); 448.4 (M−H).sup.− (ES.sup.−).

Example 57: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N,N-diethyl-1-methyl-1H-pyrazole-5-carboxamide

[1187] ##STR00202##

[1188] Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 55) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) and diethylamine to afford the title compound (33 mg, 45%) as a white solid.

[1189] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.09 (bs, 1H), 7.83 (s, 1H), 7.23 (t, J=7.7 Hz, 1H), 7.11 (d, J=7.7 Hz, 2H), 6.87 (s, 1H), 3.88 (s, 3H), 3.45 (m, 2H), 3.31 (m, 2H), 2.98 (sept, J=6.8 Hz, 2H), 1.20-0.95 (m, 18H).

[1190] LCMS; m/z 464.5 (M+H).sup.+ (ES.sup.+); 462.4 (M−H).sup.− (ES.sup.−).

Example 58: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N-isopropyl-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1191] ##STR00203##

[1192] Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 55) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) and N-methylpropan-2-amine to afford the title compound (47 mg, 8%) as a white solid.

[1193] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.13 (br s, 1H), 7.91 (s, 1H), 7.30-7.19 (m, 1H), 7.12 (d, J=7.7 Hz, 2H), 7.02 (s, 0.5H), 6.90 (s, 0.5H), 4.74-4.57 (m, 1H), 3.92-3.78 (m, 3H), 2.95-2.93 (m, 2H), 2.85-2.82 (m, 3H), 1.11-1.08 (m, 18H).

[1194] LCMS; m/z 464 (M+H).sup.+ (ES.sup.+).

Example 59: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide

[1195] ##STR00204##

[1196] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Example 30) from 1-methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide (Intermediate P7) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1). The crude product was purified by chromatography on RP Flash C18 (basic) to afford the title compound (25 mg, 28%) as a white solid.

[1197] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.9 (br s, 1H), 7.99 (s, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 3.98 (s, 3H), 3.52 and 3.47 (2×t, J=6.2 Hz, 4H),2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.02-1.75 (m, 8H).

[1198] LCMS; m/z 458 (M+H).sup.+ (ES.sup.+).

Example 60: 3-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1199] ##STR00205##

[1200] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Example 30) from N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P5) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (mg, 67%) as a white solid.

[1201] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.35 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.59 (s, 1H), 3.81 (s, 3H), 3.18-3.07 (m, 2H), 3.03 (s, 3H), 2.98 (s, 3H), 1.02 (d, J=6.9 Hz, 12H).

[1202] LCMS; m/z 454 (M+H).sup.+ (ES.sup.+).

Example 61: 5-(3-Fluoroazetidine-1-carbonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Partial Ammonium Salt

[1203] ##STR00206##

[1204] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 45) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) and 3-fluoroazetidine, HCl to afford the title compound (36 mg, 50%) as a white solid. .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.74 (s, 1H), 6.87 (s, 1H), 6.78 (s, 1H), 5.45-5.26 (m, 1H), 4.61-4.47 (m, 1H), 4.44-4.22 (m, 2H), 4.08-3.95 (m, 1H), 3.95 (s, 3H), 2.70 (t, J=7.4 Hz, 4H), 2.55 (t, J=7.4 Hz, 4H), 1.85 (quin, J=7.5 Hz, 4H).

[1205] LCMS; m/z 462.4 (M+H).sup.+ (ES.sup.+); 460.4 (M−H).sup.− (ES.sup.−).

Example 62: N-Ethyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1206] ##STR00207##

[1207] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 45) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) and N-methylethanamine to afford the title (31 mg, 44%) as a white solid.

[1208] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.98 (s, 1H), 8.00 (s, 1H), 6.96-6.87 (m, 2H), 3.90 & 3.88 (2×s, 3H), 3.47 and 3.33 (2×q, J=7.0 Hz, 2H), 3.00 and 2.97 (2×s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.94 (p, J=7.4 Hz, 4H), 1.15-1.08 (m, 3H). LCMS; m/z 446.4 (M+H).sup.+ (ES.sup.+); 444.4 (M−H).sup.− (ES.sup.−).

Example 63: N-((2,6-Diisopropylphenyl)carbamoyl)-1-methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide

[1209] ##STR00208##

[1210] Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Example 30) from 1-methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide (Intermediate P7) and 2-isocyanato-1,3-diisopropylbenzene (Intermediate A9). The crude product was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (40 mg, 43%) as a colourless solid.

[1211] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.11 (s, 1H), 7.89 (s, 1H), 7.30-7.18 (m, 1H), 7.16-7.07 (m, 3H), 4.01 (s, 3H), 3.57-3.40 (m, 4H), 3.03-2.85 (m, 2H), 1.91-1.78 (m, 4H), 1.04 (br s, 12H).

[1212] LCMS; m/z 462.5 (M+H).sup.+ (ES.sup.+).

Example 64: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-isopropyl-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1213] ##STR00209##

[1214] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate P6) and N-methylpropan-2-amine to afford the title compound (25 mg, 42%) as a white solid.

[1215] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.74 (s, 1H), 6.85 (s, 1H), 6.78 & 6.67 (2×s, 1H), 4.68 & 4.03 (s, 1H), 3.83 (s, 3H), 2.85 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 1.92 (quin, J=7.4 Hz, 4H), 1.15 (d, J=6.7 Hz, 6H). Acidic proton not observed. LCMS; m/z 460.5 (M+H).sup.+ (ES.sup.+); 458.3 (M−H).sup.− (ES.sup.−).

Example 65: N,N-Diethyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide

[1216] ##STR00210##

[1217] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate P6) and diethylamine to afford the title compound (35 mg, 58%) as a white solid.

[1218] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.96 (s, 1H), 7.92 (s, 1H), 6.90 (s, 1H), 6.83 (s, 1H), 3.86 (s, 3H), 3.45 & 3.30 (2×m, 4H),2.78 (t, J=7.3 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.94 (quin, J=7.4 Hz, 4H), 1.18-1.05 (m, 6H).

[1219] LCMS; m/z 460.5 (M+H).sup.+ (ES.sup.+); 458.4 (M−H).sup.− (ES.sup.−).

Example 66: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1220] ##STR00211##

[1221] Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 32) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate P6) and methylamine to afford the title compound (18 mg, 34%) as a white solid.

[1222] .sup.1H NMR (DMSO-d.sub.6) δ 1.88 (s, 1H), 8.61 (q, J=4.6 Hz, 1H), 7.97 (s, 1H), 7.28 (s, 1H), 6.87 (s, 1H), 4.07 (s, 3H), 2.71 (t, J=7.4 Hz, 4H), 2.67 (d, J=4.6 Hz, 3H), 2.52 (t, J=7.4 Hz, 4H), 1.87 (quin, J=7.5 Hz, 4H).

[1223] LCMS; m/z 418.4 (M+H).sup.+ (ES.sup.+); 416.3 (M−H).sup.− (ES.sup.−).

Example 67: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1224] ##STR00212##

[1225] N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P5) (105 mg, 0.452 mmol) was dissolved in THF (5 mL) and 2 M sodium tert-butoxide in THF (0.237 mL, 0.475 mmol) added. After 1 hour, 2-isocyanato-1,3-diisopropylbenzene (Intermediate A9) (92 mg, 0.452 mmol) was added and the mixture stirred at room temperature for 15 hours. The suspension was filtered and washed with THF (1 mL). The collected solid was triturated with EtOAc (5 mL) for 1 hour, filtered, and dried under vacuum to afford the title compound (137 mg, 64%) as a white solid.

[1226] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.37 (br s, 1H), 7.14-7.05 (m, 1H), 7.01 (d, J=7.5 Hz, 2H), 6.61 (s, 1H), 3.81 (s, 3H), 3.15-3.13 (m, 2H), 3.03 (s, 3H), 2.99 (s, 3H), 1.03 (d, J=6.8 Hz, 12H).

[1227] LCMS; m/z 436 (M+H).sup.+ (ES.sup.+).

Example 68:3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

[1228] ##STR00213##

[1229] 4-Chloro-2,6-diisopropylaniline, HCl (51.9 mg, 0.209 mmol) and triethylamine (0.064 ml, 0.460 mmol) were dissolved in dry THF (5 mL). Triphosgene (49.6 mg, 0.167 mmol) was added to the mixture at room temperature and stirred for 5 hours. The mixture was concentrated in vacuo and dried azeotropically with toluene (1 mL×3). Dry THF (2 mL) was added to the residue and N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P5) (48.6 mg, 0.209 mmol) added to the mixture. After 30 minutes, 60% sodium hydride (20.91 mg, 0.523 mmol) was added and the mixture heated at 60° C. for 15 hours. After cooling to room temperature, saturated aqueous ammonium chloride (10 mL) was added and the mixture extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (5 mL), dried over MgSO.sub.4, concentrated in vacuo and the residue purified by chromatography on silica gel (25 g column, 5-100% EtOAc/isohexane) to afford the title compound (17 mg, 17%) as a white solid.

[1230] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.24 (s, 1H), 7.98 (s, 1H), 7.14 (s, 2H), 7.01 (s, 1H), 3.93 (s, 3H), 3.00 (s, 3H), 2.99 (s, 3H), 2.98-2.91 (m, 2H), 1.17-0.93 (br d, 12H).

[1231] LCMS; m/z 469 and 471 (M+H).sup.+ (ES.sup.+).

Example 6A: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1232] ##STR00214##

[1233] Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 67) from N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P5) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (235 mg, 64%) as a white solid.

[1234] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.51 (s, 1H), 6.77 (s, 1H), 6.62 (s, 1H), 3.82 (s, 3H), 3.04 (s, 3H), 2.99 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.93-1.86 (m, 4H).

[1235] LCMS; m/z 432 (M+H).sup.+ (ES.sup.+).

Example 70: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(thiazol-2-ylmethyl)-1H-pyrazole-5-carboxamide

[1236] ##STR00215##

[1237] Prepared according to the general procedure of N-(2-cyanoethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 9) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt (Intermediate P8) and N-methyl-1-(thiazol-2-yl)methanamine to afford the title compound (18 mg, 26%) as a white solid.

[1238] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.95 (br s, 1H), 8.09-8.07 (2×s, 1H), 7.89-7.65 (m, 2H), 7.11-7.08 (2×s, 1H), 6.94 (s, 1H), 4.97-4.92 (2×s, 2H), 3.97-3.95 (2×s, 3H), 3.12-3.01 (2×s, 3H),2.78 (t, J=7.6 Hz, 4H), 2.64-2.53 (m, 4H), 1.94-1.92 (m, 4H).

[1239] LCMS; m/z 515 (M+H).sup.+ (ES.sup.+).

Example 71: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazole-5-carboxamide

[1240] ##STR00216##

[1241] Prepared according to the general procedure of N-(2-cyanoethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 9) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt (Intermediate P8) and N-methyl-1-(1-methyl-H-imidazol-2-yl)methanamine to afford the title compound (10 mg, 14%) as a white solid.

[1242] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.71 (s, 1H), 7.20 (s, 0.4H), 7.14 (s, 0.6H), 7.05 (s, 0.6H), 6.93 (s, 0.4H), 6.85-6.83 (m, 2H), 4.73-4.17 (m, 2H), 3.89 (s, 3H), 3.64-3.45 (2×s, 3H), 2.98-2.94 (2×s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.63-2.59 (m, 4H), 1.94-1.87 (m, 4H). NH not observed.

[1243] LCMS; m/z 512 (M+H).sup.+ (ES.sup.+).

Example 72: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(thiazol-2-yl)-1H-pyrazole-5-carboxamide

[1244] ##STR00217##

[1245] Prepared according to the general procedure of N-(2-cyanoethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 9) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) and N-methylthiazol-2-amine to afford the title compound (4 mg, 7%) as a white solid.

[1246] .sup.1H NMR (DMSO-d.sub.6) δ 11.03 (br s, 1H), 8.11 (br s, 1H), 7.66 (d, J=3.6 Hz, 1H), 7.45 (d, J=3.6 Hz, 1H), 7.38 (s, 1H), 6.95 (s, 1H), 4.05 (s, 3H), 3.72 (s, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.3 Hz, 4H), 1.99-1.92 (m, 4H).

[1247] LCMS; m/z 501 (M+H).sup.+ (ES.sup.+).

Example 73: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1248] ##STR00218##

[1249] N-Methyl-1-(1-methyl-1H-pyrazol-5-yl)methanamine (23.45 mg, 0.187 mmol), NaHCO.sub.3 (16 mg, 0.190 mmol) and HATU (72 mg, 0.189 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 2 days. The reaction was quenched with water (1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (14 mg, 17%) as a white solid.

[1250] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.65 & 7.58 (2×s, 1H), 7.50-7.00 (br s, 1H), 7.36 (d, J=1.9 Hz, 1H), 6.81 (s, 1H), 6.81 & 6.60 (2×s, 1H), 6.27 & 6.14 (2×s, 1H), 4.76 & 4.70 (2×s, 2H), 3.87 & 3.80 (2×s, 3H), 3.80 & 3.58 (2×s, 3H), 2.99 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.5 Hz, 4H), 1.89 (p, J=7.5 Hz, 4H).

[1251] LCMS; m/z 512.4 (M+H).sup.+ (ES.sup.+); 510.3 (M−H).sup.− (ES.sup.−).

Example 74:3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1252] ##STR00219##

[1253] HATU (51.4 mg, 0.135 mmol) was added to a solution of 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P11) (54.8 mg, 0.113 mmol) and 2-(methylamino)-ethanol (9.19 μL, 0.124 mmol) in DMF (1 mL) and the mixture was stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (10 mg, 18%) as a white solid.

[1254] .sup.1H NMR (DMSO-d.sub.6) rotamers: δ 11.18 (s, 1H), 7.95 (s, 1H), 7.14 (s, 2H), 6.98 (s, 1H), 4.96-4.79 (m, 1H), 3.93-3.86 (m, 3H), 3.64-3.41 (m, 4H), 3.06-2.88 (m, 5H), 1.08 (br s, 12H).

[1255] LCMS m/z 500.4/502.4 (M+H).sup.+ (ES.sup.+).

Example 75: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N-(2-hydroxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1256] ##STR00220##

[1257] 2-(Methylamino)ethanol (18 μL, 0.224 mmol) and HATU (82 mg, 0.217 mmol) were successively added to a solution of 3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P9) (70 mg, 0.155 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford a white solid. The solid was dissolved in DMF (0.5 mL), diluted with water (1 mL) and stirred for 20 hours. The resulting precipitate was filtered off, washed with water and TBME, and dried to afford the title compound (8 mg, 11%), as a white solid.

[1258] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.07 (s, 1H), 7.88 (s, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.12 (d, J=7.7 Hz, 2H), 7.02 & 7.0 (2×s, 1H),4.96 & 4.81 (t, J=5.0 & 5-7 Hz, 1H),3.94 & 3.89 (2×s, 3H),3.59 & 3.40 (2×t, J=5.6 & 5.1 Hz, 2H),3.50 (2×t, J=5.6 & 5.2 Hz, 2H), 3.03 & 2.98 (2×s, 3H), 2.95 (m, 2H), 1.06 (br s, 12H).

[1259] LCMS; m/z 466.5 (M+H).sup.+ (ES.sup.+); 464.4 (M−H).sup.− (ES.sup.−).

Example 76: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1260] ##STR00221##

[1261] 2-Aminoethanol (14 μL, 0.232 mmol) and HATU (83 mg, 0.219 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (18 mg, 25%) as a white solid.

[1262] .sup.1H NMR (DMSO-d.sub.6) δ 8.61 (t, J=5.7 Hz, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 6.88 (s, 1H), 4.73 (t, J=5.7 Hz, 1H), 4.10 (s, 3H), 3.48 (app q, J=6.0 Hz, 2H), 3.27 (app q, J=6.0 Hz, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H). One exchangeable proton not seen.

[1263] LCMS; m/z 448.4 (M+H).sup.+ (ES.sup.+); 446.4 (M−H).sup.− (ES.sup.−).

Example 77: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1264] ##STR00222##

[1265] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 76) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) and 2-methoxyethan-1-amine to afford the title compound as a colourless solid (37 mg, 51%).

[1266] .sup.1H NMR (DMSO-d.sub.6) δ 10.93 (br s, 1H), 8.74 (t, J=5.5 Hz, 1H), 7.90 (s, 1H), 7.36 (s, 1H), 6.90 (s, 1H), 4.11 (s, 3H), 3.44 (t, J=5.5 Hz, 2H), 3.39 (t, J=5.5 Hz, 2H), 3.26 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.3 Hz, 4H), 1.94 (p, J=7.5 Hz, 4H).

[1267] LCMS; m/z 462.4 (M+H).sup.+ (ES.sup.+); 460.3 (M−H).sup.− (ES.sup.−).

Example 78: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[1268] ##STR00223##

[1269] 2-(Methylamino)ethanol (19.25 μL, 0.240 mmol) and HATU (72 mg, 0.189 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P8) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 20 hours. The solution was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (39 mg, 54%) as a white solid.

[1270] .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.69 (s, 1H), 7.10 (s, 1H), 7.10 & 6.74 (2×s, 1H), 6.82 (s, 1H), 4.96 & 4.84 (2×t, J=5.5 Hz, 1H), 3.84 & 3.80 (2×s, 3H), 3.59 (m, 1H), 3.55-3.41 (m, 3H), 3.06 & 2.97 (2×s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.5 Hz, 4H), 1.92 (p, J=7.5 Hz, 4H).

[1271] LCMS; m/z 462.42 (M+H).sup.+ (ES.sup.+); 460.30 (M−H).sup.− (ES.sup.−).

Example 70: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropyl-phenyl)carbamoyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Sodium Salt

Step A: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl)carbamoyl) sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1272] ##STR00224##

[1273] A solution of N,N-bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P16) (2.2 g, 6.87 mmol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine (Intermediate A10) (2.16 g, 6.87 mmol, 1 eq) and t-BuONa (659 mg, 6.87 mmol, 1 eq) in THF (100 mL) was stirred at 25° C. for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (column: Welch Ultimate XB_C18, 41 mm*235 mm*20/40 μm, mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 0%-30%, 35 min) to give the title compound (2.5 g, 56% yield, 98% purity on LCMS) as a white solid.

[1274] .sup.1H NMR (DMSO-d.sub.6): δ 11.10 (br s, 1H), 8.06 (d, 1H), 7.79 (br s, 1H), 7.18 (d, 1H), 7.02 (d, 1H), 6.83-6.72 (m, 2H), 6.70 (s, 1H), 5.29-5.23 (m, 1H), 3.83 (s, 3H), 3.64-3.61 (m, 2H), 3.55-3.50 (m, 4H), 3.45-3.40 (m, 2H), 3.28 (s, 3H), 3.14 (s, 3H), 3.03-300 (m, 1H), 1.30 (d, 6H) and 1.09-1.05 (m, 6H).

[1275] LCMS: m/z 635.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl)carbamoyl) sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1276] ##STR00225##

[1277] To a solution of 3-(N-((4-fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl) carbamoyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (2.5 g, 3-94 mmol, 1 eq, free form) in THF (100 mL) was added with t-BuONa (378 mg, 3.94 mmol, 1 eq). The reaction mixture was stirred at 25° C. for 1 hour and then concentrated in vacuo. The residue was triturated with isopropyl ether (20 mL) to give the title compound (2.2 g, 85% yield, 99% purity on LCMS, sodium salt) as a white solid.

[1278] .sup.1H NMR (DMSO-d.sub.6): 7.99-7.88 (m, 1H), 7.53-7.40 (m, 1H), 7.15-7.08 (m, 1H), 6.94-6.82 (m, 2H), 6.68 (s, 1H), 6.51-6.44 (m, 1H), 5.28-5.22 (m, 1H), 3.75 (s, 3H), 3.74-3.56 (m, 6H), 3.45-3.38 (m, 2H), 3.29 (s, 3H), 3.17 (s, 3H), 3.12-307 (m, 1H), 1.29 (d, 6H) and 1.20-1.04 (m, 6H).

[1279] LCMS: m/z 635.1 (M+H).sup.+ (ES.sup.+).

Example 80: N,N-Bis(2-methoxyethyl)-3-(N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide, Sodium Salt

Step A: N,N-Bis(2-methoxyethyl)-3-(N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide

[1280] ##STR00226##

[1281] A solution of N,N-bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P16) (2.56 g, 7.99 mmol, 1 eq) and t-BuONa (768 mg, 7.99 mmol, 1 eq) in THF (200 mL) was stirred at 25° C. for 30 minutes. Then 4(4-isocyanato-2,3-dihydro-H-inden-5-yl)-2-methoxypyridine (Intermediate A11) (3.34 g, 8.79 mmol, 1.1 eq) was added. The reaction mixture was stirred at 70° C. for 2 hours and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (column: Welch Ultimate XB_C18, 41 mm*235 mm*20/40 μm, mobile phase: [A: water (0.05% ammonium hydroxide); B: MeCN]; B %: 0%-30%,35 min) to give the title compound (1.35 g, 29% yield, 99% purity on LCMS) as a white solid. .sup.1H NMR (DMSO-d.sub.6): δ 8.08 (d, 1H), 7.14-7.11 (m, 1H), 7.07-7.05 (m, 1H), 6.91 (d, 1H), 6.74 (s, 1H), 6.60 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.64-3.62 (m, 2H), 3.56-3.54 (m, 4H), 3.39-3.37 (m, 2H), 3.28 (s, 3H), 3.14 (s, 3H), 2.89 (t, 2H), 2.71 (t, 2H) and 1.99-1.94 (m, 2H).

[1282] LCMS: m/z 587.3 (M+H).sup.+ (ES.sup.+).

Step B: N,N-Bis(2-methoxyethyl)-3-(N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1283] ##STR00227##

[1284] To a solution of N,N-bis(2-methoxyethyl)-3-(N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide (1.35 g, 2.30 mmol, 1 eq, free form) in THF (20 mL) was added with t-BuONa (221 mg, 2.30 mmol, 1 eq). The reaction mixture was stirred at 25° C. for 1 hour and then concentrated in vacuo. The residue was triturated with isopropyl ether (20 mL) to give the title compound (1.2 g, 85% yield, 99% purity on HPLC) as a white solid.

[1285] .sup.1H NMR (DMSO-d.sub.6): δ 8.05 (d, 1H), 7.30 (br s, 1H), 7.04 (dd, 2H), 6.92 (d, 1H), 6.76 (s, 1H), 6.48 (d, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.64-3.62 (m, 2H), 3.56-3.53 (m, 4H), 3.39-3.37 (m, 2H), 3.29 (s, 3H), 3.15 (s, 3H), 2.87 (t, 2H), 2.73-2.70 (m, 2H) and 1.98-1.91 (m, 2H).

[1286] LCMS: m/z 587.1 (M+H).sup.+ (ES.sup.+).

Example 81: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropyl-phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

Step A: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

[1287] ##STR00228##

[1288] To a solution of N,N,1-trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P5) (1.7 g, 7.32 mmol, 1 eq) in THF (20 mL) was added t-BuONa (703 mg, 7.32 mmol, 1 eq) at 25° C. and stirred for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine (Intermediate A10) (2.30 g, 7.32 mmol, 1 eq) was added and the resulting mixture was stirred for 0.5 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Welch Ultimate XB_C18, 41 mm*235 mm*20/40 μm; mobile phase: [water (10 mM NH.sub.4HCO.sub.3)-ACN]; B %: 0%-30%, 35 min) to give the title compound (2.34 g, 59% yield, 98% purity on HPLC) as a white solid.

[1289] .sup.1H NMR (DMSO-d.sub.6): δ 8.03 (d, 1H), 7.65 (br s, 1H), 7.16 (d, 1H), 6.98 (d, 1H), 6.85 (d, 1H), 6.74 (s, 1H), 6.70 (s, 1H), 5.30-5.21 (m, 1H), 3.89 (s, 3H), 3.09-3.03 (m, 1H), 3.00 (s, 6H), 1.30 (d, 6H) and 1.07 (d, 6H).

[1290] LCMS: m/z 547.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1291] ##STR00229##

[1292] To a solution of 3-(N-((4-fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (1.71 g, 3.13 mmol, 1 eq, free form) in THF (40 mL) was added t-BuONa (300 mg, 3.13 mmol, 1 eq) at 25° C. Then the mixture was stirred for 1 hour. The mixture was concentrated in vacuo. The residue was triturated with MTBE (100 mL). The solid was dissolved in water (100 mL) and then lyophilized to give the title compound (1.60 g, 90% yield, 99.9% purity on HPLC) as a white solid.

[1293] .sup.1H NMR (DMSO-d.sub.6): δ 7.95 (d, 1H), 7.37 (br s, 1H), 7.09 (d, 1H), 6.93-6.90 (m, 2H), 6.69 (s, 1H), 6.53 (s, 1H), 5.29-5.22 (m, 1H), 3.83 (s, 3H), 3.15-3.09 (m, 1H), 3.01 (d, 6H), 1.29 (d, 6H) and 1.05 (d, 6H).

[1294] LCMS: m/z 547.3 (M+H).sup.+ (ES.sup.+).

Example 82: 3-(N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

[1295] ##STR00230##

[1296] A solution of N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P5) (6.59 g, 28.39 mmol, 0.9 eq) and t-BuONa (3.33 g, 34.70 mmol, 1.1 eq) in THF (200 mL) was stirred at 16° C. for 0.5 hour. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A11) (8.4 g, 31-54 mmol, 1 eq) was added. The reaction mixture was stirred at 16° C. for 0.5 hour and then filtered. The filter cake was washed with MeCN (125 mL). Then the solid was dissolved in H.sub.2O (100 mL) and filtered. The filtrate was lyophilized to give the title compound (8.02 g, 49% yield, 99.54% purity on LCMS, Na salt) as a white solid.

[1297] .sup.1H NMR (DMSO-d.sub.6): δ 8.02 (d, 1H), 7.42 (br s, 1H), 7.10-7.02 (m, 2H), 6.89 (dd, 1H), 6.74 (s, 1H), 6.59 (s, 1H), 3.84 (d, 6H), 3.02 (d, 6H), 2.87 (t, 2H), 2.72 (t, 2H) and 1.97-1.90 (m, 2H).

[1298] LCMS: m/z 499.3 (M+H).sup.+ (ES.sup.+).

Example 83: 2-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1H-pyrazol-1-yl)-N,N,2-trimethylpropanamide

[1299] ##STR00231##

[1300] Sodium tert-butoxide (2 M in THF) (0.12 mL, 0.240 mmol) was added to a solution of N,N,2-trimethyl-2-(3-sulfamoyl-1H-pyrazol-1-yl)propanamide (60 mg, 0.230 mmol) (Intermediate P17) in THF (3 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (50.5 mg, 0.254 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by chromatography on RP Flash C18 (13 g cartridge, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (22 mg, 21%) as a colourless solid.

[1301] .sup.1H NMR (DMSO-d.sub.6, rotamers) δ 10.96 (br s, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 6.90 (s, 1H), 6.77 (s, 1H), 2.89-2.68 (m, 7H), 2.60 (t, J=7.5 Hz, 4H), 2.31 (br s, 3H), 2.01-1.86 (m, 4H), 1.70 (s, 6H).

[1302] LCMS; m/z 460.4 (M+H).sup.+ (ES.sup.+)

[1303] The compound of example 84 was synthesised by methods analogous to those outlined above.

TABLE-US-00002 TABLE 1 .sup.1H NMR and MS data Ex Structure and Name .sup.1H NMR spectrum MS spectrum MW 84 [00232] .sup.1H NMR (DMSO-d.sub.6) δ 11.03 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (s, 1H), 6.68 (s, 1H), 3.89 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 2.78 (s, 3H), 2.65 (t, J = 7.3 Hz, 2H), 2.22 (s, 3H), 1.97 (p, J = 7.5 Hz, 2H), 1.70 (s, 6H). m/z 527.3 (M + H).sup.+ (ES.sup.+); 525.3 (M − H).sup.− (ES.sup.−). 526.6

Examples—Biological Studies

[1304] NLRP3 and Pyroptosis

[1305] 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.

[1306] THP-1 Cells: Culture and Preparation

[1307] 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.

[1308] THP-1 Cells Pyroptosis Assay

[1309] The following method step-by-step assay was followed for compound screening. [1310] 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 μg/ml LPS in 40 μl of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) [1311] 2. Add 5p compound (8 points half-log dilution, with 10 μM top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1312] 3. Incubate for 3 hrs at 37° C. in 5% CO.sub.2 [1313] 4. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells [1314] 5. Incubate for 1 hr at 37° C. and 5% CO.sub.2 [1315] 6. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant [1316] 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 [1317] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [1318] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[1319] 96-Well Plate Map

TABLE-US-00003 1 2 3 4 5 6 7 8 9 10 11 12 A High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low B High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low C High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low D High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low E High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low F High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low G High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low H High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low High MCC950(10 uM) Compound 8-point half-log dilution Low Drug free control

[1320] The results of the pyroptosis assay performed are summarised in Table 2 below as THP IC.sub.50.

[1321] Human Whole Blood IL1β Release Assay

[1322] 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.

[1323] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [1324] 1. Plate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [1325] 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 [1326] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1327] 4. Add 10 μl Nigericin (Sigma #N7143) (10 μM FAC) to all wells [1328] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1329] 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) [1330] 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [1331] 8. IC.sub.50 data is fitted to anon-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[1332] The results of the human whole blood assay are summarised in Table 2 below as HWB IC.sub.50.

TABLE-US-00004 TABLE 2 NLRP3 inhibitory activity [THP IC.sub.50 (≤0.04 μM = +++++, ≤0.16 μM = ++++, ≤0.64 μM = +++, ≤2.56 μM = ++, ≤10 μM = +, not determined = ND)] [HWB IC.sub.50 (≤0.4 μM = *****, ≤0.8 μM = ****, ≤1.6 μM = ***, ≤3.2 μM = **, ≤10 μM = *, not determined = ND)] Example No THP IC.sub.50 HWB IC.sub.50 1 +++ * 2 +++ ** 3 ++ ND 4 + ND 5 + ND 6 + ND 7 +++ * 8 ++ ND 9 +++ ND 10 ++ ND 11 ++ ND 12 + ND 13 + ND 14 + ND 15 +++ ***** 16 ++++ **** 17 ++ ND 18 +++ ** 19 ++ ND 20 +++ *** 21 ++ ND 22 + ND 23 + ND 24 + ND 25 + ND 26 ++++ **** 27 ++++ **** 28 ++ ND 29 ++++ **** 30 +++ ND 31 ++++ *** 32 +++ ** 33 ++ **** 34 ++ ND 35 ++ ***** 36 ++ ND 37 ++ ND 38 + ND 39 ++ *** 40 + ND 41 ++++ ***** 42 +++ ***** 43 ++++ *** 44 +++ * 45 ++++ ***** 46 + ND 47 ++++ **** 48 +++ ND 49 +++ **** 50 +++ ***** 51 +++ ***** 52 ++++ **** 53 +++ *** 54 ++++ ** 55 +++ **** 56 ++ ** 57 ++ ND 58 +++ **** 59 ++ ND 60 +++ ***** 61 ++ ND 62 ++++ **** 63 ++ ND 64 ++++ ** 65 ++++ *** 66 ++ ND 67 +++ ***** 68 ++++ ** 69 ++++ ***** 70 +++ ** 71 ++++ *** 72 +++ ND 73 ++ ND 74 ++++ *** 75 ++ ND 76 + ND 77 + ND 78 ++++ ***** 79 + * 80 +++ ***** 81 +++ ** 82 +++++ ***** 83 ++++ *** 84 +++++ *****

[1333] PK Protocol

[1334] Pharmacokinetic parameters were determined in male Sprague Dawley rats (Charles River, UK, 250-350 g; or Vital River Laboratory Animal Technology Co Ltd, Beijing, China, 7-9 weeks old). Animals were individually housed during the study and maintained under a 12 h light/dark cycle. Animals had free access to food and water except that some orally dosed animals were food deprived overnight prior to the study.

[1335] For intravenous administration, compounds were formulated as a solution in water or DMSO:PBS [10:90] in 2 mL/kg dosing volume and administered via tail vein. For oral administration, compounds were formulated as a solution in water or DMSO:water [10:90] in 5 mL/kg dosing volume and administered orally.

[1336] Serial blood samples (about 120-300 μL) were taken from each animal at each of 8 time-points post dose (0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h) or at each of 12 time-points post dose (0.03, 0.1, 0.17, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h) or pre-dose and at each of 9 time-points post dose (0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h). Samples were held on ice for no longer than 30 minutes before centrifugation (10,000 rpm (8,385 g) for 3 minutes; or 5,696 rpm (3,000 g) for 15 minutes) for plasma generation. Plasma was frozen on dry ice prior to bioanalysis. PK parameters were generated from LC-MS/MS data using Dotmatics or Phoenix WinNonlin 6.3 software.

TABLE-US-00005 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) 26 2.88 329.7 0.2 1.84 149.3 27 1 1162.1 2.9 2.24 14.4 31 1 302.7 1.6 1.66 55.3 33 1 182.5 2.3 2.72 91.3 35 1 661.2 12.1 3.03 25.2 41 1 274.4 6.3 3.95 60.7 45 1 415.0 6.4 7.96 40.3 60 1 283.3 3.3 4.08 59.2 62 2.46 1723.1 0.1 0.24 25.0 67 0.83 333.7 0.5 0.99 48.7 68 3.34 353.3 1.3 10.55 160.9 69 5.05 3389.9 25.3 17.78 24.8 78 2.41 786.6 0.3 2.37 114.1

TABLE-US-00006 TABLE 4 PK data (oral administration) Example Dose C.sub.max AUC T.sub.max T.sub.1/2 Cl/F No (mg/kg) (ng/mL) (ng .Math. hr/mL) (hr) (hr) (mL/min/kg) Bioavailability 27 3 700.6 2415.2 0.08 4.9 21.5 67 60 5 494.7 769.7 0.17 9.7 109.8 54.3 69 3 599.6 1052.0 0.25 3.4 49.5 62.0

[1337] 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.

[1338] 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. In particular, it is evident from the pharmacokinetic data that the compounds of the invention are particularly suited to topical routes of administration.

[1339] 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.