NOVEL SULFONAMIDE CARBOXAMIDE COMPOUNDS

Abstract

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

##STR00001##

wherein Q is selected from O or S; R.sup.1 is a saturated or unsaturated, optionally substituted hydrocarbyl group optionally including one or more heteroatoms N, O or S; and R.sup.2 is a cyclic group substituted at the -position with a monovalent heterocyclic group or a monovalent aromatic group, wherein a ring atom of the heterocyclic or aromatic group is directly attached to the ring atom of the cyclic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the cyclic group may optionally be further substituted.

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

Claims

1. A compound of formula (I): ##STR00650## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is selected from O or S; R.sup.1 is a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton; and R.sup.2 is a cyclic group substituted at the -position with a monovalent heterocyclic group or a monovalent aromatic group, wherein a ring atom of the heterocyclic or aromatic group is directly attached to a 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.

2. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is a 4- to 10-membered cyclic group, wherein the cyclic group may optionally be substituted.

3. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is a C.sub.1-C.sub.15 alkyl, C.sub.2-C.sub.15 alkenyl or C.sub.2-C.sub.15 alkynyl group, all of which may optionally be substituted, and all of which may optionally include one, two or three heteroatoms N, O or S in their carbon skeleton.

4. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is substituted with one, two or three substituents independently selected from halo; CN; N.sub.3; R.sup.; OH; OR.sup.; SO.sub.2R.sup.; NH.sub.2; NHR.sup.; N(R.sup.).sub.2; R.sup.NH.sub.2; R.sup.NHR.sup.; R.sup.N(R.sup.).sub.2; COR.sup.; COOR.sup.; OCOR.sup.; R.sup.COR.sup.; R.sup.COOR.sup.; R.sup.OCOR.sup.; CONH.sub.2; CONHR.sup.; CON(R.sup.).sub.2; or oxo (O); wherein each R.sup. is independently selected from a C.sub.1-C.sub.6 alkylene group, wherein one or two carbon atoms in the backbone of the alkylene group may optionally be replaced by one or two heteroatoms N, O or S, and wherein the alkylene group may optionally be substituted with one or two halo and/or R.sup. groups; and wherein each R.sup. is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group, and wherein any R.sup. may optionally be substituted with one, two or three 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, CCH or oxo (O) groups.

5. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the -substituted cyclic group of R.sup.2 is a 5- or 6-membered cyclic group, wherein the cyclic group may optionally be further substituted.

6. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the monovalent heterocyclic or aromatic group at the -position of the cyclic group of R.sup.2 is phenyl or a 5- or 6-membered heterocyclic group, all of which may optionally be substituted.

7. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the monovalent heterocyclic or aromatic group at the -position of the cyclic group of R.sup.2 is phenyl, pyridinyl, pyrimidinyl or pyrazolyl, all of which may optionally be substituted with one or two substituents independently selected from halo, OH, NH.sub.2, CN, C.sub.1-C.sub.3 alkyl or O(C.sub.1-C.sub.3 alkyl) groups.

8. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the cyclic group of R.sup.2 is further substituted with one or two substituents independently selected from halo, R.sup., OR.sup. or COR.sup. groups, wherein each R.sup. is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group, and wherein each R.sup. is optionally further substituted with one or more halo groups.

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

10. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the compound is selected from the group consisting of: ##STR00651## ##STR00652## ##STR00653## ##STR00654## ##STR00655## ##STR00656## ##STR00657## ##STR00658## ##STR00659## ##STR00660## ##STR00661## ##STR00662## ##STR00663## ##STR00664## ##STR00665## ##STR00666## ##STR00667## ##STR00668## ##STR00669## ##STR00670## ##STR00671## ##STR00672## ##STR00673## ##STR00674## ##STR00675## ##STR00676## ##STR00677## ##STR00678## ##STR00679## ##STR00680## ##STR00681## ##STR00682## ##STR00683## ##STR00684## ##STR00685## ##STR00686## ##STR00687## ##STR00688## ##STR00689## ##STR00690## ##STR00691## ##STR00692## ##STR00693## ##STR00694## ##STR00695## ##STR00696## ##STR00697## ##STR00698## ##STR00699## ##STR00700## ##STR00701## ##STR00702## ##STR00703## ##STR00704## ##STR00705## ##STR00706## ##STR00707## ##STR00708## ##STR00709## ##STR00710## ##STR00711## ##STR00712## ##STR00713## ##STR00714## ##STR00715## ##STR00716## ##STR00717## ##STR00718## ##STR00719## ##STR00720##

11. (canceled)

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

13. The pharmaceutical composition as claimed in claim 12, wherein the pharmaceutical composition is a topical pharmaceutical composition.

14. (canceled)

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

16. The method as claimed in claim 15, 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.

17. The method as claimed in claim 15, 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).

18. (canceled)

19. The method as claimed in claim 15, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

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

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

Description

EXAMPLESCOMPOUND SYNTHESIS

[0305] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0306] 2-MeTHF 2-methyltetrahydrofuran [0307] Ac.sub.2O acetic anhydride [0308] AcOH acetic acid [0309] aq aqueous [0310] Boc tert-butyloxycarbonyl [0311] br broad [0312] Cbz carboxybenzyl [0313] CDI 1,1-carbonyl-diimidazole [0314] conc concentrated [0315] d doublet [0316] DAB CO 1,4-diazabicyclo[2.2.2]octane [0317] DCE 1,2-dichloroethane, also called ethylene dichloride [0318] DCM dichloromethane [0319] DIPEA N,N-diisopropylethylamine, also called Hnig's base [0320] DMA dimethylacetamide [0321] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0322] DME dimethoxyethane [0323] DMF N,N-dimethylformamide [0324] DMSO dimethyl sulfoxide [0325] eq or equiv equivalent [0326] (ES+) electrospray ionization, positive mode [0327] Et ethyl [0328] EtOAc ethyl acetate [0329] EtOH ethanol [0330] h hour(s) [0331] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0332] HPLC high performance liquid chromatography [0333] LC liquid chromatography [0334] m multiplet [0335] m-CPBA 3-chloroperoxybenzoic acid [0336] Me methyl [0337] MeCN acetonitrile [0338] MeOH methanol [0339] (M+H)+ protonated molecular ion [0340] MHz megahertz [0341] min minute(s) [0342] MS mass spectrometry [0343] Ms mesyl, also called methanesulfonyl [0344] MSCl mesyl chloride, also called methanesulfonyl chloride [0345] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0346] m/z mass-to-charge ratio [0347] NaOtBu sodium tert-butoxide [0348] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0349] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0350] NMP N-methylpyrrolidine [0351] NMR nuclear magnetic resonance (spectroscopy) [0352] Pd(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0) [0353] Pd(dppf)Cl.sub.2 [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [0354] PE petroleum ether [0355] Ph phenyl [0356] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0357] prep-HPLC preparative high performance liquid chromatography [0358] prep-TLC preparative thin layer chromatography [0359] PTSA p-toluenesulfonic acid [0360] q quartet [0361] RP reversed phase [0362] RT room temperature [0363] s singlet [0364] Sept septuplet [0365] sat saturated [0366] SCX solid supported cation exchange (resin) [0367] t triplet [0368] T3P propylphosphonic anhydride [0369] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0370] TEA triethylamine [0371] TFA 2,2,2-trifluoroacetic acid [0372] THF tetrahydrofuran [0373] TLC thin layer chromatography [0374] wt % weight percent or percent by weight

Experimental Methods

.SUP.1.H NMR Spectroscopy

[0375] Nuclear magnetic resonance (NMR) spectra were recorded at 300, 400 or 500 MHz unless stated otherwise; the chemical shifts are reported in parts per million. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. Spectra were recorded using one of the following machines: [0376] A Bruker Advance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe. [0377] A Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control. [0378] A Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe. [0379] 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. [0380] An Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

LC-MS Methods

[0381] 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.3H.sub.2O in water (v/v); B: acetonitrile. Column: Kinetex EVO C18 2.130 mm, 5 m.

Reversed Phase HPLC Conditions for the LCMS Analytical Methods

[0382] Methods 1a and 1b:

[0383] Waters Xselect CSH C18 XP column, 2.5 m (4.630 mm) at 40 C.; flow rate 2.5-4.5 mL min.sup.1 eluted with a water-acetonitrile gradient containing either 0.1% v/v formic acid (Method 1a) or 10 mM ammonium bicarbonate in water (Method 1b) over 4 minutes employing UV detection at 254 nm. Gradient information: 0-3.00 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 3.00-3.01 min, held at 5% water-95% acetonitrile, flow rate increased to 4.5 mL min 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.

Method 1c:

[0384] Agilent 1290 series with UV detector and HP 6130 MSD mass detector using Waters XBridge BEH C18 XP column (2.150 mm, 2.5 m) 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.

Reversed Phase HPLC Conditions for the UPLC Analytical Methods

Methods 2a and 2b:

[0385] Waters BEH C18, 1.7 m, (2.130 mm) at 40 C.; flow rate 0.77 mL min.sup.1 eluted with a water-acetonitrile gradient containing either 0.1% v/v formic acid (Method 2a) or 10 mM ammonium bicarbonate in water (Method 2b) over 3 minutes employing UV detection at 254 nm. Gradient information: 0-0.11 min, held at 95% water-5% acetonitrile, flow rate 0.77 mL min.sup.1; 0.11-2.15 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 2.15-2.49 min, held at 5% water-95% acetonitrile, flow rate 0.77 mL min.sup.1; 2.49-2.56 min, returned to 95% water-5% acetonitrile; 2.56-3.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 0.77 mL min.sup.1.

Preparative Reversed Phase High Performance Liquid Chromatography General Methods

Method 1 (Acidic Preparation):

[0386] Waters X-Select CSH column C18, 5 m (1950 mm), flow rate 28 mL/min eluting with a water-acetonitrile gradient containing 0.1% v/v formic acid over 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 minutes, 20% acetonitrile; 0.2-5.5 minutes, ramped from 20% acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, ramped from 40% acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, held at 95% acetonitrile.

Method 2 (Basic Preparation):

[0387] Waters X-Bridge Prep column C18, 5 m (1950 mm), flow rate 28 mL/min eluting with a 10 mM ammonium bicarbonate-acetonitrile gradient over 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 minutes, 10% acetonitrile; 0.2-5.5 minutes, ramped from 10% acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, ramped from 40% acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, held at 95% acetonitrile.

Method 3:

[0388] Phenomenex Gemini column, 10 m (15025 mm), flow rate=25 mL/min eluting with a water-acetonitrile gradient containing 0.04% NH.sub.3 at pH 10 over 9 minutes using UV detection at 220 and 254 nm. Gradient information: 0-9 minutes, ramped from 8% to 35% acetonitrile; 9-9.2 minutes, ramped from 35% to 100% acetonitrile; 9.2-15.2 minutes, held at 100% acetonitrile.

[0389] 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 m], 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: 5-((Dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

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

[0390] ##STR00095##

[0391] A solution of 1-methyl-1H-pyrazole-3-sulfonyl chloride (13.0 g, 72.0 mmol) in dichloromethane (30 mL) was added slowly to a solution of bis-(4-methoxybenzyl)amine (20 g, 78 mmol) and triethylamine (20 mL, 143 mmol) in dichloromethane (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), hydrochloric acid (aqueous, 1 M, 200 mL) and water (200 mL), then dried (magnesium sulfate), filtered and concentrated in vacua. The residue was triturated with tert-butylmethylether (250 mL), filtered, then purified by chromatography on silica gel (330 g column, 0-60% ethyl acetate/iso-hexane) to afford the title compound (27.66 g, 93%) as a white solid.

[0392] .sup.1H NMR (CDCl.sub.3) 7.42 (d, 1H), 7.11-7.07 (m, 4H), 6.81-6.77 (m, 4H), 6.65 (d, 1H), 4.33 (s, 4H), 3.99 (s, 3H) and 3.81 (s, 6H).

[0393] LCMS m/z 402 (M+H).sup.+ (ES.sup.+).

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

[0394] ##STR00096##

[0395] A solution of n-BuLi (2.5 M in hexanes; 4.2 mL, 10.50 mmol) was added drop-wise to a stirred solution of N,N-bis-(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (4 g, 9.96 mmol) in tetrahydrofuran (60 mL) at 78 C. The reaction was stirred for 1 hour, then N-methyl-N-methylenemethanaminium iodide (4 g, 21.62 mmol) was added. The reaction mixture was left at 78 C. for 2 hours before the reaction was quenched with water (20 mL) and extracted with ethyl acetate (220 mL). The organic layer was separated, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography (Companion apparatus, 120 g column, 0-10% methanol/dichloromethane), then loaded onto a further column (SCX, 13 g) in methanol. The column was washed with methanol and then the product was eluted with 0.7 M ammonia in methanol. The resultant mixture was purified further by chromatography on silica (80 g column, 0-5% methanol/dichloromethane) to afford the title compound (1.9 g, 38%) as a colourless oil.

[0396] .sup.1H NMR (DMSO-d.sub.6) 7.07-7.01 (m, 4H), 6.84-6.78 (m, 4H), 6.58 (s, 1H), 4.21 (s, 4H), 3.89 (s, 3H), 3.72 (s, 6H), 3.47 (s, 2H) and 2.16 (s, 6H).

[0397] LCMS m/z 459.8 (M+H).sup.+ (ES.sup.+).

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

[0398] ##STR00097##

[0399] 5-((Dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (891 mg, 1.94 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was added. The solution was stirred for 16 hours and then additional trifluoroacetic acid (2 mL) was added. The solution was stirred for another 16 hours before a further aliquot of trifluoroacetic acid (2 mL) was added and the solution stirred for 16 hours. The reaction mixture was concentrated in vacua, suspended in toluene (5 mL) and concentrated again. The crude product was loaded onto a column (SCX; 4 g) in methanol and the column was washed with methanol and then the product was eluted with 0.7 M ammonia in methanol. The resultant mixture was concentrated in vacua to afford the title compound (337 mg, 79%) as a white solid.

[0400] .sup.1H NMR (DMSO-d.sub.6) 7.36 (br s, 2H), 6.51 (s, 1H), 3.86 (s, 3H), 3.32 (s, 2H) and 2.23 (s, 6H).

[0401] LCMS m/z 219.3 (M+H).sup.+ (ES.sup.+).

Intermediate P2: 5-((Dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[0402] ##STR00098##

[0403] The title compound was prepared according to the procedure for 5-((dimethylamino) methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P1) (339 mg, 73%).

[0404] .sup.1H NMR (DMSO-d.sub.6) 7.35 (s, 2H), 6.45 (s, 1H), 4.78 (sep, 1H), 3.47 (s, 2H), 2.16 (s, 6H) and 1.38 (d, 6H).

Intermediate P3: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide

[0405] ##STR00099##

[0406] A solution of 1-isopropyl-1H-pyrazole-3-sulfonamide (712 mg, 3.76 mmol) in acetonitrile (4.4 mL) was treated with N,N-dimethylpyridin-4-amine (919 mg, 7.53 mmol) and the reaction mixture was stirred at room temperature until sulfonamide had dissolved. Diphenyl carbonate (887 mg, 4.14 mmol) was added and the reaction mixture was left for 16 hours at room temperature. The resulting precipitate was separated by filtration, washed with methyl tert-butylether and dried to afford the title compound (776 mg, 61%) as a white solid, which was used without further purification.

[0407] .sup.1H NMR (CDCl.sub.3) 8.95 (d, J=7.5 Hz, 2H), 7.35 (d, J=2.3 Hz, 1H), 6.83 (d, J=2.3 Hz, 1H), 6.62 (d, J=7.5 Hz, 2H), 4.58-4.43 (m, 1H), 3.24 (s, 6H), 1.42 (d, J=6.7 Hz, 6H).

Intermediate P4: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide

Step A: 1-Methyl-3-sulfamoyl-1H-pyrazole-5-carboxylic acid, sodium salt

[0408] ##STR00100##

[0409] 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.

[0410] .sup.1H NMR (D.sub.2O) 6.79 (s, 1H) and 4.01 (s, 3H).

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

[0411] ##STR00101##

[0412] 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 (320 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%).

[0413] .sup.1H NMR (DMSO-d.sub.6) 7.50 (s, 2H), 6.82 (s, 1H), 3.90 (s, 3H), 3.03 (s, 3H) and 3.01 (s, 3H).

[0414] LCMS m/z 233.0 (M+H).sup.+ (ES.sup.+).

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

[0415] ##STR00102##

[0416] A solution of N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (459 mg, 1.976 mmol) in acetonitrile (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 acetonitrile and dried to afford the title compound (578 mg, 77%) which was used in the next step without further purification.

[0417] .sup.1H NMR (DMSO-d6) 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 P5: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide

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

[0418] ##STR00103##

[0419] Ethyl 3-(chlorosulfonyl)-1-methyl-1H-pyrazole-5-carboxylate (9.2 g, 36.4 mmol) was added drop-wise to a solution of bis(4-methoxybenzyl)amine (9.4 g, 36.5 mmol) and triethylamine (10 mL, 71.7 mmol) in dichloromethane (200 mL) cooled in an ice bath. The resulting mixture was stirred for 30 minutes, warmed to room temperature and stirred for 90 minutes before being washed with water (200 mL), aqueous hydrochloric acid (1 M, 200 mL), water (200 mL), dried (magnesium sulfate), filtered and evaporated to give a yellow oil. This was purified by chromatography on silica gel (220 g column, 0-60% ethyl acetate/iso-hexane) to afford the title compound (15.9 g, 91%) as a white solid.

[0420] .sup.1H NMR (DMSO-d.sub.6) 7.19-7.00 (m, 5H), 6.85-6.77 (m, 4H), 4.33 (q, 2H), 4.25 (s, 4H), 4.15 (s, 3H), 3.71 (s, 6H) and 1.33 (t, 3H).

[0421] LCMS m/z 496.4 (M+Na).sup.+ (ES.sup.+).

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

[0422] ##STR00104##

[0423] Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate (1.4 g, 2.96 mmol) was dissolved in dry tetrahydrofuran (50 mL) and cooled to 78 C. in a dry ice/acetone bath. Methylmagnesium chloride (3 M in tetrahydrofuran, 5 ml, 15.00 mmol) was added slowly via syringe over the course of 15 minutes. The reaction mixture was allowed to reach room temperature and stirred overnight before being cooled in an ice bath and then quenched slowly with portions of aqueous ammonium chloride (20 mL). The mixture was extracted into ethyl acetate (350 mL) and the combined organic washings were washed with brine (10 to mL), dried (sodium sulfate), filtered and concentrated in vacua to afford a colourless oil. The crude product was purified by chromatography on silica (40 g column, 0-50% ethyl acetate/iso-hexane) to afford the title compound (1.11 g, 67%) as a thick colourless oil.

[0424] .sup.1H NMR (DMSO-d.sub.6) 7.09-7.03 (m, 4H), 6.85-6.80 (m, 4H), 6.41 (s, 1H), 4.21 (s, 4H), 4.04 (s, 3H), 3.72 (s, 6H) and 1.50 (s, 6H).

[0425] LCMS m/z 460 (M+H).sup.+ (ES.sup.+); 458 (MH).sup. (ES.sup.).

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

[0426] ##STR00105##

[0427] 5-(2-Hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-rH-pyrazole-3-sulfonamide (2.5 g, 5.33 mmol) was dissolved in dry N,N-dimethylformamide (50 mL) under nitrogen atmosphere. After cooling in an ice bath, sodium hydride (60% in mineral oil, 0.25 g, 6.25 mmol) was added in a single portion and the cloudy yellow mixture was stirred for 30 minutes. Iodomethane (1.5 ml, 24.09 mmol) was added in a single portion and the mixture was stirred for a further 2 hours while warming to room temperature. The reaction mixture was quenched by slow addition of saturated aqueous ammonium chloride (10 mL) and then partitioned between ethyl acetate (100 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (450 mL) and the combined organic portions were washed with brine (20 mL), dried (sodium sulfate), filtered and concentrated in vacua to give a yellow oil. The crude product was purified by chromatography on silica (40 g column, 0-100% ethyl acetate/iso-hexane) to afford, after drying in vacua, the title compound (2.41 g, 94%) as a colourless solid.

[0428] .sup.1H NMR (DMSO-d.sub.6) 7.10-7.04 (m, 4H), 6.85-6.80 (m, 4H), 6.48 (s, 1H), 4.23 (s, 4H), 3.97 (s, 3H), 3.72 (s, 6H), 2.97 (s, 3H) and 1.50 (s, 6H).

[0429] LCMS m/z 474 (M+H).sup.+ (ES.sup.+); 472 (MH).sup. (ES.sup.).

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

[0430] ##STR00106##

[0431] N,N-Bis-(4-methoxybenzyl)-5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (2.4 g, 5.02 mmol) was dissolved in acetonitrile (40 mL). A solution of ceric ammonium nitrate (15 g, 27.4 mmol) in water (10 mL) was added in a single portion and the dark red reaction mixture was stirred at room temperature for 4 hours. Water (10 mL) and dichloromethane (250 mL) were added and the organic phase was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to give an orange oil (2.5 g). The crude product was purified by chromatography on silica (40 g column, 0-20% methanol/dichloromethane) to afford an orange oil. Trituration of this material in tert-butylmethylether (10 mL) and iso-hexanes (5 mL) gave a tan precipitate which was further purified by chromatography on silica (24 g, 20-100% ethyl acetate in hexanes) to afford the title compound (383 mg, 31%) as a yellow solid.

[0432] .sup.1H NMR (CDCl.sub.3) 6.57 (s, 1H), 5.08 (s, 2H), 4.06 (s, 3H), 3.08 (s, 3H) and 1.57 (s, 6H).

Step E: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide

[0433] ##STR00107##

[0434] A solution of 5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (160 mg, 0.686 mmol) in acetonitrile (0.8 mL) was treated with N,N-dimethylpyridin-4-amine (168 mg, 1.372 mmol) and the reaction mixture was stirred at room temperature until sulfonamide had dissolved. Diphenyl carbonate (162 mg, 0.754 mmol) was added and the reaction mixture was left for 16 hours at room temperature. The resulting precipitate was filtered, washed with methyl tert-butylether and dried to afford the title compound (46 mg, 18%) as a white solid which was used without further purification.

[0435] .sup.1H NMR (CDCl.sub.3) 9.03 (d, J=7.9 Hz, 2H), 6.77 (s, 1H), 6.74 (d, J=7.8 Hz, 2H), 4.04 (s, 3H), 3.34 (s, 6H), 3.08 (s, 3H), 1.59 (s, 6H).

Intermediate P6: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-imidazol-4-yl)sulfonyl)amide

[0436] ##STR00108##

[0437] A solution of 1-iso-propyl-1H-imidazole-4-sulfonamide (161 mg, 0.851 mmol) in acetonitrile (1 mL) was treated with N,N-dimethylpyridin-4-amine (208 mg, 1.702 mmol) and the reaction mixture was stirred at room temperature until sulfonamide had dissolved. Then diphenyl carbonate (200 mg, 0.936 mmol) was added and the reaction mixture was left for 16 hours at room temperature. The resulting precipitate was separated by filtration, washed with methyl tert-butylether and dried to afford the title compound (186 mg, 65%) as a white solid which was used without further purification.

Intermediate P7: 5-((Dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide

[0438] ##STR00109##

[0439] The title compound was prepared according to the procedure for 5-((dimethylamino) methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P1) (705 mg, 81%).

[0440] .sup.1H NMR (DMSO-d6) 7.35 (s, 2H), 6.47 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.47 (s, 2H), 2.17 (s, 6H), 1.35 (t, J=7.2 Hz, 3H).

[0441] LCMS m/z 233.4 (M+H).sup.+ (ES.sup.+).

Intermediate P8: 5-(3-Methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

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

[0442] ##STR00110##

[0443] 2.5 M n-Butyllithium in hexanes (2.0 mL, 5.00 mmol) was added dropwise to a stirred solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (2.0 g, 4.98 mmol) in THF (35 mL) cooled to 78 C. and stirred for 1 hour. A solution of oxetan-3-one (0.292 mL, 4.98 mmol) in THF (16 mL) was then added, allowed to warm to room temperature with stirring for a further 1 hour. The reaction was quenched with saturated aq. NH.sub.4Cl solution (20 mL) and extracted with EtOAc (350 mL). The combined extracts were washed with brine (20 mL), dried (MgSO.sub.4), filtered and evaporated in vacuo to give an orange oil. The crude product was purified by chromatography on silica gel (80 g column, 0-75% EtOAc/isohexane) to afford the title compound (1.44 g, 61%) as a colourless solid.

[0444] .sup.1H NMR (DMSO-d6) 7.10-7.00 (m, 4H), 6.90 (s, 1H), 6.85-6.78 (m, 4H), 6.75 (s, 1H), 4.89 (d, J=7.3 Hz, 2H), 4.76 (d, J=7.2 Hz, 2H), 4.23 (s, 4H), 3.81 (s, 3H), 3.71 (s, 6H).

[0445] LCMS m/z 496.1 (M+Na).sup.+ (ES.sup.+).

Step B: N,N-Bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[0446] ##STR00111##

[0447] Sodium hydride (60% in mineral oil) (0.193 g, 4.81 mmol) was added portionwise to 5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (2.00 g, 4.01 mmol) in dry DMF (20 mL) at 0 C. The reaction mixture was stirred for 30 minutes at 0 C., then 2M iodomethane in tert-butyl methyl ether (8.02 mL, 16.05 mmol) was added in a single portion and the mixture was stirred for a further 18 hours while warming to room temperature. The reaction mixture was quenched by slow addition of saturated aq. NH.sub.4Cl (10 mL) and then partitioned between EtOAc (30 mL) and brine (100 mL). The aqueous layer was separated and the organic layer was washed with brine (100 mL). The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacua to give a pale yellow solid. The crude product was purified by chromatography on silica gel (24 g column, 0-70% EtOAc/isohexane) to afford the title compound (1.94 g 92%) as a colourless oil.

[0448] .sup.1H NMR (DMSO-d6) 7.12-7.03 (m, 4H), 7.00 (s, 1H), 6.87-6.78 (m, 4H), 4.87 (d, J=7.7 Hz, 2H), 4.78 (d, J=7.7 Hz, 2H), 4.24 (s, 4H), 3.74 (s, 3H), 3.71 (s, 6H), 2.96 (s, 3H).

[0449] LCMS m/z 488.2 (M+H).sup.+ (ES.sup.+).

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

[0450] ##STR00112##

[0451] N,N-Bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (1.93 g, 3.60 mmol) was dissolved in acetonitrile (25 mL). A solution of ceric ammonium nitrate (9.87 g, 18.01 mmol) in water (16 mL) was added portionwise over 5 minutes. The orange mixture was stirred for 17 hours at room temperature, then concentrated to 20 mL and poured onto EtOAc (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (230 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated to dryness to give an orange oil. The crude product was purified by chromatography on reversed phase flash column C18 (130 g column, 0-20% acetonitrile/10 mM ammonium bicarbonate, monitored at 215 nm), then purified further by chromatography on silica gel (40 g column, 0-10% methanol/dichloromethane) to afford the title compound (357 mg, 40%) as a tan solid.

[0452] .sup.1H NMR (DMSO-d6) 7.46 (s, 2H), 6.92 (s, 1H), 4.94-4.82 (m, 2H), 4.83-4.70 (m, 2H), 3.73 (s, 3H), 2.99 (s, 3H).

[0453] LCMS m/z 248.3 (M+H).sup.+ (ES.sup.+).

Intermediate P9: 1-(2-(Dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide

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

[0454] ##STR00113##

[0455] To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 g, 657.06 mmol, 1 eq) in THF (1380 mL) was added n-BuLi (2.5 M, 276 mL, 1.05 eq) slowly keeping the temperature at 70 C. The reaction mixture was stirred for 1.5 hours, then SO.sub.2 was bubbled into the mixture for 15 minutes. After the reaction temperature was heated to 25 C., a lot of solid was formed. The mixture was concentrated in vacua. The residue was triturated with tert-butyl methyl ether (400 mL) and the mixture was filtered. The filter cake was washed with tert-butyl methyl ether, n-hexane and dried to afford the title compound (142 g, crude) as a white solid.

[0456] .sup.1H NMR (DMSO-d.sub.6) 7.28 (d, 1H), 6.16 (d, 1H), 5.97 (dd, 1H), 3.92-3.87 (m, 1H), 3.61-3.53 (m, 1H), 2.25-2.18 (m, 1H), 1.98-1.93 (m, 1H), 1.78-1.74 (m, 1H) and 1.52-1.49 (m, 3H).

[0457] LCMS: m/z 215 (M-Li).sup. (ES.sup.)

Step B: 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonyl chloride

[0458] ##STR00114##

[0459] To a suspension of lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (20 g, 90.01 mmol, 1 eq) in dichloromethane (250 mL) was added NCS (12.02 g, 90.01 mmol, 1 eq) cooled in an ice bath. The mixture was stirred at 0 C. for 2 hours. The solution was quenched with water (100 mL), then partitioned between dichloromethane (300 mL) and water (200 mL). The organic layer was washed with water (200 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound (15.8 g, 63.02 mmol, 70%) as a yellow oil which was used directly in next step.

Step C: N,N-Bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide

[0460] ##STR00115##

[0461] A solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonyl chloride (15 g, 59.83 mmol, 1 eq) in dichloromethane (50 mL) was added to a mixture of bis(4-methoxybenzyl)amine (16.01 g, 62.23 mmol, 1.04 eq) and triethylamine (19.33 g, 190.99 mmol, 26.58 mL, 3.19 eq) in dichloromethane (300 mL) at 0 C. The reaction mixture was stirred at 0 C. for 1 hour and then quenched with water (250 mL). The organic layer was washed with water (250 mL), 1M HCl aqueous solution (2250 mL), water (250 mL), dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacua to afford the title product (25.5 g, 49.75 mmol, 83% yield, 92% purity) as a brown oil.

[0462] LCMS: m/z 494 (M+Na).sup.+ (ES.sup.+).

Step D: N,N-Bis(4-methoxybenzyl)-1H-pyrazole-5-sulfonamide

[0463] ##STR00116##

[0464] To a solution of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (25 g, 53.01 mmol, 1 eq) in THF (183 mL) and MeOH (37 mL) was added 1M HCl aqueous solution (18.29 mL, 0.34 eq) and the mixture was stirred at 25 C. for 1 hour. Then the solvent was evaporated and the residue was partitioned between dichloromethane (200 ml) and H.sub.2O (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous MgSO.sub.4, filtered and concentrated in vacua. The residue was triturated with tert-butyl methyl ether, filtered and dried to afford the title compound (12.2 g, 30.61 mmol, 58% yield, 97% purity) as a white solid.

[0465] .sup.1H NMR (chloroform-d) 13.82-13.70 (br s, 1H), 7.92 (d, 1H), 7.07-7.01 (m, 4H), 6.78-6.75 (m, 4H), 6.61 (d, 1H), 4.34 (s, 4H) and 3.80 (s, 6H).

[0466] LCMS: m/z 410 (M+Na).sup.+ (ES.sup.+).

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

[0467] ##STR00117##

[0468] N,N-Bis(4-methoxybenzyl)-1H-pyrazole-5-sulfonamide (12 g, 30.97 mmol, 1 eq) and K.sub.2CO.sub.3 (8.39 g, 60.70 mmol, 1.96 eq) were suspended in acetonitrile (150 mL) under a nitrogen atmosphere. 2-Bromoethanol (5.03 g, 40.26 mmol, 2.86 mL, 1.3 eq) was added to this mixture and then the mixture was heated to 60 C. for 17 hours. To the reaction mixture was added water (500 mL) and dichloromethane (400 mL). The organic layer was separated and washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The crude product was purified by chromatography on silica gel (petroleum ether:ethyl acetate=30:1 to 1:1) to give the title compound (8 g, 17.98 mmol, 58% yield, 97% purity) as a yellow oil.

[0469] .sup.1H NMR (chloroform-d) 7.55 (d, 1H), 7.04-7.02 (m, 4H), 6.77-6.74 (d, 4H), 6.06 (d, 1H), 4.29 (s, 4H), 4.26-4.23 (t, 2H), 3.93-3.81 (m, 2H) and 3.69 (s, 6H).

[0470] LCMS: m/z 454 (M+Na).sup.+ (ES.sup.+).

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

[0471] ##STR00118##

[0472] To a solution of 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (7 g, 16.22 mmol, 1 eq) and diisopropylethylamine (2.94 g, 22.71 mmol, 3.96 mL, 1.4 eq) in anhydrous dichloromethane (116 mL) was added methanesulfonyl chloride (2.23 g, 19.47 mmol, 1.51 mL, 1.2 eq) under nitrogen. The reaction mixture was stirred at 25 C. for 20 minutes. Then the mixture was quenched with saturated aqueous NaHCO.sub.3 solution (50 mL) and water (30 mL). The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua to give the title compound (8.3 g, crude) as a yellow oil which was used directly in the next step.

Step G: 1-(2-(Dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0473] ##STR00119##

[0474] To a solution of dimethylamine in THF (2M, 243 mL, 29.95 eq) was added 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)ethyl methanesulfonate (8.27 g, 16.23 mmol, 1 eq) and then the mixture was heated to 60 C. for 17 hours. The reaction mixture was concentrated in vacuo. The residue was added into EtOAc (150 mL) and the mixture was stirred and filtered. The organic phase was concentrated in vacuo and purified by column chromatography on silica gel (petroleum ether:ethyl acetate=10:1 to 0:1) to give the title compound (6.5 g, 13.47 mmol, 83% yield, 95% purity) as a yellow oil.

[0475] .sup.1H NMR (chloroform-d) 7.55 (d, 1H), 7.09-7.06 (m, 4H), 6.81-6.78 (m, 4H), 6.65 (d, 1H), 4.31 (s, 4H), 4.31-4.27 (m, 2H), 3.80 (s, 6H), 2.77 (t, 2H) and 2.29 (m, 6H).

[0476] LCMS: m/z 459 (M+H).sup.+ (ES.sup.+).

Step H: 1-(2-(Dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide

[0477] ##STR00120##

[0478] To a solution of 1-(2-(dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (5.5 g, 11.99 mmol, 1 eq) in dichloromethane (10 to mL) was added trifluoroacetic acid (77.00 g, 675.32 mmol, 50 mL, 56.31 eq). The mixture was stirred at 25 C. for 17 hours. The reaction mixture was concentrated in vacua. The residue was dissolved in a mixture of dichloromethane (10 mL) and MeOH (200 mL). The resulting mixture was stirred and filtered. Basic resin was added to the solution until pH=8. Then the mixture was stirred at 25 C. for 30 minutes. The mixture was filtered and the organic phase was concentrated in vacua. The residue was recrystallized from dichloromethane (15 mL) to give the title compound (2.2 g, 10.08 mmol, 84% yield, 100% purity)

[0479] .sup.1H NMR (DMSO-d.sub.6) 7.86 (d, 1H), 7.37 (br s, 2H), 6.55 (d, 1H), 4.24 (t, 2H), 2.65 (t, 1H) and 2.16 (s, 6H).

[0480] LCMS: m/z 219 (M+H).sup.+ (ES.sup.+).

Intermediate P10: 1-(Prop-2-yn-1-yl)piperidine-4-sulfonamide

[0481] ##STR00121##

[0482] To a mixture of piperidine-4-sulfonamide hydrochloric acid (200 mg, 1.0 mmol, 1.0 equiv.), potassium carbonate (4.0 equiv., 4.0 mmol, 552 mg) and acetonitrile (10 mL) was added propargyl bromide (0.1 mL, 1.0 mmol, 1.0 equiv.). After stirring overnight at room temperature, the reaction mixture was concentrated in vacua and the crude material was suspended in methanol, coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and a mixture of ammonia (3.5 M) in methanol to afford the title compound (115 mg, 56%).

[0483] .sup.1H NMR (CDCl.sub.3): 4.42 (br s, 1H), 3.38 (s, 2H), 3.05 (d, 2H), 2.95 (m, 1H), 2.12 (m, 4H) and 1.95 (m, 2H).

Intermediate P11: 1-Ethylpiperidine-4-sulfonamide

[0484] ##STR00122##

[0485] Prepared as described for 1-(prop-2-yn-1-yl)piperidine-4-sulfonamide (Intermediate P10) using ethyliodide instead of propargyl bromide. The crude product was coated on Agilent hydromatrix (a high purity, inert diatomaceous earth sorbent) and was submitted to normal phase flash chromatography using dichloromethane and a mixture of trimethylamine-methanol (ratio 1:1) as eluent to afford the title compound contaminated with triethylamine hydrochloride (50 mg, yield 26%). The crude product was used as such in preparing examples.

[0486] .sup.1H NMR (CDCl.sub.3): 5.05 (br s, 2H), 3.10 (m, 2H), 2.95 (m, 1H), 2.45 (m, 2H), 2.20 (d, 2H), 1.95 (m, 4H) and 1.08 (t, 3H).

Intermediate P12: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

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

[0487] ##STR00123##

[0488] Bis(4-methoxybenzyl)amine (3.71 g, 14.4 mmol) was added to a solution of 2-chloropyridine-5-sulfonyl chloride (3.00 g, 13.7 mmol) and triethylamine (2.49 mL, 17.8 mmol) in DCM (50 mL) at 0 C. The reaction was stirred at 0 C. for 15 minutes and then allowed to warm up to room temperature and stirred for 20 hours. Then the reaction mixture was diluted with DCM (150 mL), washed with a saturated aqueous NH.sub.4Cl solution (340 mL) and brine (40 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give the crude product as a cream solid. The crude product was triturated with TBME (70 mL), filtered and rinsed with TBME (240 mL) to afford the title compound (4.97 g, 83%) as an off-white solid.

[0489] .sup.1H NMR (DMSO-d6) 8.76 (dd, J=2.6, 0.7 Hz, 1H), 8.19 (dd, J=8.4, 2.6 Hz, 1H), 7.69 (dd, J=8.4, 0.7 Hz, 1H), 7.08-7.02 (m, 4H), 6.83-6.76 (m, 4H), 4.29 (s, 4H), 3.71 (s, 6H).

[0490] LCMS: m/z 433.3 (M+H).sup.+ (ES.sup.+).

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

[0491] ##STR00124##

[0492] A suspension of 6-chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (0.508 g, 1.17 mmol) in ethane-1,2-diol (10 mL) was treated with 2 M KOH (aq) (2.4 mL, 4.80 mmol). The resultant suspension was stirred at 140 C. for 18 hours. Then the reaction mixture was treated with further 2 M KOH (aq) (0.6 mL, 1.2 mmol, 1 eq) and heated at 140 C. for another 6 hours, and further 2 M KOH (aq) (0.6 mL, 1.2 mmol, 1 eq) and heated at 140 C. for another 18 hours. Then the reaction mixture was diluted with water (40 mL) and DCM (30 mL). Brine (5 mL) was added and the organic layer was collected. The aqueous phase was extracted with DCM (530 mL). The combined organic extracts were washed with water (10 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was dried under reduced pressure at 50 C. overnight to afford the title compound (542 mg, 100%).

[0493] .sup.1H NMR (DMSO-d6) 12.17 (s, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.63 (dd, J=9.6, 2.9 Hz, 1H), 7.11-7.02 (m, 4H), 6.87-6.79 (m, 4H), 6.37 (d, J=9.6 Hz, 1H), 4.21 (s, 4H), 3.72 (s, 6H).

[0494] LCMS: m/z 415.4 (M+H).sup.+ (ES.sup.+), 413.4 (MH) (ES.sup.).

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

[0495] ##STR00125##

[0496] Sodium hydride (60 wt % dispersion in mineral oil) (36 mg, 0.91 mmol) was added to a mixture of 6-hydroxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (0.40 g, 0.869 mmol) and lithium bromide (0.154 g, 1.737 mmol) in DME:DMF (5 mL, 4:1) at 0 C. The mixture was stirred at 0 C. for 10 minutes and then at room temperature for a further 10 minutes. Then 2-iodopropane (0.10 mL, 1.04 mmol) was added and the mixture was stirred at room temperature for 46 hours. The reaction mixture was heated to 65 C. for 17 hours, cooled to room temperature and quenched with saturated aqueous NH.sub.4Cl (5 mL) and diluted with EtOAc (100 mL). The organic layer was washed with water (15 mL) and brine (315 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-100% EtOAc/isohexane) to afford 1-isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.28 g, 70%) as a white solid and 6-isopropoxy-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide (0.11 g, 27%).

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

[0497] .sup.1H NMR (CDCl.sub.3) 7.91 (d, J=2.7 Hz, 1H), 7.41 (dd, J=9.6, 2.6 Hz, 1H), 7.09-7.04 (m, 4H), 6.84-6.79 (m, 4H), 6.54 (dd, J=9.6, 0.5 Hz, 1H), 5.17 (sept, J=6.8 Hz, 1H), 4.26 (s, 4H), 3.79 (s, 6H), 1.34 (d, J=6.8 Hz, 6H).

[0498] LCMS: m/z 457.4 (M+H).sup.+ (ES.sup.+).

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

[0499] .sup.1H NMR (CDCl.sub.3) 8.60-8.55 (m, 1H), 7.84-7.79 (m, 1H), 7.06-6.99 (m, 4H), 6.81-6.75 (m, 4H), 6.72-6.67 (m, 1H), 5.43-5.33 (m, 1H), 4.26 (s, 4H), 3.78 (s, 6H), 1.37 (d, J=6.2 Hz, 6H).

[0500] LCMS: m/z 457.4 (M+H).sup.+ (ES.sup.+).

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

[0501] ##STR00126##

[0502] TFA (0.43 ml, 5.64 mmol) was added to a solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.26 g, 0.564 mmol) in DCM (3 mL) at room temperature and the mixture was stirred for 66 hours. Then the reaction was concentrated in vacuo and the residue was redissolved in DCM (5 mL). The product was purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford the title compound (60 mg, 49%) as a white solid.

[0503] LCMS: m/z 217.3 (M+H).sup.+ (ES.sup.+).

Intermediate P13: 4-Isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide

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

[0504] ##STR00127##

[0505] To a solution of NaH (0.755 g, 18.88 mmol) in THF (55 mL) was added benzyl mercaptan (1.5 mL, 12.68 mmol) at 0 C. The reaction mixture was diluted with THF (20 mL) and stirred at 0 C. for 10 minutes. Then a solution of 2,5-dichloropyrazine (1.370 mL, 13.42 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 0 C. for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0 C., MeOH (1 mL) was added carefully and stirred for 5 minutes. Water (20 mL), then DCM (150 mL) was added and the biphasic mixture was passed through a phase separator. The organic phase was concentrated in vacua. The crude product was purified by chromatography on silica gel (40 g column, 0-3% EtOAc/isohexane) to afford the title compound (2.373 g, 72%) as a clear yellow oil.

[0506] .sup.1H NMR (DMSO-d6) 8.68 (d, J=1.5 Hz, 1H), 8.49 (d, J=1.5 Hz, 1H), 7.43-7.39 (m, 2H), 7.34-7.29 (m, 2H), 7.28-7.23 (m, 1H), 4.46 (s, 2H).

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

[0507] ##STR00128##

[0508] A solution of 2-(benzylthio)-5-chloropyrazine (0.916 g, 3.87 mmol) in DCM (15 mL, 233 mmol) was treated with water (1.5 mL) and the resultant suspension was cooled to between 5 and 0 C. Sulfuryl chloride (2.2 mL, 26.2 mmol) was added and the reaction mixture was stirred for 2 hours maintaining the temperature between 5 and 0 C. A slurry of ice/water (10 mL) was added and the organic phase was collected. The aqueous phase was extracted with DCM (210 mL) and the combined organic extracts were dried (MgSO.sub.4) and concentrated in vacuo to afford crude intermediate 5-chloropyrazine-2-sulfonyl chloride as a pale yellow liquid (1.198 g).

[0509] A suspension of bis(4-methoxybenzyl)amine hydrochloride (1.198 g, 4.08 mmol) and TEA (1.2 mL, 8.61 mmol) in DCM (15 mL) at 0 C. was treated with a solution of 5-chloropyrazine-2-sulfonyl chloride (0.824 g, 3.87 mmol) in DCM (5 mL) dropwise. The resultant solution was stirred at 0 C. for 15 minutes and then allowed to warm to room temperature for 16 hours. A saturated aqueous NH.sub.4Cl solution (10 mL) was added and the organic phase was collected. The aqueous phase was extracted with DCM (210 mL) and the combined organic extracts were dried (MgSO.sub.4) and concentrated in vacua. The crude product was purified by chromatography on silica gel (24 g column, 0-30% EtOAc/isohexane) to afford the title compound (1.312 g, 77%) as a white solid.

[0510] .sup.1H NMR (CDCl.sub.3) 8.78 (d, J=1.4 Hz, 1H), 8.46 (d, J=1.4 Hz, 1H), 7.11-7.07 (m, 4H), 6.79-6.75 (m, 4H), 4.43 (s, 4H), 3.79 (s, 6H).

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

[0511] ##STR00129##

[0512] A suspension of 5-chloro-N,N-bis(4-methoxybenzyl)pyrazine-2-sulfonamide (1.31 g, 2.99 mmol) in glycol (15 mL) was treated with 2 M KOH (aq) (7.5 mL, 15 mmol). The resultant suspension was stirred at 140 C. for 18 hours. Then the reaction mixture was allowed to cool to room temperature, diluted with water (100 mL) and neutralised with saturated aqueous NH.sub.4Cl solution (30 mL). The white precipitate was collected by filtration, washed with water and dried at 60 C. under vacuum to afford the title compound (1.094 g, 79%) as a pale yellow solid.

[0513] .sup.1H NMR (DMSO-d6) 7.94 (d, J=1.2 Hz, 1H), 7.89 (br s, 1H), 7.10-7.06 (m, 4H), 6.84-6.79 (m, 4H), 4.28 (s, 4H), 3.71 (s, 6H). One exchangeable proton not observed.

[0514] LCMS: m/z 438.2 (M+Na).sup.+ (ES.sup.+); 414.2 (MH).sup. (ES.sup.).

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

[0515] ##STR00130##

[0516] A suspension of N,N-bis(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.503 g, 1.090 mmol) and lithium bromide (0.192 g, 2.167 mmol) in DME:DMF (6 mL, 4:1) at 0 C. was treated with NaH (0.053 g, 1.325 mmol). The resultant suspension was stirred at 0 C. for 10 minutes, treated with 2-iodopropane (0.218 ml, 2.136 mmol) and then stirred at 65 C. for 64 hours. A saturated aqueous NH.sub.4Cl solution (6 mL) and EtOAc (10 mL) were added and the organic layer was collected. The aqueous layer was extracted with EtOAc (210 mL) and the combined organic extracts were washed with water (10 mL) and brine (210 mL), dried (MgSO.sub.4) and concentrated in vacua. The crude product was purified by chromatography on silica gel (12 g column, 0-100% EtOAc/isohexane) to afford the title compound (0.293 g, 53%) as a clear yellow oil.

[0517] .sup.1H NMR (DMSO-d6) 8.07 (d, J=1.0 Hz, 1H), 7.96 (d, J=0.9 Hz, 1H), 7.13-7.09 (m, 4H), 6.83-6.79 (m, 4H), 4.78 (sept, J=6.5 Hz, 1H), 4.33 (s, 4H), 3.71 (s, 6H), 1.34 (d, J=6.8 Hz, 6H).

[0518] LCMS: m/z 480.3 (100, [M+Na]+), 458.5 (9, [M+H].sup.+) (ES.sup.+).

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

[0519] ##STR00131##

[0520] A solution of 4-isopropyl-N,N-bis(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.287 g, 0.565 mmol) in DCM (1 mL) was treated with TFA (1 mL, 12.98 mmol) at room temperature. The resultant solution was stirred for 28 hours. Then the reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (4 g column, 0-10% MeOH/DCM) to afford the title compound (0.116 g, 94%) as a white solid.

[0521] .sup.1H NMR (DMSO-d6) 8.14 (d, J=1.0 Hz, 1H), 8.08 (d, J=1.0 Hz, 1H), 7.40 (s, 2H), 4.88 (sept, J=6.7 Hz, 1H), 1.36 (d, J=6.8 Hz, 6H).

[0522] LCMS: 216.1 (MH).sup. (ES.sup.).

Intermediate P14: 1-Isopropylazetidine-3-sulfonamide

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

[0523] ##STR00132##

[0524] To a solution of azetidin-3-ol hydrochloride (45 g, 410.75 mmol, 1 eq) in MeOH (1.2 L) was added TEA (83.13 g, 821.51 mmol, 2 eq) and di-tert-butyl dicarbonate (89.65 g, 410.75 mmol, 1 eq). The mixture was stirred at 25 C. for 16 hours. Then the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtOAc (1 L). The mixture was washed with H.sub.2O (3500 mL) and brine (3500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua to give the title compound (65 g, 91%) as a yellow oil, which was used directly in the next step.

[0525] .sup.1H NMR (CDCl.sub.3) 4.59 (s, 1H), 4.19-4.12 (m, 2H), 3.4-3.79 (m, 2H), 1.45 (s, 9H).

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

[0526] ##STR00133##

[0527] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (65 g, 375.27 mmol, 1 eq) and TEA (113.92 g, 3 eq) in THF (650 mL) was added methanesulfonyl chloride (51.58 g, 450.32 mmol, 1.2 eq) at 0 C. Then the mixture was stirred at 25 C. for 12 hours. The reaction mixture was diluted with EtOAc (2 L), washed with water (31.5 L) and brine (31.5 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (90 g, 95%) as a yellow oil, which was used directly in the next step.

[0528] .sup.1H NMR (CDCl.sub.3) 5.25-5.20 (m, 1H), 4.32-4.27 (m, 2H), 4.14-4.10 (m, 2H), 3.08 (s, 3H) and 1.46 (s, 9H).

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

[0529] ##STR00134##

[0530] To a solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (90 g, 358.14 mmol, 1 eq) in DMF (1.5 L) was added potassium ethanethioate (49.08 g, 429.77 mmol, 1.2 eq). The mixture was stirred at 80 C. for 12 hours. Then the reaction mixture was diluted with EtOAc (3 L), washed with saturated aqueous NH.sub.4Cl solution (32 L) and brine (32 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 100:1 to 20:1) to give the title compound (54 g, 65%) as a yellow oil.

[0531] .sup.1H NMR (CDCl.sub.3) 4.37 (t, 2H), 4.17-4.14 (m, 1H), 3.82 (dd, 2H), 2.34 (s, 3H) and 1.44 (s, 9H).

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

[0532] ##STR00135##

[0533] To a solution of tert-butyl 3-(acetylthio)azetidine-1-carboxylate (5 g, 21.62 mmol, 1 eq) in AcOH (200 mL) and H.sub.2O (20 mL) was added NCS (8.66 g, 64.85 mmol, 3 eq). The reaction mixture was stirred at 25 C. for 1 hour. Then the reaction mixture was diluted with DCM (300 mL), washed with water (3300 mL) and brine (3300 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solution was used directly in the next step.

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

[0534] ##STR00136##

[0535] Through a solution of tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (55.28 g, crude) in DCM (1.5 L) was bubbled NH.sub.3 for 30 minutes at 0 C. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and EtOAc (21 mL, 20:1) to give the title compound (27 g, 53%) as a white solid.

[0536] .sup.1H NMR (DMSO-d.sub.6) 7.16 (br s, 2H), 4.18-4.03 (m, 2H), 4.03-3.90 (m, 3H) and 1.38 (s, 9H).

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

[0537] ##STR00137##

[0538] To a solution of tert-butyl 3-sulfamoylazetidine-1-carboxylate (1 g, 4.23 mmol, 1 eq) in DMF (10 mL) was added NaH (507 mg, 12.69 mmol, 60 wt % in mineral oil, 3 eq) at 0 C. The mixture was stirred at 0 C. for 30 minutes. Then 1-(chloromethyl)-4-methoxybenzene (1.99 g, 12.69 mmol, 3 eq) was added. The mixture was stirred at 25 C. for 14 hours. Then the reaction mixture was diluted with EtOAc (50 mL), washed with a saturated aqueous NH.sub.4Cl solution (330 mL) and brine (330 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was triturated with MeOH (10 mL) to give the title compound (1 g, 50%) as a white solid.

[0539] .sup.1H NMR (CDCl.sub.3) 7.17 (d, 4H), 6.91-6.88 (m, 4H), 4.30 (s, 4H), 4.22 (dd, 2H), 4.01 (t, 2H), 3.83 (s, 6H), 3.75-3.62 (m, 1H) and 1.44 (s, 9H).

[0540] LCMS: m/z 499.2 (M+Na).sup.+ (ES.sup.+).

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

[0541] ##STR00138##

[0542] To a solution of tert-butyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)azetidine-1-carboxylate (7 g, 14.69 mmol, 1 eq) and 2,6-lutidine (4.72 g, 44.06 mmol, 3 eq) in DCM (80 mL) was added trimethylsilyl trifluoromethanesulfonate (9.79 g, 44.06 mmol, 3 eq) at 0 C. Then the reaction mixture was stirred at 0 C. for 1 hour. The reaction mixture was quenched with a saturated aqueous NH.sub.4Cl solution (20 mL) and extracted with DCM (350 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was triturated with a mixture of petroleum ether and ethyl acetate (40 mL, 1:1) to give the title compound (4 g, 72%) as a white solid.

[0543] .sup.1H NMR (CD.sub.3OD) 7.21 (d, 4H), 6.94-6.85 (m, 4H), 4.35 (s, 4H), 4.28-4.11 (m, 5H) and 3.81 (s, 6H).

[0544] LCMS: m/z 377.2 (M+H).sup.+ (ES.sup.+).

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

[0545] ##STR00139##

[0546] To a solution of N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide (2.5 g, 6.64 mmol, 1 eq) and K.sub.2CO.sub.3 (1.38 g, 9.96 mmol, 1.5 eq) in MeCN (5 mL) was added 2-bromopropane (1.63 g, 13.28 mmol, 2 eq). The mixture was stirred at 70 C. for 12 hours. Then H.sub.2O (10 mL) was added and the reaction mixture was extracted with EtOAc (330 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua to give the title compound (2.5 g, 90%).

[0547] .sup.1H NMR (CDCl.sub.3) 7.12-7.07 (m, 4H), 6.83-6.76 (m, 4H), 4.16 (s, 4H), 3.74 (s, 6H), 3.68-3.64 (m, 1H), 3.43 (t, 2H), 3.28 (t, 2H), 2.38-2.29 (m, 1H) and 0.82 (d, 6H).

[0548] LCMS: m/z 419.2 (M+H).sup.+ (ES.sup.+).

Step I: 1-Isopropylazetidine-3-sulfonamide

[0549] ##STR00140##

[0550] A solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide (1 g, 2.39 mmol, 1 eq) in TFA (7.70 g, 67.53 mmol, 28.27 eq) was stirred at 25 C. for 12 hours. Then the reaction mixture was concentrated in vacua. The residue was treated with MeOH (10 mL), filtered and the filtrate was adjusted with NH.sub.3.H.sub.2O (30% of NH.sub.3.H.sub.2O in water) to pH=8-9. The resulting mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.1% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (220 mg, 52%) as a white solid.

[0551] .sup.1H NMR (CD.sub.3OD) 4.05-3.98 (m, 1H), 3.67 (t, 2H), 3.46 (t, 2H), 2.59-2.48 (m, 1H) and 0.97 (d, 6H). Two exchangeable protons not observed.

[0552] LCMS: m/z 179.1 (M+H).sup.+ (ES.sup.+).

Intermediate P15: 1-Cyclobutylazetidine-3-sulfonamide

Step A: Azetidine-3-sulfonamide

[0553] ##STR00141##

[0554] To a solution of tert-butyl 3-sulfamoylazetidine-1-carboxylate (3 g, 12.70 mmol, 1 eq, obtained according to Step E of the synthesis of intermediate P14) in DCM (10 mL) was added HCl/EtOAc (12.70 mmol, 20 mL, 1 eq). The mixture was stirred at 25 C. for 1 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (0.8 g, 46%) as a white solid.

[0555] .sup.1H NMR (DMSO-d.sub.6) 6.92 (s, 1H), 4.23-4.19 (m, 2H) and 3.77-3.70 (m, 3H). Two exchangeable protons not observed.

[0556] LCMS: m/z 137.1 (M+H).sup.+ (ES.sup.+).

Step B: 1-Cyclobutylazetidine-3-sulfonamide

[0557] ##STR00142##

[0558] To a solution of azetidine-3-sulfonamide (50 mg, 367.18 mol, 1 eq) in MeOH (1 mL) was added cyclobutanone (31 mg, 440.62 mol, 1.2 eq) and NaBH(OAc).sub.3 (97 mg, 458.98 mol, 1.25 eq). The reaction mixture was stirred at 20 C. for 2 hours. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (12.25 mg, 18%) as a white solid.

[0559] .sup.1H NMR (DMSO-d.sub.6) 6.92 (s, 2H), 3.88-3.85 (m, 1H), 3.41-3.33 (m, 2H), 3.32-3.29 (m, 2H), 3.12-3.09 (m, 1H), 1.89-1.86 (m, 2H) and 1.77-1.60 (m, 4H).

[0560] LCMS: m/z 191.1 (M+H).sup.+ (ES.sup.+).

Intermediate P16: 1-Ethylazetidine-3-sulfonamide

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

[0561] ##STR00143##

[0562] To a solution of N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide (1 g, 2.66 mmol, 1 eq, obtained according to Step G of the synthesis of intermediate P14) and K.sub.2CO.sub.3 (367 mg, 2.66 mmol, 1 eq) in MeCN (2 mL) was added iodoethane (414 mg, 2.66 mmol, 1 eq). The mixture was stirred at 70 C. for 1 hour. Then the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (350 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by reversed phase flash chromatography (water (0.1% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (0.7 g, 22% yield, 100% purity on LCMS) as a white solid.

[0563] .sup.1H NMR (CD.sub.3OD) 7.20 (d, 4H), 6.90 (d, 4H), 4.28 (s, 4H), 4.00-3.93 (m, 1H), 3.81 (s, 6H), 3.51 (t, 2H), 3.40 (t, 2H), 2.53 (q, 2H) and 0.96 (t, 3H).

[0564] LCMS: m/z 405.2 (M+H).sup.+ (ES.sup.+).

Step B: 1-Ethylazetidine-3-sulfonamide

[0565] ##STR00144##

[0566] A solution of 1-ethyl-N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide (800 mg, 1.98 mmol, 1 eq) in TFA (82.13 g, 720.32 mmol, 364 eq) was stirred at 50 C. for 1 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.1% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (160 mg, 47% yield, 95% purity on LCMS) as a white solid.

[0567] .sup.1H NMR (DMSO-d.sub.6) 6.94 (s, 2H), 3.95-3.86 (m, 1H), 3.47 (t, 2H), 3.31-3.25 (m, 2H), 2.43 (q, 2H) and 0.86 (t, 3H).

[0568] LCMS: m/z 165.1 (M+H).sup.+ (ES.sup.+).

Intermediate P17: 1-(Pyridin-3-ylmethyl)azetidine-3-sulfonamide

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

[0569] ##STR00145##

[0570] To a solution of N,N-bis(4-methoxybenzyl)azetidine-3-sulfonamide (1 g, 2.66 mmol, 1 eq, obtained according to Step G of the synthesis of intermediate P14) in MeCN (20 mL) was added nicotinaldehyde (341 mg, 3.19 mmol, 1.2 eq) and NaBH(OAc).sub.3 (1.13 g, 5.31 mmol, 2 eq). The mixture was stirred at 15 C. for 1 hour. Then the reaction mixture was quenched with water (80 mL) and extracted with EtOAc (6100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:1 to 0:1) to give the title compound (1.1 g, 89%) as a yellow oil.

[0571] .sup.1H NMR (DMSO-d.sub.6) 8.53 (s, 1H), 8.46 (s, 1H), 7.72 (d, 1H), 7.37-7.33 (m, 1H), 7.13 (d, 4H), 6.88 (d, 4H), 4.21-4.17 (m, 5H), 3.73 (s, 6H), 3.61 (s, 2H), 3.47-3.41 (m, 2H) and 3.33-3.31 (m, 2H).

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

[0572] ##STR00146##

[0573] A solution of N,N-bis(4-methoxybenzyl)-1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (1 g, 2.14 mmol, 1 eq) in TFA (10 mL) was stirred at to C. for 36 hours. Then the reaction mixture was concentrated in vacua. The residue was treated with MeOH (80 mL) and the mixture was stirred for another 1 hour. Then the mixture was filtered and the filtrate was concentrated in vacua. The residue was purified by reversed phase flash chromatography (water (0.1% of NH.sub.3.H.sub.2O)-MeCN) to give the title compound (240 mg, 49%) as a white solid.

[0574] .sup.1H NMR (DMSO-d.sub.6) 8.52-8.45 (m, 2H), 7.67 (d, 1H), 7.35 (dd, 1H), 6.98 (s, 2H), 3.99-3.94 (m, 1H), 3.64 (s, 2H), 3.54-3.49 (m, 2H) and 3.44-3.35 (m, 2H).

[0575] LCMS: m/z 228.1 (M+H).sup.+ (ES.sup.+).

Intermediate P18: 1-Isopropylpiperidine-4-sulfonamide

Step A: Benzyl 4-hydroxypiperidine-1-carboxylate

[0576] ##STR00147##

[0577] To a solution of piperidin-4-ol (100 g, 988.66 mmol, 1 eq) in DCM (1 L) was added TEA (100.04 g, 988.66 mmol, 1 eq) and benzyl chloroformate (168.66 g, 988.66 mmol, 1 eq) at 0 C. The mixture was warmed to 25 C. and stirred for 12 hours. Then the reaction mixture was diluted with DCM (500 mL), washed with brine (3500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (220 g, 95%) as a yellow oil, which was used in the next step without further purification.

[0578] .sup.1H NMR (CDCl.sub.3) 7.36-7.29 (m, 5H), 5.10 (s, 2H), 3.90-3.81 (m, 3H), 3.15-3.08 (m, 2H), 1.83-1.81 (m, 2H) and 1.47-1.45 (m, 2H). One exchangeable proton not observed.

[0579] LCMS: m/z 258.1 (M+Na).sup.+ (ES.sup.+).

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

[0580] ##STR00148##

[0581] To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (220 g, 935.06 mmol, 1 eq) in DCM (1.7 L) was added TEA (189.24 g, 1.87 mol, 2 eq). Then mesyl chloride (128.54 g, 1.12 mol, 1.2 eq) was added dropwise at 0 C. The solution was heated to 25 C. and stirred for 1 hour. Then the reaction mixture was quenched with saturated aqueous NaHCO.sub.3 solution (1.2 L) and the two layers were separated. The organic layer was washed with saturated aqueous NaHCO.sub.3 solution (1.2 L) and brine (21 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua to give the title compound (293 g, 100%), which was used directly in the next step.

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

[0582] ##STR00149##

[0583] To a solution of benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (290 g, 925.43 mmol, 1 eq) in DMF (1.4 L) was added Cs.sub.2CO.sub.3 (331.67 g, 1.02 mol, 1.1 eq) and ethanethioic S-acid (77.49 g, 1.02 mol, 1.1 eq). The mixture was stirred at 80 C. for 12 hours. Some solid was precipitated. The reaction mixture was filtered. The filtrate was concentrated in vacuo to remove most of the DMF. The residue was diluted with EtOAc (16 L), washed with H.sub.2O (31 L) and brine (21 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 40:1) to give the title compound (146 g, crude) as a yellow oil.

[0584] .sup.1H NMR (CDCl.sub.3) 7.37-7.35 (m, 5H), 5.13 (s, 2H), 4.07-3.93 (m, 2H), 3.66-3.61 (m, 1H), 3.19-3.12 (m, 2H), 2.33 (s, 3H), 1.94-1.91 (m, 2H) and 1.59-1.56 (m, 2H).

[0585] LCMS: m/z 294.1 (M+H).sup.+ (ES.sup.+).

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

[0586] ##STR00150##

[0587] To a solution of benzyl 4-(acetylthio)piperidine-1-carboxylate (30.00 g, 102.26 mmol, 1 eq) in AcOH (1 L) and H.sub.2O (100 mL) was added NCS (40.96 g, 306.77 mmol, 3 eq). The reaction mixture was stirred at 25 C. for 40 minutes. Then the reaction mixture was poured into water (1 L) and extracted with DCM (1 L). The organic layer was washed with water (31 L) and brine (1 L), dried over Na.sub.2SO.sub.4, and filtered to give the title compound in DCM (1 L) solution (theoretical amount: 32.4 g, crude), which was used in the next step without further purification.

Step E: Benzyl 4-sulfamoylpiperidine-1-carboxylate

[0588] ##STR00151##

[0589] NH.sub.3 was bubbled into a solution of benzyl 4-(chlorosulfonyl)piperidine-1-carboxylate (theoretical amount: 30 g, crude) in DCM (1 L) at 0 C. for 20 minutes. Then the reaction mixture was stirred at 25 C. for 40 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacua. The residue was triturated with a mixture of EtOAc (50 mL) and petroleum ether (40 mL) to give the title compound (21 g, 75%) as a yellow solid.

[0590] .sup.1H NMR (DMSO-d.sub.6) 7.38-7.32 (m, 5H), 6.79 (br s, 2H), 5.10 (s, 2H), 4.12-4.01 (m, 2H), 3.09-3.02 (m, 1H), 3.01-2.75 (m, 2H), 2.02-1.96 (m, 2H) and 1.51-1.41 (m, 2H).

Step F: Piperidine-4-sulfonamide

[0591] ##STR00152##

[0592] To a solution of benzyl 4-sulfamoylpiperidine-1-carboxylate (21 g, 70.39 mmol, 1 eq) in MeOH (200 mL) was added Pd/C (10 wt % loading on activated carbon, 4 g) under nitrogen. The suspension was degassed in vacuo and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 25 C. for 30 hours. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with EtOAc (200 mL) to give the title compound (11.2 g, 97% yield, 100% purity on LCMS) as a white solid.

[0593] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O) 3.06-2.90 (m, 2H), 2.89-2.86 (m, 1H), 2.50-2.46 (m, 2H), 1.95-1.91 (m, 2H) and 1.53-1.46 (m, 2H). Three exchangeable protons not observed.

[0594] LCMS: m/z 165.1 (M+H).sup.+ (ES.sup.+).

Step G: 1-Isopropylpiperidine-4-sulfonamide

[0595] ##STR00153##

[0596] To a solution of piperidine-4-sulfonamide (1.2 g, 7.31 mmol, 1 eq) in acetonitrile (20 mL) was added 2-bromopropane (3.59 g, 29.23 mmol, 4 eq) and NaHCO.sub.3 (1.84 g, 21.92 mmol, 3 eq). Then the reaction mixture was stirred at 70 C. for 18 hours. The hot mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.05 g, 69% yield, 98.5% purity on LCMS) as a white solid.

[0597] .sup.1H NMR (DMSO-d.sub.6) 6.61 (s, 2H), 2.81-2.77 (m, 2H), 2.66-2.61 (m, 2H), 2.05-1.99 (m, 2H), 1.91-1.87 (m, 2H), 1.50-1.45 (m, 2H) and 0.89 (dd, 6H).

[0598] LCMS: m/z 207.1 (M+H).sup.+ (ES.sup.+).

Intermediate P19: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-2-oxo-1,2-dihydropyrimidin-5-yl)sulfonyl)amide

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

[0599] ##STR00154##

[0600] A suspension of 5-bromopyrimidin-2(1H)-one (10.07 g, 57.5 mmol) and K.sub.2CO.sub.3 (8.35 g, 60.4 mmol) in DMF (200 mL) was treated with 2-iodopropane (6.4 ml, 62.7 mmol) under nitrogen. The resultant suspension was stirred at room temperature for 40 hours, concentrated in vacua and the residue was partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (350 mL). The combined organic extracts were washed with 20% v/v brine (350 mL), brine (50 mL), dried (MgSO.sub.4) and concentrated in vacua to afford crude product as a yellow oil (4.71 g). The crude product was purified by chromatography on silica gel (dry load) (40 g cartridge, 0-5% MeOH/DCM) to afford the title compound (1.34 g, 10%) as a clear yellow oil that solidified on standing.

[0601] .sup.1H NMR (CDCl.sub.3) 8.52 (dd, J=3.3, 1.6 Hz, 1H), 7.76 (d, J=3.2 Hz, 1H), 4.99 (pd, J=6.8, 1.6 Hz, 1H), 1.40 (dd, J=6.8, 1.0 Hz, 6H).

[0602] LCMS: m/z 217.0 (MBr.sup.79+H).sup.+ (ES.sup.+).

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

[0603] ##STR00155##

[0604] A solution of 5-bromo-1-isopropylpyrimidin-2(1H)-one (1.217 g, 5.05 mmol), DIPEA (1.8 ml, 10.31 mmol) and benzyl mercaptan (0.6 ml, 5.07 mmol) in dioxane (25 mL) was sparged with nitrogen for 15 minutes before Pd.sub.2(dba).sub.3 (0.233 g, 0.254 mmol) and Xantphos (0.294 g, 0.508 mmol) were added. The reaction mixture was heated at 100 C. for 22 hours and then concentrated in vacua. The residue was partitioned between EtOAc (30 mL) and saturated aqueous NaHCO.sub.3 (20 mL). The aqueous layer was extracted with EtOAc (330 mL) and the combined organic extracts were washed with brine (30 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford crude product as a brown oil (2.3 g). The crude product was purified by chromatography on silica gel (dry load) (40 g cartridge, 0-5% MeOH/DCM) to afford the title compound (1.49 g, 99%) as a brown oil.

[0605] .sup.1H NMR (CDCl.sub.3) 8.46 (d, J=3.1 Hz, 1H), 7.30-7.22 (m, 3H), 7.15 (d, J=3.2 Hz, 1H), 7.09-7.06 (m, 2H), 4.84 (sept, J=6.8 Hz, 1H), 3.80 (s, 2H), 1.13 (d, J=6.8 Hz, 6H).

[0606] LCMS; m/z 261.1 (M+H).sup.+ (ES.sup.+).

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

[0607] ##STR00156##

[0608] A suspension of 5-(benzylthio)-1-isopropylpyrimidin-2(1H)-one (1.012 g, 3.69 mmol) in DCM (15 mL) and water (1.5 mL) at 0 C. was treated with SO.sub.2Cl.sub.2 (2 ml, 23.86 mmol) dropwise. The resultant yellow suspension was stirred at 0 C. for 1 hour. A slurry of ice/water (20 mL) was added and the organic phase was collected and retained. The aqueous layer was extracted with DCM (210 mL) and the combined organic extracts were dried (MgSO.sub.4) and concentrated in vacuo to afford crude sulfonyl chloride intermediate as a pale yellow liquid (1.024 g) which was used without further purification. A solution of bis(4-methoxybenzyl)amine (1.007 g, 3.91 mmol) and Et.sub.3N (0.6 ml, 4.30 mmol) in DCM (20 mL) at 0 C. was treated with a solution of the crude sulfonyl chloride intermediate in DCM (10 mL). The resultant solution was allowed to warm to room temperature, stirred for 1 hour and then diluted with DCM (20 mL) and saturated aqueous NH.sub.4Cl (20 mL). The organic layer was collected and washed with saturated aqueous NH.sub.4Cl (20 mL) and water (20 mL), dried (MgSO.sub.4) and concentrated in vacua to afford crude product as an orange oil (2.0 g). The crude product was triturated with TBME (30 mL), filtered, rinsing with TBME, and dried in vacua to afford crude product which was purified by chromatography on silica gel (24 g cartridge, 0-5% MeOH/DCM) to afford the title compound (0.941 g, 44%) as a sticky orange oil.

[0609] .sup.1H NMR (CDCl.sub.3) 8.65 (d, J=3.3 Hz, 1H), 7.96 (d, J=3.3 Hz, 1H), 7.15-7.10 (m, 4H), 6.85-6.82 (m, 4H), 4.88 (sept, J=6.8 Hz, 1H), 4.32 (s, 4H), 3.79 (s, 6H), 1.34 (d, J=6.8 Hz, 6H).

[0610] LCMS: m/z 458.1 (M+H).sup.+ (ES.sup.+).

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

[0611] ##STR00157##

[0612] 1-Isopropyl-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyrimidine-5-sulfonamide (0.941 g, 1.625 mmol) was treated with TFA (15 ml, 195 mmol) and the resultant solution was stirred at room temperature for 64 hours. Then the reaction mixture was concentrated in vacua and the crude product was purified by chromatography on silica gel (dry load) (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (0.350 g, 94%) as a tan solid.

[0613] .sup.1H NMR (DMSO-d6) 8.81 (d, J=3.2 Hz, 1H), 8.51 (d, J=3.3 Hz, 1H), 7.45 (s, 2H), 4.77 (sept, J=6.8 Hz, 1H), 1.37 (d, J=6.8 Hz, 6H).

[0614] LCMS; m/z 218.1 (M+H).sup.+ (ES.sup.+); 215.8 (MH).sup. (ES.sup.).

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

[0615] ##STR00158##

[0616] A suspension of 1-isopropyl-2-oxo-1,2-dihydropyrimidine-5-sulfonamide (0.150 g, 0.690 mmol) and DMAP (0.169 g, 1.383 mmol) in dry MeCN (2 mL) was stirred at room temperature for 10 minutes before diphenyl carbonate (0.163 g, 0.761 mmol) was added in one portion. The reaction was stirred for 18 hours, diluted with TBME (20 mL) and DCM (2 mL), and the precipitate was collected by filtration and used crude in the next step.

Intermediate P20: 1-Isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide

Step A: Lithium 2-chloropyridine-4-sulfinate

[0617] ##STR00159##

[0618] A solution of 4-bromo-2-chloropyridine (5.8 ml, 52.3 mmol) in dry THF (100 mL) at 78 C. was treated with 2.5 M BuLi (in hexanes) (22 ml, 55.0 mmol) dropwise under nitrogen. The resultant solution was stirred at 78 C. for 10 minutes and then SO.sub.2 gas was bubbled through the solution for 20 minutes. The reaction was allowed to warm to room temperature and then concentrated in vacua. The residue was triturated with TBME (100 mL). The resultant solid was filtered, rinsing with TBME, and dried in vacua to afford the title compound (8.80 g, 92%) as a dark purple solid that was used crude in the next step.

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

[0619] ##STR00160##

[0620] A suspension of lithium 2-chloropyridine-4-sulfinate (6.55 g, 35.7 mmol) in DCM (100 mL) at 0 C. was treated with NCS (4.862 g, 35.7 mmol) in one portion. The resultant suspension was stirred at 0 C. for 2 hours, quenched with water (50 mL) and the organic layer was collected. The aqueous layer was extracted with DCM (250 mL) and the combined organic extracts were washed with water (50 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford the crude sulfonyl chloride intermediate. A solution of the sulfonyl chloride intermediate in DCM (10 mL) was added dropwise to a suspension of bis(4-methoxybenzyl)amine (9.42 g, 36.6 mmol) and triethylamine (15.92 ml, 114 mmol) in DCM (100 mL) at 0 C. The reaction mixture was allowed to warm to room temperature, stirred for 16 hours and then water (100 mL) was added. The organic layer was collected and the aqueous layer was extracted with DCM (250 mL). The combined organic extracts were washed with water (100 mL), 1 M HCl (aq) (2100 mL), water (100 mL), dried (MgSO.sub.4) and concentrated in vacua to afford crude product which was purified by chromatography on silica gel (dry load) (80 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.677 g, 4%) as an orange solid.

[0621] .sup.1H NMR (CDCl.sub.3) 8.51 (dd, J=4.8, 1.9 Hz, 1H), 8.30 (dd, J=7.8, 1.9 Hz, 1H), 7.30 (dd, J=7.8, 4.8 Hz, 1H), 7.04-6.99 (m, 4H), 6.81-6.75 (m, 4H), 4.38 (s, 4H), 3.78 (s, 6H).

[0622] LCMS: m/z 433 (MCl.sup.35++H).sup.+ (ES.sup.+).

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

[0623] ##STR00161##

[0624] A suspension of 2-chloro-N,N-bis(4-methoxybenzyl)pyridine-4-sulfonamide (0.365 g, 0.759 mmol) in ethane-1,2-diol (5 ml, 0.759 mmol) was treated with 2 M KOH (aq) (1.9 ml, 3.80 mmol). The resultant suspension was stirred at 140 C. for 72 hours, allowed to cool to room temperature and then diluted with saturated aqueous NH.sub.4Cl (30 mL) and EtOAc (20 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (220 mL). The combined organic extracts were dried (MgSO.sub.4) and concentrated in vacua to afford crude product as a yellow solid (510 mg). The crude product was purified by chromatography on silica gel (dry load) (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.437 g, 68%) as a pale yellow solid.

[0625] LCMS: m/z 437.3 (M+Na).sup.+ (ES.sup.+); 413.1 (MH).sup. (ES.sup.).

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

[0626] ##STR00162##

[0627] A suspension of N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-4-sulfonamide (0.437 g, 0.949 mmol) and lithium bromide (0.171 g, 1.930 mmol) in DME:DMF (7.5 mL, 4:1) at 0 C. was treated with NaH in one portion. The resultant suspension was stirred at 0 C. for 15 minutes, treated with 2-iodopropane (0.194 ml, 1.898 mmol) and heated to 65 C. for 65 hours. Further lithium bromide (0.171 g, 1.930 mmol) followed by NaH (0.053 g, 1.328 mmol) were added and the reaction mixture was stirred at 65 C. for 10 minutes. Then further 2-iodopropane (0.194 ml, 1.898 mmol) was added and the reaction mixture was stirred at 65 C. for 18 hours. EtOAc (10 mL) and saturated aqueous NH.sub.4Cl (5 mL) were added and the organic layer was collected. The aqueous layer was extracted with EtOAc (210 mL) and the combined organic extracts were washed with 20% v/v brine (310 mL) and brine (10 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford crude product as a yellow oil. The crude product was purified by chromatography on silica gel (dry load) (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.385 g, 77%) as a pale yellow oil.

[0628] .sup.1H NMR (DMSO-d6) 8.06 (dd, J=6.8, 2.1 Hz, 1H), 7.99 (dd, J=7.2, 2.0 Hz, 1H), 7.07-7.03 (m, 4H), 6.82-6.78 (m, 4H), 6.39 (t, J=7.0 Hz, 1H), 4.99 (sept, J=6.8 Hz, 1H), 4.34 (s, 4H), 3.71 (s, 6H), 1.28 (d, J=6.8 Hz, 6H).

[0629] LCMS; m/z 479.3 (M+Na).sup.+ (ES.sup.+).

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

[0630] ##STR00163##

[0631] 1-Isopropyl-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-4-sulfonamide (0.375 g, 0.715 mmol) was treated with TFA (2 ml, 26.0 mmol) and the resultant red solution was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo, azeotroped with DCM (25 mL) and the crude product was purified by chromatography on silica gel (dry load) (4 g cartridge, 0-10% MeOH/DCM) to afford the title compound (0.160 g, 100%) as a white solid.

[0632] .sup.1H NMR (CDCl.sub.3) 8.09 (dd, J=7.1, 2.1 Hz, 1H), 7.61 (dd, J=6.9, 2.1 Hz, 1H), 6.42 (t, J=7.0 Hz, 1H), 5.38 (br s, 2H), 5.32 (sept, J=7.0 Hz, 1H), 1.41 (d, J=6.8 Hz, 6H).

[0633] LCMS: m/z 217.3 (M+H).sup.+ (ES.sup.+); 215.1 (MH).sup. (ES.sup.).

Intermediate P21: 6-(Dimethylamino)pyrazine-2-sulfonamide

Step A: 2-(Benzylthio)-6-chloropyrazine

[0634] ##STR00164##

[0635] A solution of 2,6-dichloropyrazine (5 g, 33.56 mmol, 1.1 eq) and sodium phenylmethanethiolate (4.46 g, 30.51 mmol, 1 eq) in DMF (50 mL) was stirred at 25 C. for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NH.sub.4Cl solution (350 mL) and brine (350 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 50:1) to give the title compound (2 g, 28%) as a colourless oil.

[0636] .sup.1H NMR (CDCl.sub.3): 8.33 (d, 1H), 8.23 (s, 1H), 7.46-7.42 (m, 2H), 7.37-7.29 (m, 3H) and 4.43 (s, 2H).

[0637] LCMS: m/z 237.0 (M+H).sup.+ (ES.sup.+).

Step B: 6-Chloropyrazine-2-sulfonyl chloride

[0638] ##STR00165##

[0639] To a solution of 2-(benzylthio)-6-chloropyrazine (2 g, 8.45 mmol, 1 eq) in CCl.sub.4 (80 mL) and H.sub.2O (20 mL) was bubbled with C12 at 0 C. for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacua to give the title compound (1.8 g, crude), which was used directly in the next step.

Step C: 6-Chloropyrazine-2-sulfonamide

[0640] ##STR00166##

[0641] To a solution of 6-chloropyrazine-2-sulfonyl chloride (1.8 g, crude) in THF (50 mL) was bubbled with NH.sub.3 at 0 C. for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (21 mL, v:v=20:1) to give the title compound (1.2 g, 73%) as a yellow solid.

[0642] .sup.1H NMR (DMSO-d.sub.6): 9.09 (d, 2H) and 7.96 (s, 2H).

Step D: 6-(Dimethylamino)pyrazine-2-sulfonamide

[0643] ##STR00167##

[0644] To a solution of 6-chloropyrazine-2-sulfonamide (1 g, 5.16 mmol, 1 eq) in MeCN (10 mL) was added with dimethylamine (2 M in THF, 3.23 mL, 1.25 eq). The mixture was stirred at 25 C. for 3 hours. The reaction mixture was concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:1 to 1:10) to give the title compound (210 mg, 20%) as a yellow solid.

[0645] .sup.1H NMR (CD.sub.3OD): 8.26 (s, 1H), 8.22 (s, 1H) and 3.22 (s, 6H).

[0646] LCMS: m/z 203.1 (M+H).sup.+ (ES.sup.+).

Intermediate P22: 5-(Dimethylamino)pyrazine-2-sulfonamide

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

[0647] ##STR00168##

[0648] To a solution of 2,5-dichloropyrazine (3 g, 20.14 mmol, 1 eq) in MeCN (30 mL) was added phenylmethanethiol (2.25 g, 18.12 mmol, 0.9 eq) and K.sub.2CO.sub.3 (5.57 g, 40.27 mmol, 2 eq). The reaction mixture was stirred at 25 C. for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 0:1) to give the title compound (4.5 g, 94%) as a yellow oil.

[0649] .sup.1H NMR (CDCl.sub.3): 8.43 (s, 1H), 8.19 (s, 1H), 7.42-7.38 (m, 2H), 7.35-7.28 (m, 3H) and 4.42 (s, 2H).

Step B: 5-Chloropyrazine-2-sulfonyl chloride

[0650] ##STR00169##

[0651] Cl.sub.2 (15 psi) was bubbled into a solution of 2-(benzylthio)-5-chloropyrazine (4.5 g, 19.01 mmol, 1 eq) in CCl.sub.4 (50 mL) and H.sub.2O (10 mL) at 10 C. for 15 minutes. The reaction mixture was used directly in the next step without further work-up and purification.

Step C: 5-Chloropyrazine-2-sulfonamide

[0652] ##STR00170##

[0653] A saturated solution of NH.sub.3 in THF (20 mL) was added into a solution of 5-chloropyrazine-2-sulfonyl chloride (theoretical amount: 4 g, crude) in CCl.sub.4 (50 mL) and H.sub.2O (10 mL) at 10 C. for 10 minutes. Then the reaction mixture was warmed to 25 C. and stirred at 25 C. for 50 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 30:1 to 1:1) to give the title compound (1.6 g, 44%) as a yellow oil.

[0654] .sup.1H NMR (CDCl.sub.3): 8.98 (dd, 1H) and 7.88 (s, 1H).

Step D: 5-(Dimethylamino)pyrazine-2-sulfonamide

[0655] ##STR00171##

[0656] 5-Chloropyrazine-2-sulfonamide (800 mg, 4.13 mmol, 1 eq) was added into a solution of dimethylamine in water (2 M, 10.00 mL, 33 wt % in H.sub.2O, 4.84 eq). Then the mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was triturated with EtOAc (30 mL) to give the title compound (800 mg, 96%) as a white solid.

[0657] .sup.1H NMR (DMSO-d.sub.6): 8.46 (s, 1H), 8.20 (s, 1H), 7.28 (s, 2H) and 3.17 (s, 6H).

Intermediate P23: 3-(Difluoromethyl)pyrazine-2-sulfonamide

Step A: 3-Chloropyrazine-2-carbaldehyde

[0658] ##STR00172##

[0659] To a solution of 2,2,6,6-tetramethylpiperidine (27.13 g, 192.08 mmol, 2.2 eq) in THF (200 mL) was added n-BuLi (2.5 M, 73.34 mL, 2.1 eq) at 78 C. The reaction mixture was warmed to 0 C. and stirred for 15 minutes. Then the reaction mixture was cooled down to 78 C. and 2-chloropyrazine (10 g, 87.31 mmol, 1 eq) was added. The resulting mixture was stirred at 78 C. for 30 minutes. To the reaction mixture was added DMF (12.76 g, 174.62 mmol, 2 eq) at 78 C. The mixture was stirred at 78 C. for 30 minutes and then stirred at 0 C. for another 15 minutes. The reaction mixture was quenched with a solution of AcOH (50 mL) in THF (50 mL) at 78 C. Then the reaction mixture was poured into water (300 mL) and extracted with EtOAc (3300 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 5:1) to give the title compound (2.4 g, 19%) as a yellow oil.

[0660] .sup.1H NMR (CDCl.sub.3): 10.35 (s, 1H), 8.78-8.72 (m, 1H) and 8.62-8.58 (m, 1H).

Step B: 2-Chloro-3-(difluoromethyl)pyrazine

[0661] ##STR00173##

[0662] To a solution of 3-chloropyrazine-2-carbaldehyde (1.2 g, 8.42 mmol, 1 eq) in DCM (so mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (2.79 g, 12.63 mmol, 1.5 eq) at 78 C. The mixture was warmed to 25 C. and stirred for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with DCM (380 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacua. 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 (800 mg, 58%) as a yellow oil.

[0663] .sup.1H NMR (CDCl.sub.3): 8.54 (d, 1H), 8.47 (d, 1H) and 6.85 (t, 1H).

Step C: 2-(Benzylthio)-3-(difluoromethyl)pyrazine

[0664] ##STR00174##

[0665] To a solution of 2-chloro-3-(difluoromethyl)pyrazine (800 mg, 4.86 mmol, 1 eq) in MeCN (15 mL) was added phenylmethanethiol (664 mg, 5.35 mmol, 1.1 eq) and K.sub.2CO.sub.3 (874 mg, 6.32 mmol, 1.3 eq). The mixture was stirred at 25 C. for 12 hours. Then the reaction mixture was poured into water (50 mL) and extracted with EtOAc (250 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacua. 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 (1.1 g, 90%) as a colourless oil.

[0666] .sup.1H NMR (CDCl.sub.3): 8.56-8.52 (m, 1H), 8.33 (d, 1H), 7.45-7.42 (m, 2H), 7.36-7.30 (m, 3H), 6.71 (t, 1H) and 4.51 (s, 2H).

Step D: 3-(Difluoromethyl)pyrazine-2-sulfonyl chloride

[0667] ##STR00175##

[0668] Cl.sub.2 (15 psi) was bubbled into a solution of 2-(benzylthio)-3-(difluoromethyl)pyrazine (500 mg, 1.98 mmol, 1 eq) in DCM (20 mL) and H.sub.2O (2 mL) at 10 C. for 5 minutes. The reaction mixture was used directly in the next step without purification.

Step E: 3-(Difluoromethyl)pyrazine-2-sulfonamide

[0669] ##STR00176##

[0670] To a solution of 3-(difluoromethyl)pyrazine-2-sulfonyl chloride (theoretical amount: 453 mg, crude) in DCM (20 mL) and H.sub.2O (2 mL) was added NH.sub.3.H.sub.2O (15 mL, 25 wt % in water) at 0 C. The reaction mixture was stirred at 0 C. for 5 minutes and then concentrated in vacuo. The residue was treated with water (50 mL) and the mixture was washed with EtOAc (380 mL). The aqueous layer was concentrated in vacua. The residue was treated with EtOAc (100 mL) and the mixture was stirred for 10 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (260 mg, 63%) as a yellow oil.

[0671] .sup.1H NMR (DMSO-d.sub.6): 9.08 (d, 1H), 9.02 (s, 1H), 8.10 (br 5, 2H) and 7.52 (t, 1H).

[0672] LCMS: m/z 210.1 (M+H).sup.+ (ES.sup.+).

Intermediate P24: 4,6-Dimethylpyrimidine-2-sulfonamide

Step A: 4,6-Dimethylpyrimidine-2-thiol and 1,2-bis(4,6-dimethylpyrimidin-2-yl)disulfane

[0673] ##STR00177##

[0674] To a solution of pentane-2,4-dione (10.03 g, 100.17 mmol, 1.25 eq) in concentrated HCl solution (12 M, 20 mL, 2.99 eq) and EtOH (100 mL) was added thiourea (6.1 g, 80.14 mmol, 1 eq) at 10 C. The reaction mixture was stirred at 70 C. for 2 hours. The reaction mixture was cooled to 20 C. and a large amount of solid precipitated out. The mixture was filtered and the filter cake was treated with saturated aqueous NaHCO.sub.3 solution (300 mL). The mixture was filtered again and the filter cake was triturated with MeOH (200 mL) to give the title compound (10.3 g, 44% yield, 97.2% purity on LCMS) as a yellow solid.

[0675] .sup.1H NMR (DMSO-d.sub.6): 6.39 (s, 2H) and 2.13 (s, 12H).

[0676] LCMS: m/z 279.1 (M+H).sup.+ (ES.sup.+).

Step B: 4,6-Dimethylpyrimidine-2-sulfonyl chloride

[0677] ##STR00178##

[0678] Cl.sub.2 (15 psi) was bubbled into a solution of 1,2-bis(4,6-dimethylpyrimidin-2-yl)disulfane (1 g, 3.59 mmol, 1 eq) in DCM (40 mL) and H.sub.2O (6 mL) at 10 C. for 10 minutes. The reaction mixture was quenched with water (20 mL) and extracted with DCM (240 mL). The solution of the title compound (crude) in DCM (80 mL) was used directly in the next step without further purification.

Step C: 4,6-Dimethylpyrimidine-2-sulfonamide

[0679] ##STR00179##

[0680] NH.sub.3 (15 psi) was bubbled into a solution of 4,6-dimethylpyrimidine-2-sulfonyl chloride (theoretical amount: 0.74 g, crude) in DCM (80 mL) at 0 C. for 10 minutes. The reaction mixture was quenched with water (20 mL) and washed with DCM (40 mL). Then the aqueous phase was concentrated in vacua. The residue was triturated with EtOAc (300 mL) to give the title compound (0.35 g, 52% yield, 100% purity on LCMS) as a yellow solid.

[0681] .sup.1H NMR (DMSO-d.sub.6): 7.49-7.47 (m, 3H) and 2.52 (s, 6H).

[0682] LCMS: m/z 188.1 (M+H).sup.+ (ES.sup.+).

Intermediate P25: 5-(Dimethylamino)pyridazine-3-sulfonamide

Step A: 6-Chloro-N,N-dimethylpyridazin-4-amine

[0683] ##STR00180##

[0684] To a mixture of 3,5-dichloropyridazine (13.5 g, 90.62 mmol, 1 eq) in THF (100 mL) was added dimethylamine (270 mL, 543.70 mmol, in THF solution, 6 eq) in one portion at 25 C. Then the reaction mixture was stirred at 25 C. for 12 hours. The reaction mixture was concentrated in vacua. The residue was purified by reversed phase flash chromatography (0.05% of NH.sub.3.H.sub.2O in water/MeCN) to give the title compound (7 g, 49% yield, 99.35% purity on LCMS) as a brown solid.

[0685] .sup.1H NMR (CDCl.sub.3): 8.63 (d, 1H), 6.53 (d, 1H) and 3.09 (s, 6H).

[0686] LCMS: m/z 158.1 (M+H).sup.+ (ES.sup.+).

Step B: 6-(Benzylthio)-N,N-dimethylpyridazin-4-amine

[0687] ##STR00181##

[0688] To a mixture of phenylmethanethiol (4.31 g, 34.70 mmol, 1.22 eq) in DMF (100 mL) was added NaH (1.37 g, 34.26 mmol, 60 wt % in mineral oil, 1.2 eq) at 0 C. in one portion under N.sub.2. Then mixture was stirred at 0 C. for 0.5 hour. Then 6-chloro-N,N-dimethylpyridazin-4-amine (4.5 g, 28.55 mmol, 1 eq) was added. The reaction mixture was heated to 70 C. and stirred for 1 hour. Then the reaction mixture was quenched with water (200 mL) and extracted with EtOAc (3200 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 20:1, then flushed through with EtOAc:EtOH, 50:1 to 10:1) to give the title compound (5.2 g, 74%) as a brown solid.

[0689] .sup.1H NMR (CDCl.sub.3): 8.53 (d, 1H), 7.45-7.43 (m, 2H), 7.32-7.30 (m, 2H), 7.26-7.23 (m, 1H), 6.34 (d, 1H), 4.58 (s, 2H) and 3.09 (s, 6H).

Step C: 5-(Dimethylamino) pyridazine-3-sulfonyl chloride

[0690] ##STR00182##

[0691] To a solution of 6-(benzylthio)-N,N-dimethylpyridazin-4-amine (1 g, 4.08 mmol, 1 eq) in DCM (50 mL) was added a solution of CaCl.sub.2) (4.52 g, 40.76 mmol, 10 eq) in HCl (1 M, 20.38 mL, 5 eq) at 30 C. Then a solution of CaCl.sub.2) (14.70 g, 132.47 mmol, 32.5 eq) in aqueous NaClO solution (19.22 g, 15.49 mmol, 6 wt % in water, 3.8 eq) was added dropwise at 30 C. The resulting mixture was stirred at 30 C. for 30 minutes. The reaction mixture was quenched with water (20 mL) and extracted with DCM (250 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua to give a solution of the title compound (theoretical amount: 0.9 g, crude) in DCM (100 mL), which was used directly in the next step without further purification.

Step D: 5-(Dimethylamino) pyridazine-3-sulfonamide

[0692] ##STR00183##

[0693] NH.sub.3 (15 psi) was bubbled into a solution of 5-(dimethylamino)pyridazine-3-sulfonyl chloride (theoretical amount: 0.9 g, crude) in DCM (100 mL) at 20 C. for 10 minutes. The mixture was quenched with water (50 mL) and washed with DCM (30 mL). Then the aqueous phase (50 mL) was concentrated in vacua. The residue was purified by trituration with EtOAc (300 mL) to give the title compound (0.23 g, 28%) as a yellow solid.

[0694] .sup.1H NMR (DMSO-d.sub.6): 8.89 (d, 1H), 7.55 (s, 2H), 7.05 (d, 1H) and 3.09 (s, 6H).

[0695] LCMS: m/z 203.1 (M+H).sup.+ (ES.sup.+).

Intermediate P26: 2-Methylpropane-1-sulfonamide

[0696] ##STR00184##

[0697] A solution of 2-methylpropane-1-sulfonyl chloride (1.5 g, 9.58 mmol, 1 eq) in THF (20 mL) was cooled to 0 C. Then NH.sub.3 (15 psi) was bubbled into the mixture at 0 C. for 10 minutes. The mixture was stirred at 0 C. for another 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1 g, 76%) as a colourless oil.

[0698] .sup.1H NMR (DMSO-d.sub.6): 6.72 (s, 2H), 2.86 (d, 2H), 2.19-2.07 (m, 1H) and 1.01 (d, 6H).

Intermediate P27: 2-Phenylethanesulfonamide

[0699] ##STR00185##

[0700] NH.sub.3 was bubbled into THF (10 mL) at 78 C. for 5 minutes. Then a solution of 2-phenylethanesulfonyl chloride (0.5 g, 2.44 mmol, 1 eq) in THF (10 mL) was added to the NH.sub.3/THF solution at 25 C. The resulting mixture was stirred for 12 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (0.38 g, 84%) as a white solid.

[0701] .sup.1H NMR (CDCl.sub.3): 7.38-7.33 (m, 2H), 7.29-7.24 (m, 3H), 4.42 (br s, 2H), 3.45-3.40 (m, 2H) and 3.22-3.17 (m, 2H).

[0702] LCMS: m/z 208.1 (M+Na).sup.+ (ES.sup.+).

Intermediate P28: 1-Phenylethanesulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-phenylmethanesulfonamide

[0703] ##STR00186##

[0704] To a solution of bis(4-methoxybenzyl)amine (4.05 g, 15.74 mmol, 1 eq) in DCM (40 mL) was added TEA (3.18 g, 31.47 mmol, 2 eq) and phenylmethanesulfonyl chloride (3 g, 15.74 mmol, eq). The mixture was stirred at 20 C. for 12 hours. The reaction mixture was concentrated in vacuo. The residue was treated with water (50 mL) and extracted with EtOAc (250 mL). The organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 5:1 to 3:1) to give the title compound (4 g, 62%) as a yellow solid.

[0705] .sup.1H NMR (CDCl.sub.3): 7.24-7.20 (m, 3H), 7.11 (dd, 4H), 7.00-6.95 (m, 2H), 6.80 (dd, 4H), 4.03 (s, 2H), 3.96 (s, 4H) and 3.74 (s, 6H).

Step B: N,N-Bis(4-methoxybenzyl)-1-phenylethanesulfonamide

[0706] ##STR00187##

[0707] To a solution of N,N-bis(4-methoxybenzyl)-1-phenylmethanesulfonamide (1 g, 2.43 mmol, 1 eq) in THF (10 mL) was added LDA (2 M, 1.34 mL, 1.1 eq) at 78 C. under N.sub.2 atmosphere. The mixture was stirred at 78 C. for 1 hour. Iodomethane (379 mg, 2.67 mmol, 1.1 eq) was added and the resulting mixture was stirred at 20 C. for 2 hours. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution (20 mL) and then concentrated in vacuo to remove THF. The mixture was treated with water (10 mL) and extracted with EtOAc (315 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 5:1) to give the title compound (0.9 g, 87%) as a white solid.

[0708] .sup.1H NMR (CDCl.sub.3): 7.33-7.28 (m, 3H), 7.14 (d, 4H), 7.10-7.08 (m, 2H), 6.86 (dd, 4H), 4.09 (d, 2H), 4.03-4.01 (m, 1H), 3.83 (s, 6H), 3.76 (d, 2H) and 1.79 (d, 3H).

Step C: 1-Phenylethanesulfonamide

[0709] ##STR00188##

[0710] To a solution of N,N-bis(4-methoxybenzyl)-1-phenylethanesulfonamide (900 mg, 2.11 mmol, 1 eq) in DCM (30 mL) was added TFA (46.20 g, 405.19 mmol, 191.58 eq). The mixture was stirred at 20 C. for 12 hours. The reaction mixture was concentrated in vacuo. The residue was treated with MeOH (is mL). The suspension was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (v:v=20:1, 10 mL) to give the title compound (300 mg, 77%) as a white solid.

[0711] .sup.1H NMR (CDCl.sub.3): 7.47-7.39 (m, 5H), 4.46 (br s, 2H), 4.29 (q, 1H) and 1.82 (d, 3H).

Intermediate P29: 1-Cyclopropyl-1H-pyrazole-3-sulfonamide

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

[0712] ##STR00189##

[0713] To a solution of cyclopropylboronic acid (36.77 g, 428.04 mmol, 1.1 eq) in DCE (500 mL) was added 3-nitro-1H-pyrazole (44 g, 389.12 mmol, 1 eq), 2,2-bipyridine (60.77 g, 389.12 mmol, 1 eq) and Na.sub.2CO.sub.3 (64.59 g, 609.44 mmol, 1.57 eq) at 25 C. The mixture was stirred at 25 C. for 0.5 hour. Then Cu(OAc).sub.2 (70.68 g, 389.12 mmol, 1 eq) was added and the resulting mixture was warmed to 70 C. and stirred at 70 C. for 15.5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 30:1 to 3:1) to give impure product (26.7 g). The impure product was dissolved in pyrrolidine (10 mL) and the resulting mixture was stirred at 70 C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyrrolidine. The residue was diluted with H.sub.2O (33 mL) and the pH was adjusted to 5-6 with aqueous HCl solution (1N). Then the mixture was extracted with EtOAc (350 mL). The combined organic layers were washed with brine (233 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (17.7 g, 30%) as yellow oil.

[0714] .sup.1H NMR (CDCl.sub.3): 7.54 (d, 1H), 6.84 (d, 1H), 3.73-3.67 (m, 1H), 1.24-1.22 (m, 2H) and 1.13-1.07 (m, 2H).

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

[0715] ##STR00190##

[0716] To a solution of 1-cyclopropyl-3-nitro-1H-pyrazole (36 g, 235.08 mmol, 1 eq) in EtOH (400 mL) was added a solution of NH.sub.4Cl (62.87 g, 1.18 mol, 5 eq) in H.sub.2O (150 mL). Then the reaction mixture was warmed to 60 C. and iron power (39.38 g, 705.24 mmol, 3 eq) was added in portions. The reaction mixture was stirred at 60 C. for 16 hours and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3500 mL). The combined organic layers were washed with brine (2250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 30:1 to 1:1) to give the title compound (20 g, 69%) as yellow oil.

[0717] .sup.1H NMR (CDCl.sub.3): 7.14 (d, 1H), 5.11 (d, 1H), 3.57 (br s, 2H), 3.38-3.32 (m, 1H), 0.99-0.95 (m, 2H) and 0.90-0.87 (m, 2H).

[0718] LCMS: m/z 124.2 (M+H).sup.+ (ES.sup.+).

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

[0719] ##STR00191##

[0720] To a solution of 1-cyclopropyl-1H-pyrazol-3-amine (19 g, 154.28 mmol, 1 eq) in MeCN (500 mL) and H.sub.2O (50 mL) at 0 C. was added concentrated HCl solution (50 mL). Then an aqueous solution of NaNO.sub.2 (12.77 g, 185.13 mmol, 1.2 eq) in H.sub.2O (50 mL) was added slowly. The resulting solution was stirred at 0 C. for 40 minutes. AcOH (50 mL), CuCl.sub.2 (10.37 g, 77.14 mmol, 0.5 eq) and CuCl (763 mg, 7.71 mmol, 0.05 eq) were added. Then SO.sub.2 gas (15 psi) was bubbled into the resulting mixture for 20 minutes at 0 C. The reaction mixture was stirred at 0 C. for 1 hour and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (250 mL) and extracted with EtOAc (3250 mL). The combined organic layers were washed with brine (2150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 100:0 to 1:1) to give the title compound (14 g, 44%) as yellow oil.

[0721] .sup.1H NMR (CDCl.sub.3): 7.62 (d, 1H), 6.83 (d, 1H), 3.78-3.72 (m, 1H), 1.28-1.24 (m, 2H) and 1.16-1.12 (m, 2H).

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

[0722] ##STR00192##

[0723] To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride (28 g, 135.49 mmol, 1 eq) in THF (300 mL) was added TEA (27.42 g, 270.99 mmol, 2 eq) and bis(4-methoxybenzyl)amine (34.87 g, 135.49 mmol, 1 eq). The mixture was stirred at 25 C. for 1 hour. The reaction mixture was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3500 mL). The combined organic layers were washed with brine (2500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography (0.5% NH.sub.3.H.sub.2O-MeCN) to give the title compound (30 g, 52% yield, 99.8% purity on LCMS).

[0724] .sup.1H NMR (CDCl.sub.3): 7.49 (d, 1H), 7.08-7.06 (m, 4H), 6.79-6.77 (m, 4H), 6.62 (d, 1H), 4.32 (s, 4H), 3.80 (s, 6H), 3.68-3.64 (m, 1H), 1.15-1.13 (m, 2H) and 1.09-1.06 (m, 2H)

[0725] LCMS: m/z 428.2 (M+H).sup.+ (ES.sup.+).

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

[0726] ##STR00193##

[0727] To a solution of 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (1 g, 2.34 mmol, 1 eq) in DCM (10 mL) was added TFA (15.40 g, 135.06 mmol, 57.74 eq). The mixture was stirred at 25 C. for 12 hours. Most of the solvent was evaporated and the residue was re-dissolved in MeOH (30 mL). Solids were formed and the mixture was filtered. The filtrate was concentrated in vacuo and then the crude product was triturated with a mixture of PE and EtOAc (30 mL, 20:1) to give the title compound (430 mg, 88% yield, 90% purity on LCMS) as a white solid.

[0728] .sup.1H NMR (DMSO-d.sub.6): 7.92 (s, 1H), 7.38 (s, 2H), 6.55 (s, 1H), 3.84-3.78 (m, 1H) and 1.10-0.98 (m, 4H).

Intermediate P30: 1-Cyclopropyl-1H-pyrazole-4-sulfonamide

Step A: 4-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

[0729] ##STR00194##

[0730] To a mixture of 4-iodo-1H-pyrazole (50 g, 257.77 mmol, 1 eq) and pyridin-1-ium 4-methylbenzenesulfonate (32.39 g, 128.88 mmol, 0.5 eq) in DCM (500 mL) at 20 C. was added 3,4-dihydro-2H-pyran (43.4 g, 515.54 mmol, 2 eq). The reaction mixture was stirred at 20 C. for 12 hours and then concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 20:1) to give the title compound (65 g, 91%) as a colourless oil.

[0731] .sup.1H NMR (CDCl.sub.3): 7.67 (s, 1H), 7.55 (s, 1H), 3.84-3.82 (m, 1H), 4.15-4.01 (m, 1H), 3.72-3.66 (m, 1H), 2.07-2.04 (m, 2H) and 1.69-1.62 (m, 4H).

Step B: S-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzothioate

[0732] ##STR00195##

[0733] CuI (2.05 g, 10.79 mmol, 0.1 eq) was added to the mixture of 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (30 g, 107.88 mmol, 1 eq), benzenecarbothioic S-acid (17.89 g, 129.45 mmol, 1.2 eq), 1,10-phenanthroline (3.89 g, 21.58 mmol, 0.2 eq) and DIPEA (27.89 g, 215.76 mmol, 2 eq) in toluene (300 mL) at 20 C. under N.sub.2. The mixture was stirred for 12 hours at 110 C. under N.sub.2. The residue was poured into 1 M HCl solution (500 mL). The aqueous phase was extracted with ethyl acetate (3200 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 20:1 to 5:1) to give the title compound (28 g, 85% yield, 94% purity on LCMS) as a yellow oil.

[0734] .sup.1H NMR (CDCl.sub.3): 8.01 (d, 2H), 7.83 (s, 1H), 7.64-7.59 (m, 2H), 7.49 (t, 2H), 5.49 (t, 1H), 4.09-4.05 (m, 1H), 3.76-3.69 (m, 1H), 2.16-2.13 (m, 2H), 1.74-1.62 (m, 4H).

Step C: 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-sulfonyl chloride

[0735] ##STR00196##

[0736] 1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (13.30 g, 57.22 mmol, 1.1 eq) was added into a solution of benzyltrimethylammonium chloride (31.88 g, 171.66 mmol, 29.79 mL, 3.3 eq) in MeCN (300 mL) at 20 C. The mixture was stirred for 30 minutes. The clear yellow solution was added dropwise into a solution of S-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzothioate (15 g, 52.02 mmol, 1 eq) in MeCN (150 mL) at 0 C. An aqueous sodium carbonate solution (1 M, 52.02 mL, 1 eq) was added dropwise into the mixture at 0 C. The mixture was stirred for 30 minutes. The reaction solution was diluted with saturated aqueous sodium carbonate solution (100 mL) and extracted with EtOAc (2100 mL). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 20:1 to 5:1) to give the title compound (3.5 g, 27%) as a colourless oil.

[0737] .sup.1H NMR (CDCl.sub.3): 8.29 (s, 1H), 8.00 (s, 1H), 5.45 (q, 1H), 4.16-4.08 (m, 1H), 3.78-3.74 (m, 1H), 2.02-1.96 (m, 2H) and 1.71-1.60 (m, 4H).

Step D: N,N-Bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-sulfonamide

[0738] ##STR00197##

[0739] 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-sulfonyl chloride (2.5 g, 9.97 mmol, 1 eq) was added into the solution of bis(4-methoxybenzyl)amine (2.31 g, 8.97 mmol, 0.9 eq) and TEA (3.03 g, 29.92 mmol, 3 eq) in THF (50 mL) at 0 C. The reaction mixture was stirred at 20 C. for 12 hours. The residue was poured into 1 M HCl solution (100 mL). The aqueous phase was extracted with ethyl acetate (230 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The solid was triturated with a mixture of PE and EtOAc (20 mL, v:v=5:1) to give the title compound (3 g, 60% yield, 94.4% purity on LCMS) as a white solid.

[0740] .sup.1H NMR (CDCl.sub.3): 7.76 (s, 1H), 7.65 (s, 1H), 7.11 (d, 4H), 6.81 (d, 4H), 3.35 (q, 1H), 4.23 (s, 4H), 4.05 (d, 1H), 3.80 (s, 6H), 3.73-3.64 (m, 1H), 2.10-1.97 (m, 2H) and 1.76-1.64 (m, 4H).

[0741] LCMS: m/z 472.1 (M+H).sup.+ (ES.sup.+).

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

[0742] ##STR00198##

[0743] HCl (1 M, 8.48 mL, 2 eq) was added to the mixture of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-sulfonamide (2 g, 4.24 mmol, 1 eq) in EtOH (20 mL) and THF (20 mL) at 20 C. The mixture was stirred at 20 C. for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (30 mL). The aqueous phase was extracted with ethyl acetate (320 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua to give the title compound (2 g, crude) as a yellow oil, which was used in the next step without further purification.

[0744] .sup.1H NMR (CDCl.sub.3): 7.78 (s, 2H), 7.10 (d, 4H), 6.81 (d, 4H), 4.24 (s, 4H) and 3.79 (s, 6H).

[0745] LCMS: m/z 388.1 (M+H).sup.+ (ES.sup.+).

Step F: 1-Cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide

[0746] ##STR00199##

[0747] To a solution of cyclopropylboronic acid (109 mg, 1.28 mmol, 1.1 eq) in dioxane (5 mL) was added N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (450 mg, 1.16 mmol, 1 eq), 2,2-bipyridine (181.39 mg, 1.16 mmol, 1 eq) and Na.sub.2CO.sub.3 (193 mg, 1.82 mmol, 1.57 eq). The reaction mixture was stirred at 25 C. for 0.5 hour. Then Cu(OAc).sub.2 (211 mg, 1.16 mmol, 1 eq) was added and the resulting mixture was warmed to 70 C. and stirred at 70 C. for 11.5 hours. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (350 mL). The combined organic layers were washed with brine (220 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 20:1 to 1:1) to give the title compound (210 mg, 42%) as a yellow solid.

[0748] .sup.1H NMR (DMSO-d.sub.6): 8.31 (s, 1H), 7.78 (s, 1H), 7.09-7.05 (m, 4H), 6.83-6.80 (m, 4H), 4.14 (s, 4H), 3.83-3.77 (m, 1H), 3.72 (s, 6H), 1.08-1.03 (m, 2H) and 1.02-1.00 (m, 2H).

[0749] LCMS: m/z 428.2 (M+H).sup.+ (ES.sup.+)

Step G: 1-Cyclopropyl-1H-pyrazole-4-sulfonamide

[0750] ##STR00200##

[0751] To a solution of 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (170 mg, 397.65 mol, 1 eq) in DCM (1 mL) was added TFA (5.24 g, 45.92 mmol, 115.48 eq). The mixture was stirred at 25 C. for 2 hours. Most of the solvent was evaporated to give the crude product. The crude product was added into MeOH (3 mL) and solid was formed. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (44 mg, 59%) as a red solid.

[0752] .sup.1H NMR (DMSO-d.sub.6): 8.29 (s, 1H), 7.74 (s, 1H), 7.23 (s, 2H), 3.3-3.79 (m, 1H), 1.08-1.05 (m, 2H) and 1.01-0.98 (m, 2H).

[0753] LCMS: m/z 188.1 (M+H).sup.+ (ES.sup.+).

Intermediate P31: (1-Methylpyrrolidin-3-yl)methanesulfonamide

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

[0754] ##STR00201##

[0755] To a mixture of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (13 g, 64.59 mmol, 1 eq) and TEA (13.07 g, 129.18 mmol, 2.0 eq) in DCM (200 mL) was added dropwise MSCl (8.23 g, 71.85 mmol, 1.1 eq) at 0 C. Then the reaction mixture was warmed to 25 C. and stirred for 1 hour under N.sub.2. The reaction mixture was quenched with water (100 mL) and extracted with DCM (3100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (20 g, crude) as brown oil, which was used directly in the next step without further purification.

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

[0756] ##STR00202##

[0757] To a mixture of tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (20 g, 71.59 mmol, 1 eq) in acetonitrile (300 mL) was added potassium ethanethioate (10 g, 87.56 mmol, 1.22 eq) in one portion. Then the reaction mixture was heated to 50 C. and stirred for 12 hours. The mixture was concentrated in vacua. The residue was treated with water (100 mL) and the mixture was extracted with EtOAc (3100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 5:1) to give the title compound (14.2 g, 76%) as a yellow oil.

[0758] .sup.1H NMR (CDCl.sub.3): 3.61-3.41 (m, 2H), 3.33-3.23 (m, 1H), 3.05-2.87 (m, 3H), 2.42-2.29 (m, 4H), 2.08-1.99 (m, 1H), 1.64-1.59 (m, 1H) and 1.46 (s, 9H).

Step C: tert-Butyl 3-((chlorosulfonyl)methyl)pyrrolidine-1-carboxylate

[0759] ##STR00203##

[0760] To a mixture of tert-butyl 3-((acetylthio)methyl)pyrrolidine-1-carboxylate (4 g, 15.42 mmol, 1 eq) in AcOH (200 mL) and H.sub.2O (20 mL) was added NCS (6.18 g, 46.27 mmol, 3 eq) in one portion at 25 C. Then the reaction mixture was stirred at 25 C. for 1 hour. The mixture was quenched with water (200 mL) and extracted with DCM (2100 mL). The combined organic phases were washed with brine (2100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua to give a solution of the title compound (4.38 g, crude) in DCM (200 mL), which was used directly in the next step without further purification.

Step D: tert-Butyl 3-(sulfamoylmethyl)pyrrolidine-1-carboxylate

[0761] ##STR00204##

[0762] NH.sub.3 (15 psi) was bubbled into a solution of tert-butyl 3-((chlorosulfonyl)methyl)pyrrolidine-1-carboxylate (4.38 g, crude) in DCM (200 mL) at 20 C. for 10 minutes. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (2 g, crude) as a brown solid.

[0763] .sup.1H NMR (CDCl.sub.3): 3.78-3.73 (m, 1H), 3.56-3.47 (m, 1H), 3.37-3.31 (m, 1H), 3.25-3.15 (m, 2H), 3.14-3.04 (m, 1H), 2.78-2.72 (m, 1H), 2.26-2.20 (m, 1H), 1.77-1.71 (m, 1H) and 1.47 (s, 9H).

Step E: Pyrrolidin-3-ylmethanesulfonamide hydrochloride

[0764] ##STR00205##

[0765] To a mixture of tert-butyl 3-(sulfamoylmethyl)pyrrolidine-1-carboxylate (2 g, 7.57 mmol, 1 eq) in EtOAc (5 mL) was added a solution of HCl in EtOAc (4 M, 30 mL, 15.86 eq) in one portion. Then the reaction mixture was stirred at 25 C. for 0.5 hour. The reaction mixture was concentrated in vacua to give the title compound (2 g, crude, HCl salt) as a brown oil, which was used directly in the next step without further purification.

[0766] .sup.1H NMR (DMSO-d.sub.6): 9.35-9.23 (m, 2H), 6.99 (s, 2H), 3.39-3.36 (m, 1H), 3.22-3.19 (m, 2H), 3.08-3.05 (m, 1H), 2.93-2.85 (m, 1H), 2.65-2.59 (m, 2H), 2.20-2.13 (m, 1H) and 1.71-1.63 (m, 1H).

Step F: (1-Methylpyrrolidin-3-yl)methanesulfonamide

[0767] ##STR00206##

[0768] To a solution of pyrrolidin-3-ylmethanesulfonamide hydrochloride (2 g, 9.97 mmol, 1 eq), TEA (1.21 g, 11.96 mmol, 1.2 eq) and HCHO (849 mg, 10.46 mmol, 1.05 eq) in MeCN (20 mL) was added NaBH(OAc).sub.3 (2.64 g, 12.46 mmol, 1.25 eq) in one portion. Then the reaction mixture was stirred at 25 C. for 12 hours. The mixture was concentrated in vacuo. The residue was purified by reversed phase flash (0.05% NH.sub.3.H.sub.2O in water/MeCN) and then further purified by silica gel chromatography (0.1% NH.sub.3.H.sub.2O, EtOAc: EtOH, 1:0 to 1:1) to give the title compound (1.5 g, 84%) as a yellow solid.

[0769] .sup.1H NMR (DMSO-d.sub.6): 5.60 (br s, 2H), 3.04-3.01 (m, 2H), 2.70-2.65 (m, 1H), 2.45-2.37 (m, 2H), 2.30-2.21 (m, 5H), 2.08-1.95 (m, 1H) and 1.56-1.50 (m, 1H).

[0770] LCMS: m/z 179.1 (M+H).sup.+ (ES.sup.+).

Intermediate P32: 3-(Diethylamino)propane-1-sulfonamide

[0771] ##STR00207##

[0772] To a solution of 3-chloropropane-1-sulfonamide (203 mg, 1.29 mmol) in acetonitrile (10 mL) was added triethylamine (214 L, 1.55 mmol, 1.2 equiv.), N,N-diethylamine (159 L, 1.55 mmol, 1.2 equiv.) and potassium iodide (43 mg, 0.26 mmol) and the reaction mixture was irradiated in the microwave at 100 C. for 90 minutes. Additional potassium iodide (150 mg) was added and the resulting mixture was heated conventionally for another 2 hours at 100 C. Upon cooling to room temperature the mixture was concentrated in vacua to afford the crude title compound (>100% yield); the material still contained salts and impurities but was used without further purification.

[0773] .sup.1H NMR (CD.sub.3OD) 2.86 (m, 6H), 2.47 (m, 2H), 2.23 (m, 2H) and 1.18 (t, 6H).

[0774] LCMS: m/z 195.1 (M+H).sup.+ (ES.sup.+).

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

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

[0775] ##STR00208##

[0776] To a solution of 1,2-oxathiolane 2,2-dioxide (1 g, 8.19 mmol, 719.42 L,1 eq) in DCM (5 mL) was added N-benzylethanamine (3.94 g, 29.15 mmol, 3.56 eq) at 0 C. Then the resulting mixture was stirred at 25 C. for 2.5 hours. The mixture was concentrated in vacua. The residue was triturated with EtOAc (40 mL) to give the title compound (2.4 g, crude) as a white solid.

[0777] .sup.1H NMR (DMSO-d.sub.6): 7.37-7.23 (m, 5H), 4.08 (s, 2H), 2.91 (q, 2H), 2.50-2.40 (m, 4H), 1.81-1.73 (m, 2H) and 0.98 (t, 3H).

[0778] LCMS: m/z 258.1 (M+H).sup.+ (ES.sup.+).

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

[0779] ##STR00209##

[0780] A solution of 3-(benzyl(ethyl)amino)propane-1-sulfonic acid (2.1 g, 8.16 mmol, 1 eq) in SOCl.sub.2 (17.22 g, 144.74 mmol, 17.74 eq) was stirred at 80 C. for 6 hours. The mixture was concentrated in vacua to give the title compound (2 g, crude) as a yellow oil, which was used directly in the next step.

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

[0781] ##STR00210##

[0782] To a solution of 3-(benzyl(ethyl)amino)propane-1-sulfonyl chloride (2 g, crude) in THF (3 mL) was added to a saturated solution of NH.sub.3 in THF (100 mL) at 0 C. Then the mixture was stirred at 20 C. for 14 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (1.15 g, 62% yield, 100% purity on LCMS) as a white solid.

[0783] .sup.1H NMR (CDCl.sub.3): 7.37-7.28 (m, 5H), 4.98 (br s, 2H), 3.57 (s, 2H), 3.15 (t, 2H), 2.61-2.52 (m, 4H), 2.06-2.00 (m, 2H) and 1.07 (t, 3H).

Intermediate P34: 3-Methoxypropane-1-sulfonamide

Step A: Sodium 3-methoxypropane-1-sulfonate

[0784] ##STR00211##

[0785] A mixture of 1-bromo-3-methoxypropane (2 g, 13.07 mmol, 1 eq) and Na.sub.2SO.sub.3 (1.65 g, 13.07 mmol, 1 eq) in H.sub.2O (20 mL) was heated to 100 C. and stirred for 16 hours. Then the reaction mixture was cooled and lyophilized to give the title compound (2.25 g, 97% yield, Na salt) as a white solid.

[0786] .sup.1H NMR (D.sub.2O): 3.56 (t, 2H), 3.34 (s, 3H), 2.95-2.92 (m, 2H) and 2.02-1.94 (m, 2H).

[0787] LCMS: m/z 155.1 (M-Na+H).sup.+ (ES.sup.+).

Step B: 3-Methoxypropane-1-sulfonyl chloride

[0788] ##STR00212##

[0789] A solution of sodium 3-methoxypropane-1-sylfonate (0.7 g, 4.54 mmol, 1 eq) in POCl.sub.3 (8.25 g, 53.80 mmol, 11.85 eq) was stirred at 80 C. for 5 hours. Then the mixture was stirred at 100 C. for 2 hours. The mixture was diluted with DCM (80 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (600 mg, crude) as a yellow oil, which was used directly in the next step.

Step C: 3-Methoxypropane-1-sulfonamide

[0790] ##STR00213##

[0791] NH.sub.3 (15 psi) was bubbled into THF (20 mL) at 0 C. for 5 minutes. A solution of 3-methoxypropane-1-sulfonyl chloride (600 mg, crude) in THF (2 mL) was added to the NH.sub.3/THF solution (20 mL). Then the mixture was stirred at 20 C. for 14 hours. The reaction mixture was filtered and the filtrate was concentrated in vacua to give the crude compound (300 mg, crude) as a yellow oil.

[0792] .sup.1H NMR (CDCl.sub.3): 4.94 (br s, 2H), 3.53 (t, 2H), 3.35 (s, 3H), 3.25 (t, 2H) and 2.17-2.10 (m, 2H).

Intermediate P35: N,N-Bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

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

[0793] ##STR00214##

[0794] A solution of 1-methyl-1H-pyrazol-3-amine (25 g, 257.42 mmol, 1 eq) in MeCN (boo 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 L, 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 (21.2 L). The combined organic layers were washed with brine (32 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.

[0795] .sup.1H NMR (CDCl.sub.3): 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

[0796] ##STR00215##

[0797] 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, 426.33 mmol, 1 eq). Then the reaction mixture was stirred at 25 C. for 12 hours. The reaction mixture was concentrated in vacua 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 (2500 mL). The combined organic layers were washed with brine (2600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was 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.

[0798] .sup.1H NMR (CDCl.sub.3): 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).

[0799] 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

[0800] ##STR00216##

[0801] 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 (21 L). The combined organic layers were washed with brine (21 L), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacua. 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.

[0802] .sup.1H NMR (DMSO-d.sub.6): 6.98-7.16 (m, 5H), 6.82 (d, 4H), 4.25 (s, 4H), 4.15 (s, 3H) and 3.72 (s, 6H).

[0803] LCMS: m/z 468.2 (M+Na)+ (ES+).

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

[0804] ##STR00217##

[0805] 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.4Cl solution (350 mL) and brine (350 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. 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.

[0806] .sup.1H NMR (CD.sub.3OD): 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).

[0807] 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

[0808] ##STR00218##

[0809] 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.

[0810] .sup.1H NMR (DMSO-d.sub.6): 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 P36: N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

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

[0811] ##STR00219##

[0812] A solution of 1-methyl-1H-pyrazol-3-amine (25 g, 257.42 mmol, 1 eq) in MeCN (boo 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 L, 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 (21.2 L). The combined organic layers were washed with brine (32 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.

[0813] .sup.1H NMR (CDCl.sub.3): 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

[0814] ##STR00220##

[0815] 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, 426.33 mmol, 1 eq). Then the reaction mixture was stirred at 25 C. for 12 hours. The reaction mixture was concentrated in vacua 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 (2500 mL). The combined organic layers were washed with brine (2600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was 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.

[0816] .sup.1H NMR (CDCl.sub.3): 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).

[0817] 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

[0818] ##STR00221##

[0819] 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 (21 L). The combined organic layers were washed with brine (21 L), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacua. 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.

[0820] .sup.1H NMR (DMSO-d.sub.6): 6.98-7.16 (m, 5H), 6.82 (d, 4H), 4.25 (s, 4H), 4.15 (s, 3H) and 3.72 (s, 6H).

[0821] LCMS: m/z 468.2 (M+Na)+ (ES+).

Step D: 3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

[0822] ##STR00222##

[0823] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (100 g, 224.47 mmol, 1 eq), DIPEA (58.02 g, 448.95 mmol, 78.20 mL, 2 eq) and dimethylamine (2 M, 448.95 mL, 4 eq) in DMF (1 L) was added a solution of propylphosphonic anhydride in EtOAc (285.69 g, 448.95 mmol, 267.00 mL, 50% in EtOAc, 2 eq) at 25 C. Then the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched by addition of H.sub.2O (2 L) and then extracted with EtOAc (21.1 L). The combined organic layers were washed with brine (21.2 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of EtOAc and petroleum ether (v:v=5:1, 150 mL) to give the title compound (92.7 g, 87% yield, 100% purity on LCMS).

[0824] .sup.1H NMR (CDCl.sub.3): 7.09 (d, 4H), 6.78 (d, 4H), 6.63-6.70 (m, 1H), 4.32 (s, 4H), 4.02 (s, 3H), 3.79 (s, 6H) and 3.11 (d, 6H).

[0825] LCMS: m/z 473.3 (M+H).sup.+ (ES.sup.+).

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

[0826] ##STR00223##

[0827] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (80 g, 169.29 mmol, 1 eq) in DCM (180 mL) was added TFA (381.33 g, 3.34 mol, 247.62 mL, 19.75 eq). The reaction mixture was stirred at 15 C. for 15 hours and then concentrated in vacuo. The residue was re-dissolved in dichloromethane (200 mL). The resulting solution was added into MeOH (1.2 L) and a solid precipitated. The suspension was filtered and the filtrate was concentrated in vacua. The residue was re-dissolved in dichloromethane (150 mL). Then the resulting solution was added into tert-butyl methyl ether (700 mL) and a solid precipitated. The suspension was filtered and the filter cake was dried to give the title compound (32 g, 81%) as a white solid.

[0828] .sup.1H NMR (DMSO-d.sub.6): 7.50 (s, 2H), 6.81 (s, 1H), 3.89 (s, 3H) and 3.02 (d, 6H).

[0829] LCMS: m/z 233.2 (M+H).sup.+ (ES.sup.+).

Intermediate P37: ((1-Cyclopropyl-1H-pyrazol-3-yl)sulfonyl)(4-(dimethylamino) pyridin-1-ium-1-carbonyl)amide

[0830] ##STR00224##

[0831] A mixture of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (1.35 g, 7.21 mmol) and N,N-dimethylpyridin-4-amine (1.762 g, 14.42 mmol) in anhydrous MeCN (15 mL) was stirred at room temperature for 10 minutes. Then diphenyl carbonate (1.70 g, 7.93 mmol) was added and the reaction was stirred for 16 hours. The solid obtained was collected by filtration and rinsed with MTBE (5 mL) to afford the title compound as a solid (1.57 g, 55%).

[0832] .sup.1H NMR (DMSO-d.sub.6) 8.82-8.63 (m, 2H), 7.81 (d, J=2.3 Hz, 1H), 7.04-6.86 (m, 2H), 6.57 (d, J=2.4 Hz, 1H), 3.76 (m, 1H), 3.25 (s, 6H), 1.07-1.01 (m, 2H), 1.00-0.95 (m, 2H).

Intermediate P38: 1-Cyclobutyl-1H-pyrazole-3-sulfonamide

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

[0833] ##STR00225##

[0834] 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%).

[0835] .sup.1H NMR (DMSO-d6) 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).

[0836] LCMS; m/z 215 (MH).sup. (ES).

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

[0837] ##STR00226##

[0838] 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 (2250 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.

[0839] LCMS; m/z 494.2 (M+Na).sup.+ (ES.sup.+).

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

[0840] ##STR00227##

[0841] 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.

[0842] .sup.1H NMR (CDCl.sub.3) 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.

[0843] LCMS; m/z 388 (M+H).sup.+ (ES.sup.+); 386 (MH).sup. (ES.sup.).

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

[0844] ##STR00228##

[0845] A solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (5 g, 12.90 mmol) in DMF (60 mL) was cooled to 0 C., before sodium hydride (0.671 g, 16.78 mmol) was added. The mixture was warmed to room temperature and stirred for 30 minutes, before bromocyclobutane (1.3 ml, 13.81 mmol) was added slowly via syringe. The resulting mixture was stirred at 50 C. over the weekend. The mixture was diluted with EtOAc (100 mL). H.sub.2O (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2100 mL) and the combined organic extracts were washed with brine (380 mL), passed through a phase separator and concentrated in vacua. The residue was loaded onto silica and purified by chromatography (80 g column, 0-100% EtOAc/isohexane) to afford the title compound (4.72 g, 75%) as a pale yellow oil.

[0846] .sup.1H NMR (DMSO-d6) 8.03 (d, J=2.4 Hz, 1H), 7.04 (d, J=8.6 Hz, 4H), 6.81 (d, J=8.6 Hz, 4H), 6.71 (d, J=2.3 Hz, 1H), 4.94 (p, J=8.4 Hz, 1H), 4.22 (s, 4H), 3.72 (s, 6H), 2.49-2.38 (m, 4H), 1.87-1.77 (m, 2H).

[0847] LCMS; m/z 464.2 (M+Na).sup.+ (ES.sup.+).

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

[0848] ##STR00229##

[0849] 1-Cyclobutyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (4.72 g, 10.69 mmol) was dissolved in TFA (5 mL) and DCM (5 mL) and stirred overnight at room temperature. The reaction mixture was concentrated in vacua and the residue was purified by chromatography on silica gel (40 g cartridge, 0-10% MeOH/DCM) to afford the title compound (1.5 g, 66%) as a pale white solid.

[0850] .sup.1H NMR (DMSO-d6) 7.96 (d, J=2.4 Hz, 1H), 7.39 (s, 2H), 6.59 (d, J=2.4 Hz, 1H), 4.96-4.86 (m, 1H), 2.50-2.44 (m, 2H), 2.44-2.36 (m, 2H), 1.85-1.77 (m, 2H).

[0851] LCMS; m/z 202.0 (M+H).sup.+ (ES.sup.+).

Intermediate P39: 1-(1-(Azetidin-1-yl)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide

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

[0852] ##STR00230##

[0853] N,N-Bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (2.00 g, 5.16 mmol) (Intermediate P38, Step C) 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 MTBE (250 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.

[0854] .sup.1H NMR (DMSO-d.sub.6) 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).

[0855] LCMS; m/z 511 (M+Na)+ (ES+).

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

[0856] ##STR00231##

[0857] A mixture of methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoate (2.4 g, 4.92 mmol) and aq 2 M NaOH (5 mL, 10.00 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 1 M HCl (100 mL). The organic layer was 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.

[0858] .sup.1H NMR (CDCl.sub.3) 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.

[0859] LCMS; m/z 472 (MH) (ES).

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

[0860] ##STR00232##

[0861] A mixture of 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid (1.15 g, 2.234 mmol), Hunig's base (1.557 ml, 8.91 mmol) and HATU (0.921 g, 2.422 mmol) in DMF (6.5 ml) was stirred at 0-5 C. for 10 minutes. Then azetidine HCl (0.272 g, 2.90 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 20 hours. Additional HATU (0.263 g, 1.117 mmol) was added, followed by Hunig's base (0.390 ml, 2.234 mmol). The mixture was cooled to 0-5 C. for 10 minutes. Then additional azetidine HCl (0.064 g, 1.117 mmol) was added. The mixture was allowed to warm to room temperature, stirred for a further hour, and then partitioned between TBME (75 ml) and water (40 ml). The organic layer was washed with aq 1M HCl (40 ml), water (25 ml), dried (MgSO.sub.4), filtered, evaporated, and then purified by chromatography on silica gel (120 g column, 0-100% TBME/isohexane) to afford the title compound (615 mg, 51%) as a clear gum.

[0862] .sup.1H NMR (CDCl.sub.3) 7.56 (d, J=2.4 Hz, 1H), 7.13-7.09 (m, 4H), 6.80-6.76 (m, 5H), 4.32 (s, 4H), 3.99 (t, J=7.8 Hz, 2H), 3.79 (s, 6H), 3.23 (t, J=7.7 Hz, 2H), 2.08-2.01 (m, 2H), 1.78 (s, 6H).

[0863] LCMS; m/z 513.1 (M+H).sup.+ (ES.sup.+).

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

[0864] ##STR00233##

[0865] BH.sub.3.THF (1 M in THF) (21.53 ml, 21.53 mmol) was added to a solution of 1-(1-(azetidin-1-yl)-2-methyl-1-oxopropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (3.1537 g, 6.15 mmol) in THF (26.3 mL). The mixture was stirred for 3 minutes, and then heated to reflux over the weekend. The reaction was allowed to cool to room temperature, before being placed in an ice-bath. MeOH (50 mL) was added dropwise and the mixture was heated at 60 C. for 3 hours, and then allowed to cool to room temperature overnight. The mixture was concentrated under reduced pressure and loaded onto a column of SCX (30 g) in MeOH (50 mL). The column was washed with MeOH (100 mL), 0.7 M ammonia in MeOH (100 mL), and then the product was eluted with 7 M ammonia in MeOH (100 mL). The resultant mixture was concentrated in vacuo to afford the title compound (2.89 g, 85%) as a colourless viscous oil.

[0866] .sup.1H NMR (DMSO-d6) =7.98 (d, J=2.5 Hz, 1H), 7.07-7.02 (m, 4H), 6.84-6.79 (m, 4H), 6.69 (d, J=2.4 Hz, 1H), 4.19 (s, 4H), 3.72 (s, 6H), 2.92 (t, J=7.0 Hz, 4H), 2.68 (s, 2H), 1.84 (p, J=7.0 Hz, 2H), 1.48 (s, 6H).

[0867] LCMS; m/z 499.2 (M+H).sup.+ (ES.sup.+).

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

[0868] ##STR00234##

[0869] 1-(1-(Azetidin-1-yl)-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (2.89 g, 5.80 mmol) was dissolved in TFA (15 mL) and DCM (15 mL) and allowed to stir overnight. Additional TFA (5 ml, 5.80 mmol) was added and the reaction stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacua, MeOH (50 mL) was added, the precipitate was filtered off and the filtrate loaded onto a column of SCX (30 g). The column was washed with MeOH (100 mL). The product was then eluted with 7N NH.sub.3 in MeOH (100 mL) and concentrated in vacua. The product was purified by chromatography on silica gel (40 g column, 0-10% MeOH/DCM) to afford the title compound (1.06 g, 69%) as a white solid.

[0870] .sup.1H NMR (DMSO-d6) 7.89 (d, J=2.5 Hz, 1H), 7.34 (s, 2H), 6.54 (d, J=2.4 Hz, 1H), 2.94 (t, J=7.0 Hz, 4H), 2.68 (s, 2H), 1.84 (p, J=7.0 Hz, 2H), 1.47 (s, 6H).

[0871] LCMS; m/z 259.1 (M+H).sup.+ (ES.sup.+).

Intermediate A1: 4-Fluoro-2-isopropyl-6-(pyridin-3-yl)aniline

Step A: 2-Bromo-4-fluoro-6-iso-propylaniline

[0872] ##STR00235##

[0873] N-Bromosuccinimide (5.64 g, 31.7 mmol) was added portionwise to 4-fluoro-2-isopropylaniline (4.62 g, 30.2 mmol) in dichloromethane (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, 250 mL), dried (magnesium sulfate), filtered and concentrated in vacua to give a brown residue. The crude product was then filtered through a plug of silica (50 g) and washed through with 50% dichloromethane 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, 0-10% dichloromethane/iso-hexane) to afford the title compound (4.99 g, 70%) as a red oil.

[0874] .sup.1H NMR (CDCl.sub.3) 7.07 (dd, 1H), 6.86 (dd, 1H), 4.14 (s, 2H), 2.93 (sep, 1H) and 1.25 (d, 6H).

[0875] LCMS m/z 232.2/234.3 (M+H).sup.+ (ES.sup.+).

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

[0876] ##STR00236##

[0877] To a stirred, nitrogen-degassed mixture of 2-bromo-4-fluoro-6-iso-propylaniline (1.00 g, 4.27 mmol) was added pyridin-3-ylboronic acid (0.577 g, 4.69 mmol), [1,1bis(diphenylphosphino)ferrocene] dichloropalladium(II) (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 ethyl acetate (230 mL). The filtrate was poured onto water (50 mL) and the organic layer collected. The aqueous layer was extracted with ethyl acetate (220 mL) and 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% ethyl acetate/iso-hexane) to afford the title compound (273 mg, 27%) as a brown gum.

[0878] .sup.1H NMR (CDCl.sub.3) 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).

[0879] LCMS m/z 231.1 (M+H).sup.+ (ES.sup.+).

[0880] The following intermediates were synthesised following the general procedure for Intermediate A1:

TABLE-US-00001 Intermediate Structure Analytical data A2 [00237] .sup.1H NMR (CDCl.sub.3) 7.68 (d, 1 H), 7.58 (d, 1 H), 6.86 (dd, 1 H), 6.78 (dd, 1 H), 3.99 (s, 3 H), 3.74 (br s, 2 H), 2.94 (sept, 1 H) and 1.29 (d, 6 H). (85 mg, 22%) 4-Fluoro-2-isopropyl-6-(1- methyl-1H-pyrazol-4- yl)aniline A3 [00238] .sup.1H NMR (CDCl.sub.3) 7.68 (s, 1 H), 7.20 (s, 1 H), 6.94 (dd, 1 H), 6.67 (dd, 1 H), 3.53 (s, 3 H), 2.94-2.82 (m, 1 H), 2.47 (s, 2 H) and 1.27 (d, 6H). LCMS m/z 234.1 (M + H).sup.+ (ES.sup.+). (56 mg, 13%) 4-Fluoro-2-isopropyl-6-(1- methyl-1H-imidazol-5- yl)aniline A4 [00239] .sup.1H NMR (CDCl.sub.3) 7.50-7.32 (m, 5 H), 6.90 (dd, 1 H), 6.74 (dd, 1 H), 4.11 (br s, 2 H), 3.15- 2.80 (m, 1 H) and 1.29 (d, 6 H). LCMS m/z 230.1 (M + H).sup.+ (ES.sup.+). (161 mg, 82%) 5-Fluoro-3-isopropyl-[1,1- biphenyl]-2-amine A5 [00240] .sup.1H NMR (CDCl.sub.3) 7.69 (d, 1 H), 7.01 (dd, 1 H), 6.71 (dd, 1 H), 6.42 (d, 1 H), 3.85 (s, 3 H), 2.94 (sept, 1 H) and 1.29 (d, 6 H). LCMS m/z 234.1 (M + H).sup.+ (ES.sup.+). (125 mg, 57%) 4-Fluoro-2-isopropyl-6-(1- methyl-1H-pyrazol-5- yl)aniline A6 [00241] .sup.1H NMR (CDCl.sub.3) 8.87 (s, 1 H), 7.97 (s, 1 H), 6.93 (dd, 1 H), 6.83 (dd, 1 H), 3.80 (s, 2 H), 2.92 (sept, 1 H) and 1.28 (d, 6 H). LCMS m/z 237.1 (M + H).sup.+ (ES.sup.+). (23 mg, 7%) 4-Fluoro-2-isopropyl-6- (thiazol-5-yl)aniline A7 [00242] .sup.1H NMR (CDCl.sub.3) 8.69 (s, 1 H), 8.52 (s, 1 H), 6.95 (dd, 1 H), 6.78 (dd, 1 H), 3.09-2.90 (m, 1 H), 1.48 (s, 2 H) and 1.29 (d, 6 H). LCMS m/z 221.1 (M + H).sup.+ (ES.sup.+). (40 mg, 20%) 4-Fluoro-2-isopropyl-6- (isoxazol-4-yl)aniline A8 [00243] .sup.1H NMR (CDCl.sub.3) 7.82-7.74 (m, 1 H), 7.73- 7.66 (m, 1 H), 7.66-7.60 (m, 1 H), 7.59-7.49 (m, 1 H), 6.96 (dd 1 H), 6.69 (dd, 1 H), 3.10- 2.84 (m, 1 H) and 1.29 (d, 6 H). LCMS m/z 255.1 (M + H).sup.+ (ES.sup.+). (182 mg, 81%) 2-Amino-5-fluoro-3- isopropyl-[1,1-biphenyl]-3- carbonitrile A9 [00244] .sup.1H NMR (CDCl.sub.3) 7.97-7.86 (m, 2 H), 7.74- 7.52 (m, 2 H), 6.94 (dd, 1 H), 6.73 (dd, 1 H), 4.46 (s, 2 H), 3.19-2.97 (m, 1 H) and 1.19 (d, 6H). LCMS m/z 255.1 (M + H).sup.+ (ES.sup.+). (189 mg, 83%) 2-Amino-5-fluoro-3- isopropyl-[1,1-biphenyl]-4- carbonitrile A10 [00245] .sup.1H NMR (CDCl.sub.3) 8.72-8.65 (m, 2 H), 7.50- 7.42 (m, 2 H), 6.95 (dd, 1 H), 6.72 (dd, 1 H), 3.39 (br s, 2 H), 3.00-2.85 (m, 1 H) and 1.29 (d, 6 H). LCMS m/z 231.1 (M + H).sup.+ (ES.sup.+). (148 mg, 75%) 4-Fluoro-2-isopropyl-6- (pyridin-4-yl)aniline A11 [00246] .sup.1H NMR (CDCl.sub.3) 6.95 (dd, 1 H), 6.68 (dd, 1 H), 6.09 (s, 1 H), 3.69 (s, 3 H), 2.98-2.81 (m, 1 H), 2.33 (s, 3 H) and 1.28 (d, 6 H). LCMS m/z 248.1 (M + H).sup.+ (ES.sup.+). (72 mg, 34%) 2-(1,3-Dimethyl-1H- pyrazol-5-yl)-4-fluoro-6- isopropylaniline A12 [00247] .sup.1H NMR (CDCl.sub.3) 8.25 (d, 1 H), 7.00 (dd, 1 H), 6.93 (dd, 1 H), 6.85 (s, 1 H), 6.71 (dd, 1 H), 4.01 (s, 3 H), 2.92 (sept, 1 H) and 1.28 (d, 6 H). Exchangeable NH.sub.2 observed as broad signal from 4.5-0.5 ppm. LCMS m/z 261.1 (M + H).sup.+ (ES.sup.+). (174 mg, 78%) 4-Fluoro-2-isopropyl-6-(2- methoxypyridin-4- yl)aniline A13 [00248] .sup.1H NMR (CDCl.sub.3) 8.57 (dd, 1 H), 7.29 (d, 1 H), 7.25-7.22 (m, 1H), 6.93 (dd, 1 H), 6.70 (dd, 1 H), 3.62 (br s, 2 H), 2.92 (sept, 1 H), 2.64 (s, 3 H) and 1.29 (d, 6 H). LCMS m/z 245.1 (M + H).sup.+ (ES.sup.+). (130 mg, 62%) 4-Fluoro-2-isopropyl-6-(2- methylpyridin-4-yl)aniline A14 [00249] .sup.1H NMR (CDCl.sub.3) 8.57 (s, 1 H), 7.64 (d, 1 H), 7.31 (s, 1 H), 6.94 (dd, 1 H), 6.60 (dd, 1 H), 3.33 (s, 2 H), 2.92 (sept, 1 H), 2.48 (s, 3 H) and 1.29 (dd, 6 H). LCMS m/z 245.1 (M + H).sup.+ (ES.sup.+). (104 mg, 44%) 4-Fluoro-2-isopropyl-6-(2- methylpyridin-3-yl)aniline A15 [00250] .sup.1H NMR (CDCl.sub.3) 8.58 (d, 1 H), 7.73 (dd, 1 H), 7.29 (d, 1 H), 6.92 (dd, 1 H), 6.69 (dd, 1 H), 3.54 (br s, 2 H), 3.00-2.85 (m, 1 H), 2.65 (s, 3 H) and 1.29 (d, 6 H). LCMS m/z 245.1 (M + H).sup.+ (ES.sup.+). (211 mg, 95%) 4-Fluoro-2-isopropyl-6-(6- methylpyridin-3-yl)aniline A16 [00251] .sup.1H NMR (CDCl.sub.3) 8.62-8.56 (m, 2 H), 7.83 (t, 1 H), 6.96 (dd, 1 H), 6.69 (dd, 1 H), 3.46- 3.02 (br s, 2 H), 2.93 (sept, 1 H) and 1.29 (d, 6 H). LCMS m/z 265.1/267.1 (M + H).sup.+ (ES.sup.+). (150 mg, 53%) 2-(5-Chloropyridin-3-yl)-4- fluoro-6-isopropylaniline A17 [00252] .sup.1H NMR (CDCl.sub.3) 8.34 (d, 1 H), 8.33 (d, 1 H), 7.45 (dd, 1 H), 6.96 (dd, 1 H), 6.71 (dd, 1 H), 3.93 (s, 3 H), 2.92 (sept, 1 H), 1.29 (d, 6 H). Exchangeable NH.sub.2 signal not observed LCMS m/z 261.2 (M + H).sup.+ (ES.sup.+). (146 mg, 61%) 4-Fluoro-2-isopropyl-6-(5- methoxypyridin-3-yl)aniline A18 [00253] .sup.1H NMR (CDCl.sub.3) 9.23 (s, 1 H), 8.86 (s, 2 H), 6.98 (dd, 1 H), 6.69 (dd, 1 H), 3.55 (br s, 2 H), 2.92 (sept, 1 H) and 1.29 (d, 6 H). (126 mg, 60%) 4-Fluoro-2-isopropyl-6- (pyrimidin-5-yl)aniline A19 [00254] .sup.1H NMR (CDCl.sub.3) 8.25 (d, 1 H), 7.71 (dd, 1 H), 6.93 (dd, 1 H), 6.87 (d, 1 H), 6.69 (dd, 1 H), 4.01 (s, 3 H), 3.08-2.90 (m, 1 H) and 1.29 (d, 6 H). Exchangeable NH.sub.2 signal not observed LCMS m/z 261.4 (M + H).sup.+ (ES.sup.+). (62 mg, 26%) 4-Fluoro-2-isopropyl-6-(6- methoxypyridin-3-yl)aniline A20 [00255] .sup.1H NMR (CDCl.sub.3) 8.54 (s, 1 H), 8.48 (s, 1 H), 7.75 (s, 1 H), 6.95 (dd, 1 H), 6.69 (dd, 1 H), 2.92 (sept, 1 H), 2.45 (s, 3 H) and 1.29 (d, 6 H). Exchangeable NH.sub.2 signal not observed. LCMS m/z 245.4 (M + H).sup.+ (ES.sup.+). (70 mg, 29%) 4-Fluoro-2-isopropyl-6-(4- methylpyridin-3-yl)aniline A21 [00256] .sup.1H NMR (CDCl.sub.3) 8.56 (t, 1 H), 8.50 (d, 1 H), 7.60 (ddd, 1 H), 6.97 (dd, 1 H), 6.71 (dd, 1 H), 2.95 (sept, 1 H), 3.26-2.49 (br s, 2 H) and 1.29 (d, 6 H). LCMS m/z 249.2 (M + H).sup.+ (ES.sup.+). (58 mg, 26%) 4-Fluoro-2-(5- fluoropyridin-3-yl)-6- isopropylaniline A22 [00257] .sup.1H NMR (CDCl.sub.3) 8.56 (s, 1 H), 8.51 (d, 1 H), 7.33 (d, 1 H), 6.94 (dd, 1 H), 6.55 (dd, 1 H), 2.88 (sept, 1 H), 2.22 (s, 3 H) and 1.26 (d, 6 H). Exchangeable NH.sub.2 signal not observed. LCMS m/z 245 (M + H).sup.+ (ES.sup.+). (225 mg, 54%) 4-Fluoro-2-isopropyl-6-(3- methylpyridin-4-yl)aniline A23 [00258] .sup.1H NMR (CDCl.sub.3) 8.10-7.90 (m, 1 H), 6.94 (dd, 1 H), 6.85-6.78 (m, 1 H), 6.76-6.66 (m, 2 H), 5.55 (br s, 2 H), 3.68 (br s, 2 H), 2.91 (sept, 1 H) and 1.28 (d, 6 H). LCMS m/z 246.4 (M + H).sup.+ (ES.sup.+). (70 mg, 26%) 4-(2-Amino-5-fluoro-3- isopropylphenyl)pyridin-2- amine A24 [00259] .sup.1H NMR (CDCl.sub.3) 8.22 (d, 1 H), 6.97 (dd, 1 H), 6.92 (dd, 1 H), 6.83 (s, 1 H), 6.71 (dd, 1 H), 4.42 (q, 2 H), 2.92 (sept, 1 H), 1.43 (t, 3 H) and 1.28 (d, 6 H). LCMS m/z 275.4 (M + H).sup.+ (ES.sup.+). (203 mg, 80%) 2-(2-Ethoxypyridin-4-yl)-4- fluoro-6-isopropylaniline A25 [00260] .sup.1H NMR (DMSO-d.sub.6) 11.55 (s, 1 H), 7.45- 7.38 (m, 1 H), 6.92 (dd, 1 H), 6.71 (dd, 1 H), 6.30-6.27 (m, 1 H), 6.20 (dd, 1 H), 4.50 (s, 2 H), 3.06 (sept, 1 H) and 1.17 (d, 6 H). LCMS m/z 247 (M + H).sup.+ (ES.sup.+); 245 (M H).sup. (ES.sup.). (40 mg, 11%) 4-(2-Amino-5-fluoro-3- isopropylphenyl)pyridin-2- ol A26 [00261] .sup.1H NMR (CDCl.sub.3) 6.91 (dd, 1 H), 6.81 (dd, 1 H), 6.69 (dd, 1 H), 6.62 (dd, 1 H), 4.08-3.39 (br s, 2 H), 3.96 (s, 3 H), 2.91 (sept, 1 H), 2.50 (d, 3 H) and 1.28 (d, 6 H). LCMS m/z 275.4 (M + H).sup.+ (ES.sup.+). (228 mg, 85%) 4-Fluoro-2-isopropyl-6-(2- methoxy-6-methylpyridin- 4-yl)aniline A27 [00262] .sup.1H NMR (CDCl.sub.3) 8.21 (dd, 1 H), 6.99-6.83 (m, 2 H), 6.76 (dd, 1 H), 6.71 (dd, 1 H), 5.34 (sept, 1 H), 3.75 (s, 2 H), 2.92 (sept, 1 H), 1.38 (d, 6 H) and 1.28 (d, 6 H). LCMS m/z 289.4 (M + H).sup.+ (ES.sup.+). (214 mg, 85%) 4-Fluoro-2-(2-isopropoxy- pyridin-4-yl)-6-isopropyl- aniline A28 [00263] .sup.1H NMR (CDCl.sub.3) 8.78 (dd, 1 H), 7.86 (dd, 1 H), 7.65 (dd, 1 H), 6.99 (dd, 1 H), 6.69 (dd, 1 H), 3.49 (br s, 2 H), 2.93 (sept, 1 H) and 1.29 (d, 6 H). LCMS m/z 256.5 (M + H).sup.+ (ES.sup.+). (89 mg, 29%) 4-(2-Amino-5-fluoro-3- isopropylphenyl)picolino- nitrile A29 [00264] .sup.1H NMR (CDCl.sub.3) 8.64 (dd, 1 H), 7.46-7.41 (m, 2 H), 6.99 (dd, 1 H), 6.75 (dd, 1 H), 3.68 (br s, 2 H), 3.04 (q, 2 H), 2.95 (sept, 1 H), 1.42 (t, 3 H) and 1.32 (d, 6 H). LCMS m/z 259 (M + H).sup.+ (ES.sup.+); 257 (M H).sup. (ES.sup.). (234 mg, 70%) 2-(2-Ethylpyridin-4-yl)-4- fluoro-6-isopropylaniline A31 [00265] .sup.1H NMR (CDCl.sub.3) 8.75 (s, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.64 (dd, J = 5.0, 1.5 Hz, 1H), 7.06 (dd, J = 9.9, 2.9 Hz, 1H), 6.77 (dd, J = 8.2, 2.9 Hz, 1H), 3.20-1.20 (br s, 2H), 3.05 (s, 1H), 1.32 (d, J = 6.7 Hz, 6H). LCMS m/z 299 (M + H).sup.+ (ES.sup.+). (308 mg, 75%) 4-Fluoro-2-isopropyl-6-(2- (trifluoromethyl)pyridin-4- yl)aniline

Intermediate A30: 4-Fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)aniline

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

[0881] ##STR00266##

[0882] 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 vacua and the residue purified by chromatography on silica gel (120 g column, 0-2% ethyl acetate/iso-hexane) to afford the title compound (1.95 g, 43%) as an oil.

[0883] .sup.1H NMR (CDCl.sub.3) 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).

[0884] 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

[0885] ##STR00267##

[0886] 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(0) (251 mg, 0.218 mmol), sodium carbonate (923 mg, 8.70 mmol) and water (4 mL) were added to a sealed vialed containing a solution of 2-bromo-4-fluoro-6-(prop-1-en-2-yl)aniline (500 mg, 2.173 mmol) in N,N-dimethylformamide (22 mL). The reaction mixture was heated under nitrogen at 100 C. overnight and allowed to cool before the residue was diluted with ethyl acetate (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% ethyl acetate/iso-hexanes) to afford the title compound (355 mg, 65%) as a brownish oil.

[0887] .sup.1H NMR (CDCl.sub.3) 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, 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

[0888] ##STR00268##

[0889] 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 ethyl acetate (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%).

[0890] .sup.1H NMR (CDCl.sub.3) 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, 4l H), 3.01-2.89 (m, 1H), 2.85-2.74 (m, 1H), 1.86-1.78 (m, 4H) and 1.28 (d, 6H).

[0891] LCMS m/z 238.1 (M+H).sup.+ (ES.sup.+).

Intermediate A32: 4-(2-Amino-5-fluoro-3-isopropylphenyl)-N,N-dimethylpyridin-2-amine

Step A: 4-Fluoro-2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0892] ##STR00269##

[0893] In an oven dried round bottom flask, 2-bromo-4-fluoro-6-isopropylaniline (3.0 g, 12.93 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (8.21 g, 32.3 mmol), KOAc (4.44 g, 45.2 mmol) and Pd(dppf)Cl.sub.2. CH.sub.2Cl.sub.2 (2.11 g, 2.59 mmol) were added and the vessel was purged with nitrogen. Anhydrous 1,4-dioxane (86 mL) was added and the reaction was stirred at 110 C. for 2 hours. Upon completion, the reaction mixture was diluted with water, extracted with EtOAc (250 mL) and the combined organic extracts washed with brine (50 mL), dried and concentrated in vacuo. The crude product was purified by chromatography on silica (80 g column, 0-10% EtOAc/isohexane) then loaded onto a column of SCX (10 g) in acetonitrile. The column was washed with acetonitrile and then the product was eluted with 0.7 M ammonia in methanol. The resultant mixture was concentrated in vacua to afford the title compound (1.18 g, 32%) as a light yellow oil.

[0894] .sup.1H NMR (CDCl.sub.3) 7.21 (dd, J=8.7, 3.1 Hz, 1H), 6.96 (dd, J=10.0, 3.1 Hz, 1H), 4.72 (bs, 2H), 2.93-2.82 (m, 1H), 1.37 (s, 12H), 1.26 (d, J=6.8 Hz, 6H).

Step B: 4-(2-Amino-5-fluoro-3-isopropylphenyl)-N,N-dimethylpyridin-2-amine

[0895] ##STR00270##

[0896] 4-Fluoro-2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.379 g, 1.356 mmol), 4-bromo-N,N-dimethylpyridin-2-amine (0.3 g, 1.49 mmol) and potassium carbonate (0.6 g, 4.34 mmol) were suspended in a mixture of dioxane (10 mL) and water (1 mL). After degassing with nitrogen for 15 minutes, Pd(dppf)Cl.sub.2. CH.sub.2Cl.sub.2 (0.055 g, 0.068 mmol) was added and the mixture was heated to 75 C. for 1 hour. The mixture was cooled to room temperature, and diluted with EtOAc (10 mL) and water (5 mL). The organic phase was separated, dried (MgSO.sub.4), filtered and concentrated in vacuo to give a brown oil. The crude product was purified by chromatography on silica (24 g column, 0-60% EtOAc/isohexane) to afford the title compound (201 mg, 49%) as an orange oil.

[0897] .sup.1H NMR (CDCl.sub.3) 8.27 (d, J=5.6 Hz, 1H), 6.96 (dd, J=9.9, 3.0 Hz, 1H), 6.79-6.72 (m, 2H), 6.69 (s, 1H), 3.70 (s, 2H), 3.26 (s, 6H), 2.94 (sept, J=7.0 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H).

[0898] LCMS m/z 274.4 (M+H).sup.+ (ES.sup.+); 272.8 (MH).sup. (ES.sup.).

Intermediate A33: 4-Fluoro-2-isopropyl-6-(2-(prop-1-yn-1-yl)pyridin-4-yl)aniline

[0899] ##STR00271##

[0900] The title compound was prepared according to the procedure for 4-(2-amino-5-fluoro-3-isopropylphenyl)-N,N-dimethylpyridin-2-amine (Intermediate A32) (218 mg, 57%).

[0901] .sup.1H NMR (CDCl.sub.3) 8.63 (d, J=5.3 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J=5.3 Hz, 1H), 6.97 (dd, J=9.9, 2.9 Hz, 1H), 6.72 (dd, J=8.5, 3.0 Hz, 1H), 4.30-2.50 (br s, 2H), 2.93 (sept, J=6.6 Hz, 1H), 2.14 (s, 3H), 1.31 (d, J=6.8 Hz, 6H).

[0902] LCMS m/z 269.3 (M+H).sup.+ (ES.sup.+); 267.2 (MH).sup. (ES.sup.).

Intermediate A34: 7-Fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

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

[0903] ##STR00272##

[0904] To an ice-cooled solution of N-(2,3-dihydro-1H-inden-4-yl)pivalamide (2.5 g, 11.50 mmol) in dry dichloromethane (50 mL) was added pyridine hydrofluoride (9 ml, 69.9 mmol). The pale yellow mixture was stirred for 30 minutes at 0 C. A solution of bis(tert-butylcarbonyloxy)iodobenzene (7.5 g, 17.91 mmol) in dichloromethane (10 mL) was then slowly added over 10 minutes to the mixture. The reaction was slowly allowed to reach room temperature and stirred overnight. It was then quenched with triethylamine (0.5 ml, 3.58 mmol) and the whole mixture was absorbed onto silica gel and purified by chromatography on silica gel (120 g column, 0-30% EtOAc/isohexane) to afford the title compound (0.635 g, 22%) as a yellow crystalline solid.

[0905] .sup.1H NMR (CDCl.sub.3) 7.68 (dd, J=8.8, 4.5 Hz, 1H), 7.14 (s, 1H), 6.87 (t, J=8.6 Hz, 1H), 3.01 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.18 (p, J=7.5 Hz, 2H), 1.34 (s, 9H).

[0906] LCMS m/z 236.3 (M+H).sup.+ (ES.sup.+); 234.2 (MH).sup. (ES.sup.).

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

[0907] ##STR00273##

[0908] N-(7-Fluoro-2,3-dihydro-1H-inden-4-yl)pivalamide (0.632 g, 2.69 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature. H.sub.2SO.sub.4 (95% aq.) (5 ml, 89 mmol) was slowly added to water (5 mL) and this mixture was then added to the reaction mixture. The slurry was heated to 100 C. (bath temperature) over the weekend. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and then basified with 2M aq. NaOH. The mixture was extracted with dichloromethane (3100 mL). The combined organics were washed, dried by passing through a hydrophobic frit and concentrated in vacua. The crude product was purified by chromatography on silica gel (24 g column, 0-30% EtOAc/isohexane) to afford the title compound (350 mg, 82%) as a pale pink oil that solidified on standing. .sup.1H NMR (CDCl.sub.3) 6.71 (dd, J=9.0, 8.2 Hz, 1H), 6.46 (dd, J=8.5, 3.9 Hz, 1H), 3.45 (s, 2H), 2.96 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.16 (p, J=7.6 Hz, 2H).

[0909] LCMS m/z 152.3 (M+H).sup.+ (ES.sup.+).

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

[0910] ##STR00274##

[0911] 7-Fluoro-2,3-dihydro-1H-inden-4-amine (345 mg, 2.282 mmol) was dissolved in dichloromethane (10 mL). NBS (450 mg, 2.53 mmol) was added at room temperature in a single portion. The mixture turned dark brown immediately and was stirred for 15 minutes at room temperature. The reaction mixture was partitioned between dichloromethane and 1M aq. NaOH (20 mL) and stirred for 15 minutes. The organic phase was separated and washed with brine (10 mL), and then dried by passing through a hydrophobic frit. The solvent was removed in vacua to give a dark brown oil. The crude product was purified by chromatography on silica gel (24 g column, 0-20% EtOAc/isohexane) to afford the title compound (323 mg, 55%) as a dark purple oil.

[0912] .sup.1H NMR (CDCl.sub.3) 7.08 (d, J=7.8 Hz, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.95 (t, J=7.5 Hz, 2H), 2.20 (p, J=7.6 Hz, 2H), NH.sub.2 not observed.

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

[0913] ##STR00275##

[0914] 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (320 mg, 1.391 mmol) was dissolved in dioxane (5 mL). A solution of potassium carbonate (600 mg, 4.34 mmol) in water (1 mL) and solid (2-methoxypyridin-4-yl)boronic acid (250 mg, 1.635 mmol) were added. The mixture was degassed with nitrogen for 15 minutes before Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80 C. (bath temperature) for 24 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (30 mL) and water (20 mL). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacua to give a brown oil. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc/isohexane) to afford the title compound (0.185 g, 49%) as a pale brown oil that crystallized on standing.

[0915] .sup.1H NMR (CDCl.sub.3) 8.27 (d, J=5.4 Hz, 1H), 7.06 (d, J=5.3 Hz, 1H), 6.95 (s, 1H), 6.73 (d, J=9.0 Hz, 1H), 4.03 (s, 3H), 3.00 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.23 (p, J=7.5 Hz, 2H), NH.sub.2 not observed.

[0916] LCMS m/z 259.3 (M+H).sup.+ (ES.sup.+).

Intermediate A35: 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

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

[0917] ##STR00276##

[0918] N-(2,3-Dihydro-1H-inden-4-yl)pivalamide (1 g, 4.60 mmol), p-toluenesulfonic acid monohydrate (0.45 g, 2.366 mmol), Pd(OAc).sub.2 (0.05 g, 0.223 mmol), and NBS (0.9 g, 5.06 mmol) were suspended in toluene (20 mL) and stirred under air for 16 hours. The dark green mixture was diluted with EtOAc (20 mL), and then washed with saturated aq. NaHCO.sub.3 (210 mL), water (210 mL) and brine (10 mL). The organic phase was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacua to give a dark green amorphous solid. The crude product was purified by chromatography on silica gel (40 g column, 0-30% EtOAc/isohexane) to afford the title compound (1.662 g, 100%) as a colourless crystalline solid that was contaminated with a small amount of reaction byproducts.

[0919] LCMS m/z 296.3/298.3 (M+H).sup.+ (ES.sup.+).

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

[0920] ##STR00277##

[0921] N-(5-Bromo-2,3-dihydro-1H-inden-4-yl)pivalamide (0.632 g, 2.134 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature. H.sub.2SO.sub.4 (95% aq.) (5 ml, 89 mmol) was slowly added to water (5 mL) and this mixture was then added to the reaction mixture. The slurry was heated to 100 C. (bath temperature) at which point the mixture became homogeneous and it was stirred at this temperature over the weekend. The mixture was cooled to room temperature and then basified with 2M aq. NaOH. The mixture was extracted with dichloromethane (320 mL). The organic phase was dried by passing through a hydrophobic frit, and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-50% EtOAc/isohexane) to afford the title compound (0.138 g, 29%).

[0922] .sup.1H NMR (CDCl.sub.3) 7.23 (d, J=7.9 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.92 (s, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), 2.15 (p, J=7.5 Hz, 2H).

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

[0923] ##STR00278##

[0924] 5-Bromo-2,3-dihydro-1H-inden-4-amine (280 mg, 1.320 mmol) was dissolved in dioxane (5 mL). A solution of potassium carbonate (boo mg, 4.34 mmol) in water (1 mL) and (2-methoxypyridin-4-yl)boronic acid (250 mg, 1.635 mmol) were added. The mixture was degassed with nitrogen for 15 minutes before Pd(dppf)Cl.sub.2. CH.sub.2Cl.sub.2 (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80 C. (bath temperature) for 2 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (30 mL) and water (20 mL). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacua to give a brown oil. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc/isohexane) to afford the title compound (0.289 g, 87%) as a pale yellow crystalline solid.

[0925] .sup.1H NMR (CDCl.sub.3) 8.26 (d, J=5.4 Hz, 1H), 7.11 (d, J=5.0 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.97 (s, 1H), 6.80 (d, J=7.6 Hz, 1H), 4.06 (s, 3H), 2.98 (t, J=7.6 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.19 (p, J=7.5 Hz, 2H), NH.sub.2 not observed.

[0926] LCMS m/z 241.3 (M+H).sup.+ (ES.sup.+).

Intermediate A36: 4-(4-Amino-2,3-dihydro-1H-inden-5-yl)picolinonitrile

[0927] ##STR00279##

[0928] Prepared according to the general procedure of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35, Step C) from 5-bromo-2,3-dihydro-1H-inden-4-amine (Intermediate A35, Step B) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile to afford the title compound (215 mg, 61%) as a pale yellow solid.

[0929] 1H (DMSO-d6) 8.72 (dd, J=5.1, 0.8 Hz, 1H), 8.03 (dd, J=1.8, 0.8 Hz, 1H), 7.74 (dd, J=5.1, 1.8 Hz, 1H), 6.91 (d, J=7.7 Hz, 1H), 6.61 (d, J=7.7 Hz, 1H), 4.94 (s, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.03 (p, J=7.4 Hz, 2H).

[0930] LCMS: m/z 236.3 (M+H).sup.+ (ES.sup.+).

Intermediate A37: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile

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

[0931] ##STR00280##

[0932] To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (36.21 g, 215.51 mmol, 1.05 eq) and K.sub.2CO.sub.3 (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H.sub.2O (40 mL) was added Pd(dppf)Cl.sub.2 (7.51 g, 10.26 mmol, 0.05 eq) under a nitrogen atmosphere. Then the reaction mixture was stirred at 80 C. for 5 hours. The reaction mixture was quenched by addition of H.sub.2O (600 mL) and extracted with EtOAc (2500 mL). The combined organic layers were washed with brine (2600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate 1:0 to 100:1) to give the title compound (27 g, 77% yield, 89% purity on LCMS) as a yellow oil.

[0933] .sup.1H NMR (CDCl.sub.3) 6.81-6.76 (m, 2H), 6.66-6.62 (m, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 3.69 (br s, 2H) and 1.25 (s, 3H).

[0934] LCMS: m/z 152.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Fluoro-2-isopropylaniline

[0935] ##STR00281##

[0936] To a solution of 4-fluoro-2-(prop-1-en-2-yl)aniline (21 g, 138.91 mmol, 1 eq) in MeOH (300 mL) was added Pd/C (2.1 g, 178.59 mmol, 10 wt % loading on activated carbon) under a nitrogen atmosphere. The reaction mixture was degassed in vacua and purged with hydrogen several times. The reaction mixture was stirred at 25 C. for 12 hours under hydrogen (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (20 g, crude) as a yellow oil.

[0937] .sup.1H NMR (CDCl.sub.3) 6.86 (dd, 1H), 6.75-6.72 (m, 1H), 6.63-6.61 (m, 1H), 3.50 (br s, 2H), 2.95-2.84 (m, 1H) and 1.25 (d, 6H).

[0938] LCMS: m/z 154.2 (M+H).sup.+ (ES.sup.+).

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

[0939] ##STR00282##

[0940] To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 mL) was added NBS (23.24 g, 130.55 mmol, 1 eq) at 25 C. The reaction mixture was stirred at 25 C. for 10 minutes. The reaction mixture was poured into H.sub.2O (300 mL) and extracted with EtOAc (2250 mL). The combined organic phases were washed with brine (2400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, eluting only by using petroleum ether) to give the title compound (30 g, 99%) as a black brown oil.

[0941] .sup.1H NMR (CDCl.sub.3) 6.99 (dd, 1H), 6.78 (dd, 1H), 3.91 (br s, 2H), 2.88-2.71 (m, 1H) and 1.17 (d, 6H).

[0942] LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

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

[0943] ##STR00283##

[0944] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (3.6 g, 15.51 mmol, 1 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (3.60 g, 15.67 mmol, 1.01 eq) in dioxane (90 mL) and H.sub.2O (9 mL) was added Na.sub.2CO.sub.3 (4.11 g, 38.78 mmol, 2.5 eq). Then Pd(dppf)Cl.sub.2 (1.13 g, 1.55 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere. The resulting mixture was stirred at 80 C. for 2 hours under nitrogen. Then the mixture was concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 20:1 to 5:1) and then triturated with petroleum ether (10 mL) to give the title compound (2.65 g, 65% yield, 97% purity on LCMS) as a yellow solid.

[0945] 1HNMR (CDCl.sub.3) 8.79 (d, 1H), 7.86 (d, 1H), 7.65 (dd, 1H), 6.99 (dd, 1H), 6.70 (dd, 1H), 3.63 (br s, 2H), 2.98-2.87 (m, 1H) and 1.30 (d, 6H).

[0946] LCMS: m/z 256.2 (M+H).sup.+ (ES.sup.+).

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

[0947] ##STR00284##

[0948] To a solution of 4-(2-amino-5-fluoro-3-isopropylphenyl)picolinonitrile (1 g, 3.92 mmol, 1 eq) in THF (40 mL) was added TEA (793 mg, 7.83 mmol, 2 eq). To the above mixture was added triphosgene (465 mg, 1.57 mmol, 0.4 eq) in portions at 5 C. Then the mixture was stirred at 70 C. for 1 hour. The mixture was diluted with EtOAc (200 mL) and then filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.2 g, crude) as a yellow solid, which was used directly in the next step.

Intermediate A38: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine

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

[0949] ##STR00285##

[0950] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (12 g, 51.70 mmol, 1 eq) in dioxane (240 mL) and H.sub.2O (48 mL) was added (2-methoxypyridin-4-yl)boronic acid (9.49 g, 62.04 mmol, 1.2 eq) and Na.sub.2CO.sub.3 (13.70 g, 129.26 mmol, 2.5 eq). The reaction mixture was purged with nitrogen three times. Then Pd(dppf)Cl.sub.2 (3.78 g, 5.17 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere. The resulting mixture was heated at 80 C. for 2 hours. The reaction mixture was quenched with H.sub.2O (800 mL) and extracted with EtOAc (2600 mL). The combined organic layers were washed with brine (2800 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 70:1 to 10:1) and then triturated with hexane (100 mL) to give the title compound (10.05 g, 72% yield, 96% purity on LCMS).

[0951] .sup.1H NMR (CDCl.sub.3) 8.24 (d, 1H), 6.97 (d, 1H), 6.93 (d, 1H), 6.83 (s, 1H), 6.73-6.70 (m, 1H), 3.99 (s, 3H), 3.66 (br s, 2H), 2.97-2.89 (m, 1H) and 1.29 (dd, 6H).

[0952] LCMS: m/z 261.1 (M+H).sup.+ (ES.sup.+).

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

[0953] ##STR00286##

[0954] To a solution of 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (1 g, 3.84 mmol, 1 eq) in THF (40 mL) was added TEA (777 mg, 7.68 mmol, 2 eq). Then triphosgene (456 mg, 1.54 mmol, 0.4 eq) was added in portions at 5 C. The mixture was stirred at 70 C. for 1 hour. The mixture was diluted with EtOAc (200 mL) and filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.1 g, crude) as a yellow oil, which was used directly in the next step.

Intermediate A39: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

[0955] ##STR00287##

[0956] To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35) (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50.35 mmol, 1.1 eq) in THF (275 mL) was added in portions bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) at 0 C. Then the reaction mixture was stirred at 16 C. for 0.5 hour. The reaction mixture was filtered and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacua to give the title compound (9.04 g, 74%) as a light yellow solid.

[0957] .sup.1H NMR (CDCl.sub.3) 8.28 (d, 1H), 7.20-7.16 (m, 3H), 7.02 (s, 1H), 4.16 (s, 3H), 3.04-2.99 (m, 4H) and 2.23-2.15 (m, 2H).

Intermediate A40: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

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

[0958] ##STR00288##

[0959] To a mixture of 7-fluoro-2,3-dihydro-1H-inden-1-one (9.5 g, 63.27 mmol, 1 eq) in concentrated H.sub.2SO.sub.4 (100 mL) was added dropwise a solution of HNO.sub.3 (5.37 mL, 82.25 mmol, 69 wt % in water, 1.3 eq) in concentrated H.sub.2SO.sub.4 (20 mL) at 15 C. Then the reaction mixture was stirred at 0 C. for 0.5 hour. The mixture was quenched with water (500 mL) at 0 C., and then extracted with EtOAc (3300 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 3:1) to give the title compound (11.4 g, 92%) as a yellow solid.

[0960] .sup.1H NMR (CDCl.sub.3) 8.51 (dd, 1H), 7.22 (t, 1H), 3.69-3.65 (m, 2H) and 2.88-2.82 (m, 2H).

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

[0961] ##STR00289##

[0962] To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-one (30 g, 153.73 mmol, 1 eq) in EtOH (450 mL) was added NaBH.sub.4 (11.63 g, 307.46 mmol, 2 eq) in portions. The reaction mixture was stirred at 15 C. for 1 hour. Then the mixture was poured into water (500 mL) and extracted with DCM (2200 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (30 g, crude) as brown oil.

[0963] .sup.1H NMR (CDCl.sub.3) 8.21 (dd, 1H), 7.08 (t, 1H), 5.59-5.56 (m, 1H), 3.66-3.59 (m, 1H), 3.44-3.39 (m, 1H), 2.56-2.51 (m, 1H) and 2.22-2.17 (m, 2H).

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

[0964] ##STR00290##

[0965] To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol (4.5 g, 22.82 mmol, 1 eq) in TFA (20 mL) was added Et.sub.3SiH (7.96 g, 68.47 mmol, 3 eq) in one portion. The reaction mixture was stirred at 25 C. for 12 hours. Then the mixture was quenched with water (100 mL) and extracted with EtOAc (3100 mL). The combined organic layers were washed with saturated aqueous NaHCO.sub.3 solution (2100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua to give the title compound (5 g, crude) as brown oil.

[0966] .sup.1H NMR (CDCl.sub.3) 8.06 (dd, 1H), 7.01 (t, 1H), 3.46 (t, 2H), 3.04 (t, 2H) and 2.25-2.20 (m, 2H).

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

[0967] ##STR00291##

[0968] To a mixture of 4-fluoro-7-nitro-2,3-dihydro-1H-indene (5 g, 27.60 mmol, 1 eq) in MeOH (50 mL) was added Pd/C (0.5 g, 10 wt % loading on activated carbon) at 25 C. under a nitrogen atmosphere. Then the reaction mixture was stirred at 25 C. for 12 hours under hydrogen (15 psi). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 10:1) to give the title compound (1.8 g, 43%) as a brown solid.

[0969] .sup.1H NMR (CDCl.sub.3) 6.69 (t, 1H), 6.44 (dd, 1H), 3.47 (br s, 2H), 2.95 (t, 2H), 2.75 (t, 2H) and 2.19-2.11 (m, 2H).

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

[0970] ##STR00292##

[0971] To a solution of 7-fluoro-2,3-dihydro-1H-inden-4-amine (8.3 g, 54.90 mmol, 1 eq) in toluene (100 mL) was added NBS (10.26 g, 57.65 mmol, 1.05 eq) in one portion at 25 C. The reaction mixture turned dark brown immediately and then the mixture was stirred at 25 C. for 30 minutes. The reaction mixture was quenched with saturated aqueous Na.sub.2SO.sub.3 solution (200 mL) and extracted with EtOAc (2100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 20:1) to give the title compound (8.51 g, 67%) as a brown solid.

[0972] .sup.1H NMR (CDCl.sub.3) 6.99 (d, 1H), 3.81 (br s, 2H), 2.92 (t, 2H), 2.78 (t, 2H) and 2.21-2.13 (m, 2H).

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

[0973] ##STR00293##

[0974] To a mixture of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (3.5 g, 15.21 mmol, 1 eq) and pyridin-4-ylboronic acid (1.96 g, 15.97 mmol, 1.05 eq) in dioxane (50 mL) and H.sub.2O (5 mL) was added K.sub.2CO.sub.3 (6.31 g, 45.64 mmol, 3 eq) and Pd(dppf)Cl.sub.2 (1.11 g, 1.52 mmol, 0.1 eq) in one portion under a nitrogen atmosphere. Then the reaction mixture was heated to 80 C. for 12 hours. The reaction mixture was filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (3100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 2:1) to give the title compound (1.7 g, 45% yield, 90.98% purity on HPLC) as a brown solid.

[0975] .sup.1H NMR (CDCl.sub.3) 8.68 (dd, 2H), 7.40 (dd, 2H), 6.72 (d, 1H), 3.76 (br s, 2H), 3.01 (t, 2H), 2.80 (t, 2H) and 2.26-2.18 (m, 2H).

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

[0976] ##STR00294##

[0977] To a solution of 7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (400 mg, 1.75 mmol, 1 eq) and TEA (355 mg, 3.50 mmol, 2 eq) in THF (30 mL) was added bis(trichloromethyl) carbonate (208 mg, 700.94 mol, 0.4 eq) at 0 C. The reaction mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was filtered through a pad of silica gel and the filter cake was washed with THF (20 mL). The filtrate was concentrated in vacuo to reduce to 10 mL, which was used directly in the next step.

Intermediate A41: 3-(5-Fluoro-2-isocyanato-3-isopropylphenyl)pyridine

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

[0978] ##STR00295##

[0979] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (21 g, 90.48 mmol, 1 eq) in dioxane (450 mL) and H.sub.2O (90 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (22.26 g, 108.58 mmol, 1.2 eq) and Na.sub.2CO.sub.3 (23.98 g, 226.20 mmol, 2.5 eq). The reaction mixture was purged with nitrogen three times. Then Pd(dppf)Cl.sub.2 (5.10 g, 6.97 mmol, 0.077 eq) was added under a nitrogen atmosphere. The resulting mixture was heated to 80 C. and stirred for 2 hours. The reaction mixture was quenched by addition of H.sub.2O (800 mL) and extracted with EtOAc (2600 mL). The combined organic layers were washed with brine (2800 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 1:1) and then triturated with hexane (40 mL) to give the title compound (17 g, 82%) as a grey solid.

[0980] .sup.1H NMR (CDCl.sub.3) 8.70 (d, 1H), 8.63 (dd, 1H), 7.79 (dd, 1H), 7.41-7.38 (m, 1H), 6.94 (dd, 1H), 6.71 (dd, 1H), 3.57 (s, 2H), 2.97-2.88 (m, 1H) and 1.30 (d, 6H).

[0981] LCMS: m/z 231.2 (M+H).sup.+ (ES.sup.+).

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

[0982] ##STR00296##

[0983] To a solution of 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (0.5 g, 2.17 mmol, 1 eq) and TEA (439 mg, 4.34 mmol, 2 eq) in THF (10 mL) was added triphosgene (257 mg, 868.51 mol, 0.4 eq) in portions at 5 C. Then the reaction mixture was heated to 70 C. and stirred for 1 hour. The reaction mixture was concentrated in vacua. The residue was treated with EtOAc (100 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (0.2 g, crude) as a yellow oil, which was used directly in the next step.

Intermediate A42: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

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

[0984] ##STR00297##

[0985] To a mixture of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (Intermediate A4.0, Step E) (8.5 g, 36.94 mmol, 1 eq) and (2-methoxypyridin-4-yl)boronic acid (5.93 g, 38.79 mmol, 1.05 eq) in dioxane (150 mL) and water (15 mL) were added K.sub.2CO.sub.3 (15.32 g, 110.83 mmol, 3 eq) and Pd(dppf)Cl.sub.2 (2.70 g, 3.69 mmol, 0.1 eq) in one portion under nitrogen. Then the reaction mixture was heated to 80 C. and stirred for 12 hours. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (3300 mL). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel chromatography (petroleum ether:EtOAc, 1:0 to 10:1) and then purified by trituration with a mixture of TBME and n-hexane (50 mL, 1:20) to give the title compound (5.06 g, 52% yield, 97.44% purity on LCMS) as an off-white solid.

[0986] .sup.1H NMR (CDCl.sub.3) 8.23 (d, 1H), 6.99 (dd, 1H), 6.86 (s, 1H), 6.71 (d, 1H), 3.99 (s, 3H), 3.67 (br s, 2H), 3.00 (t, 2H), 2.79 (t, 2H) and 2.25-2.17 (m, 2H).

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

[0987] ##STR00298##

[0988] To a solution of phosgene (1.5 mL, 20 wt % in toluene, 2.9 mmol) in toluene (40 mL) was added dropwise a solution of 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (300 mg, 1.16 mmol) in toluene (20 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and upon cooling was concentrated in vacua to afford the title compound as a brown oil (325 mg, 98%). The crude product was used directly in the next step without further purification.

[0989] .sup.1H NMR (CDCl.sub.3) 8.24 (d, 1H), 6.95 (dd, 1H), 6.88 (s, 1H), 6.85-6.75 (m, 1H), 4.00 (s, 3H), 3.15-2.95 (m, 4H), 2.32-2.12 (m, 2H).

Intermediate A43: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)picolinonitrile

[0990] ##STR00299##

[0991] To a solution of phosgene (1.7 mL, 20 wt % in toluene, 3.2 mmol) in toluene (40 mL) was added dropwise a solution of 4-(4-amino-2,3-dihydro-1H-inden-5-yl)picolinonitrile (Intermediate A36) (300 mg, 1.3 mmol) in toluene (20 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and upon cooling was concentrated in vacua to afford the title compound as a brown oil (333 mg, 100%). The crude product was used directly in the next step without further purification.

[0992] .sup.1H NMR (CDCl.sub.3) 8.75 (dd, 1H), 7.81 (dd, 1H), 7.63 (dd, 1H), 7.22-7.08 (m, 2H), 3.04 (m, 4H), 2.23 (m, 2H).

Intermediate A44: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

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

[0993] ##STR00300##

[0994] 5-Bromo-2,3-dihydro-1H-inden-4-amine (1.2 g, 5.7 mmol) was dissolved in dioxane (25 mL). A solution of potassium carbonate (3.1 g, 23 mmol) in water (6 mL) and pyridin-4-ylboronic acid (0.83 g, 6.8 mmol) were added. The mixture was degassed with nitrogen for 20 minutes before Pd(dppf)Cl.sub.2.DCM (0.74 g, 0.91 mmol) was added. The reaction mixture was heated to 77 C. for 2 hours. Then the mixture was cooled to room temperature and filtered over Celite with DCM (100 mL) and water (25 mL). The organic phase was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a brown oil (3.3 g). The crude product was purified by chromatography on silica gel (80 g column, 0-100% EtOAc/heptane) to afford the title compound (0.75 g, 63%) as a pale yellow crystalline solid.

[0995] .sup.1H NMR (CDCl.sub.3) 8.72-8.54 (m, 2H), 7.50-7.37 (m, 2H), 6.97 (d, 1H), 6.78 (d, 1H), 3.72 (s, 2H), 2.96 (t, 2H), 2.77 (t, 2H), 2.18 (m, 2H).

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

[0996] ##STR00301##

[0997] To a solution of phosgene (1.1 mL, 20 wt % in toluene, 2.06 mmol) in toluene (40 mL) was added dropwise a solution of 5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (175 mg, 0.83 mmol) in toluene (20 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 70 minutes and upon cooling to room temperature a yellow precipitate was formed. The solid was filtered and dried in vacua to afford the title compound as a yellow solid (145 mg, 74%). The crude product was used directly in the next step without further purification.

[0998] .sup.1H NMR (CDCl.sub.3) 8.76 (d, 2H), 8.04 (d, 2H), 7.26-7.08 (m, 2H), 3.08 (t, 4H), 2.26 (m, 2H).

Intermediate A45: 4-(6-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

Step A: 6-Bromo-2,3-dihydro-1H-inden-5-amine

[0999] ##STR00302##

[1000] To a solution of 2,3-dihydro-1H-inden-5-amine (10.6 g, 79.59 mmol, 1 eq) in toluene (150 mL) was added NBS (17.00 g, 95.50 mmol, 1.2 eq) in portions, and then the mixture was stirred at 25 C. for 12 hours. The reaction mixture was quenched with saturated aqueous Na.sub.2SO.sub.3 solution (100 mL) and then extracted with EtOAc (3150 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 1:0 to 20:1) to give the title compound (9.5 g, 56%) as a brown solid.

[1001] .sup.1H NMR (CDCl.sub.3): 7.15 (s, 1H), 6.56 (s, 1H), 3.72 (br s, 2H), 2.70-2.61 (m, 4H) and 1.95-1.85 (m, 2H).

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

[1002] ##STR00303##

[1003] To a solution of 6-bromo-2,3-dihydro-1H-inden-5-amine (1 g, 4.72 mmol, 1 eq) and (2-methoxypyridin-4-yl)boronic acid (793 mg, 5.19 mmol, 1.1 eq) in dioxane (15 mL) and H.sub.2O (2 mL) was added K.sub.2CO.sub.3 (1.95 g, 14.15 mmol, 3 eq) and Pd(dppf)Cl.sub.2 (345 mg, 471.51 mol, 0.1 eq) in one portion under N.sub.2. Then the reaction mixture was heated to 80 C. and stirred for 2 hours. The reaction mixture was washed with water (20 mL) and extracted with EtOAc (320 mL). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 15:1 to 10:1) to give the title compound (556.4 mg, 49%) as a yellow solid.

[1004] .sup.1H NMR (CDCl.sub.3): 8.24 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.85 (s, 1H), 6.71 (s, 1H), 3.96 (s, 3H), 2.92-2.76 (m, 4H) and 2.15-2.05 (m, 2H).

Step C: 4-(6-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

[1005] ##STR00304##

[1006] To a solution of 6-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-5-amine (200 mg, 832.29 mol, 1 eq) and TEA (168 mg, 1.66 mmol, 2 eq) in THF (2 mL) was added triphosgene (99 g, 332.92 mol, 0.4 eq) at 0 C. Then the reaction mixture was heated to 70 C. for 1 hour. The reaction mixture was filtered by silica gel and washed with THF (50 mL). Then the filtrate was concentrated in vacua to give the title compound (246 mg, crude) as a light yellow solid, which was used directly in the next step.

Intermediate A46: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine

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

[1007] ##STR00305##

[1008] 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 (2500 mL). The combined organic layers were washed with brine (2600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (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.

[1009] .sup.1H NMR (CDCl.sub.3): 6.81-6.76 (m, 2H), 6.66-6.62 (m, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 3.69 (br s, 2H) and 1.25 (s, 3H).

[1010] LCMS: m/z 152.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Fluoro-2-isopropylaniline

[1011] ##STR00306##

[1012] 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 H2 several times. The reaction mixture was stirred at 25 C. for 12 hours under H2 (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.

[1013] .sup.1H NMR (CDCl.sub.3): 6.86 (dd, 1H), 6.75-6.72 (m, 1H), 6.63-6.61 (m, 1H), 3.50 (br s, 2H), 2.95-2.84 (m, 1H) and 1.25 (d, 6H).

[1014] LCMS: m/z 154.2 (M+H).sup.+ (ES.sup.+).

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

[1015] ##STR00307##

[1016] 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 (2250 mL). The organic phases were washed with brine (2400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. 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.

[1017] .sup.1H NMR (CDCl.sub.3): 6.99 (dd, 1H), 6.78 (dd, 1H), 3.91 (br s, 2H), 2.88-2.71 (m, 1H) and 1.17 (d, 6H).

[1018] LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

Step D: 4-Bromo-2-isopropoxypyridine

[1019] ##STR00308##

[1020] 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 (2200 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.

[1021] .sup.1H NMR (CDCl.sub.3): 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

[1022] ##STR00309##

[1023] 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.

[1024] 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.

[1025] .sup.1H NMR (CDCl.sub.3): 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).

[1026] LCMS: m/z 264.2 (M+H).sup.+ (ES.sup.+).

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

[1027] ##STR00310##

[1028] 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 vacua. 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.

[1029] .sup.1H NMR (CDCl.sub.3): 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).

[1030] LCMS: m/z 289.2 (M+H).sup.+ (ES.sup.+).

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

[1031] ##STR00311##

[1032] 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 A47: 7-Cyclopropyl-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

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

[1033] ##STR00312##

[1034] NBS (389 mg, 2.185 mmol) was added to a mixture of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35) (500 mg, 2.081 mmol) in CHCl.sub.3 (5 ml) with cooling in an ice bath. The resultant solution was stirred at room temperature for 16 hours, washed with 10% sodium thiosulfate solution (20 ml), brine (10 ml), dried over MgSO.sub.4 and concentrated in vacua. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-30% EtOAc/isohexane) to afford the title compound (400 mg, 57%) as a tan solid.

[1035] .sup.1H NMR (DMSO-d6) 8.20 (d, J=5.3 Hz, 1H), 7.04-6.97 (m, 2H), 6.80 (d, J=1.3 Hz, 1H), 4.84 (s, 2H), 3.89 (s, 3H), 2.83 (q, J=7.1 Hz, 4H), 2.06 (p, J=7.6 Hz, 2H).

[1036] LCMS; m/z 318.9/320.9 (M+H)+ (ES+).

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

[1037] ##STR00313##

[1038] A stirred mixture of 7-bromo-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (100 mg, 0.313 mmol), K.sub.2CO.sub.3 (87 mg, 0.627 mmol), tricyclohexylphosphine (11.42 mg, 0.041 mmol), and cyclopropylboronic acid (29.6 mg, 0.345 mmol) in toluene (10 ml) and water (2 ml) at room temperature was degassed with nitrogen for 15 minutes. After this time palladium (II) acetate (7.03 mg, 0.031 mmol) was added and the reaction mixture was left to stir at 90 C. for 24 hours. The reaction mixture was cooled and concentrated in vacua. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-30% EtOAc/isohexane) to afford the title compound (56 mg, 54%) as a colourless solid on standing.

[1039] .sup.1H NMR (DMSO-d6) 8.17 (d, J=5.2 Hz, 1H), 7.00 (dd, J=5.3, 1.5 Hz, 1H), 6.78 (d, J=1.4 Hz, 1H), 6.43 (s, 1H), 4.48 (s, 2H), 3.88 (s, 3H), 2.91 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.4 Hz, 2H), 2.04 (q, =7.3 Hz, 2H), 1.78-1.71 (m, 1H), 0.81-0.75 (m, 2H), 0.55-0.48 (m, 2H).

[1040] LCMS; m/z 281.5 (M+H).sup.+ (ES.sup.+).

Intermediate A48: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

[1041] ##STR00314##

[1042] 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35) (500 mg, 2.081 mmol) was dissolved in DCM (10 to mL) and sat aq NaHCO.sub.3 (5 mL) was added. A solution of triphosgene (250 mg, 0.842 mmol) in DCM (5 mL) was added and the mixture stirred at room temperature for 1 hour. The organic phase was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to afford the title compound (523 mg, 94%) as a pale yellow oil that was used without further purification.

[1043] .sup.1H NMR (CDCl.sub.3) 8.25 (d, J=5.2 Hz, 1H), 7.18-7.13 (m, 2H), 7.01 (dd, J=5.3, 1.5 Hz, 1H), 6.86 (s, 1H), 4.03 (s, 3H), 3.04 (t, J=7.5 Hz, 4H), 2.21 (p, J=7.5 Hz, 2H).

Intermediate A49: 4-(4-Isocyanato-2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine

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

[1044] ##STR00315##

[1045] N-(2,3-dihydrobenzofuran-4-yl)acetamide (13.1 g, 73.9 mmol), 4-methylbenzenesulfonic acid hydrate (7.73 g, 4.07 mmol) and diacetoxypalladium (0.830 g, 3.70 mmol) were suspended in toluene (250 mL) and stirred for 20 minutes. NBS (14.47 g, 81 mmol) was added and the mixture was stirred for 30 minutes, diluted with EtOAc (150 mL), and washed with aq NaHCO.sub.3 (100 mL) and aq Na.sub.2S.sub.2O.sub.3 (10 wt %, 100 mL). The aqueous phases were further extracted with DCM (150 mL). The organic phases were combined, dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the title compound (22.27 g, quant., purity 85% by LCMS) which was used crude in the next step.

[1046] LCMS; m/z 255.9, 257.9 (M+H).sup.+ (ES.sup.+).

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

[1047] ##STR00316##

[1048] A solution of N-(5-bromo-2,3-dihydrobenzofuran-4-yl)acetamide (22.27 g, 73.9 mmol) in MeOH (400 mL) and cone H.sub.2SO.sub.4 (40 mL) was stirred at reflux for 18 hours. The volatiles were removed under reduced pressure, the residue taken up in DCM (300 mL) and basified with aq NaOH 1 M (100 mL). The organic phase was separated, dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (220 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (9.17 g, 57%) as an off white solid.

[1049] .sup.1H NMR (CDCl.sub.3) 7.16 (dt, J=8.4, 0.9 Hz, 1H), 6.17 (d, J=8.4 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.99 (br. s, 2H), 3.05 (t, J=8.7 Hz, 2H).

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

[1050] ##STR00317##

[1051] Prepared according to the general procedure of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35) from 5-bromo-2,3-dihydrobenzofuran-4-amine and (2-methoxypyridin-4-yl)boronic acid to afford the title compound (2.25 g, 79%) as an off white solid.

[1052] .sup.1H NMR (DMSO-d.sub.6) 8.15 (d, J=5.2 Hz, 1H), 6.99 (dd, J=5.3, 1.5 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.78 (s, 1H), 6.14 (d, J=8.1 Hz, 1H), 4.91 (s, 2H), 4.54 (t, J=8.7 Hz, 2H), 3.87 (s, 3H), 3.01 (t, J=8.7 Hz, 2H).

[1053] LCMS; m/z 243.1 (M+H).sup.+ (ES.sup.+).

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

[1054] ##STR00318##

[1055] Prepared according to the general procedure of 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A48) from 5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-amine to afford the title compound (926 mg, 79%) as a pale yellow solid.

[1056] .sup.1H NMR (CDCl.sub.3) 8.23 (d, J=5.3 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.98 (dd, J=5.3, 1.4 Hz, 1H), 6.83 (s, 1H), 6.74 (d, J=8.3 Hz, 1H), 4.72 (t, J=8.7 Hz, 2H), 4.02 (s, 3H), 3.33 (t, J=8.7 Hz, 2H).

PREPARATION OF EXAMPLES

Example 1: N-((4-Fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1057] ##STR00319##

[1058] 4-Fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A1; 50 mg, 0.213 mmol) in acetonitrile (2 mL) was added to (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3; 71.8 mg, 0.213 mmol) and the mixture was stirred at 50 C. for 10 minutes*, then at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC (basic method, 10-40% acetonitrile in 10 mM aqueous ammonium bicarbonate, 6.5 minute run) to afford the title compound (41 mg, 42%) as a white solid.

[1059] (*The reaction was usually performed for between 10 minutes and 1 hour heating.)

[1060] .sup.1H NMR (DMSO-d.sub.6) 11.34 (s, 1H), 8.96 (dd, 1H), 8.93 (d, 1H), 8.35 (d, 1H), 8.29 (s, 1H), 8.14 (dt, 1H), 7.78 (dd, 1H), 7.62 (dd, 1H), 7.48 (dd, 1H), 7.05-6.85 (m, 1H), 5.02 (sept, 1H), 3.48-3.34 (m, 1H), 1.86 (d, 6H) and 1.51 (d, 6H).

[1061] LCMS m/z 446.4 (M+H).sup.+ (ES.sup.+); 444.3 (MH).sup. (ES.sup.).

[1062] The following examples 2-35 were synthesised following the general procedure for N-((4-fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide (Example 1) above. Sodium salts were synthesised using sodium tert-butoxide where stated.

Example 2: N-((4-Fluoro-2-iso-propyl-6-(1-methyl-1H-pyrazol-4-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1063] ##STR00320##

[1064] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(1-methyl-1H-pyrazol-4-yl)aniline (Intermediate A2) to afford the title compound (50 mg, 53%). .sup.1H NMR (DMSO-d.sub.6) 11.07 (br s, 1H), 7.95 (d, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.64 (br s, 1H), 7.14 (dd, 1H), 6.99 (dd, 1H), 6.65 (d, 1H), 4.60 (sept, 1H), 3.85 (s, 3H), 3.02-2.88 (m, 1H), 1.43 (d, 6H) and 1.06 (d, 6H).

[1065] LCMS m/z 449.4 (M+H).sup.+ (ES.sup.+).

Example 3: N-((4-Fluoro-2-iso-propyl-6-(1-methyl-1H-imidazol-5-yl) phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1066] ##STR00321##

[1067] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(1-methyl-1H-imidazol-5-yl)aniline (Intermediate A3) to afford the title compound (20.1 mg, 42%) as an off-white solid.

[1068] .sup.1H NMR (DMSO-d.sub.6) 10.96 (s, 1H), 7.92 (s, 1H), 7.65 (s, 2H), 7.18 (dd, 1H), 7.04 (dd, 1H), 6.77 (s, 1H), 6.53 (s, 1H), 4.61 (sept, 1H), 3.40 (s, 3H), 3.06-2.87 (m, 1H), 1.45 (d, 6H) and 1.08 (d, 6H).

[1069] LCMS m/z 449.4 (M+H).sup.+ (ES.sup.+); 447.1 (MH).sup. (ES.sup.).

Example 4: N-((5-Fluoro-3-iso-propyl-[1,1-biphenyl]-2-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1070] ##STR00322##

[1071] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 5-fluoro-3-isopropyl-[1,1-biphenyl]-2-amine (Intermediate A4) to afford the title compound (26 mg, 38%) as a white solid.

[1072] .sup.1H NMR (DMSO-d.sub.6) 10.79 (br s, 1H), 7.97 (d, 1H), 7.68 (s, 1H), 7.43-7.21 (m, 5H), 7.15 (dd, 1H), 6.96 (dd, 1H), 6.57 (d, 1H), 4.60 (sept, 1H), 3.02-2.87 (m, 1H), 1.44 (d, 6H) and 1.08 (d, 6H).

[1073] LCMS m/z 445.4 (M+H).sup.+ (ES.sup.+); 443.4 (MH).sup. (ES.sup.).

Example 5: N-((4-Fluoro-2-iso-propyl-6-(1-methyl-1H-pyrazol-5-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1074] ##STR00323##

[1075] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(1-methyl-1H-pyrazol-5-yl)aniline (Intermediate A5) to afford the title compound (44 mg, 64%) as a white solid.

[1076] .sup.1H NMR (DMSO-d.sub.6) 10.90 (s, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.38 (d, 1H), 7.25 (dd, 1H), 7.09 (d, 1H), 6.58 (s, 1H), 6.11 (d, 1H), 4.61 (sept, 1H), 3.55 (s, 3H), 3.08-2.86 (m, 1H), 1.45 (d, 6H) and 1.09 (d, 6H).

[1077] LCMS m/z 449.5 (M+H).sup.+ (ES.sup.+); 447.4 (MH).sup. (ES.sup.).

Example 6: N-((4-Fluoro-2-iso-propyl-6-(thiazol-5-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1078] ##STR00324##

[1079] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(thiazol-5-yl)aniline (Intermediate A6) to afford the title compound (10 mg, 34%) as a white solid.

[1080] .sup.1H NMR (DMSO-d.sub.6) 11.20 (br s, 1H), 9.08 (s, 1H), 8.19 (s, 1H), 7.86 (s, 2H), 7.40 (dd, 1H), 7.21-7.08 (m, 1H), 6.56 (s, 1H), 4.77-4.29 (m, 1H), 3.10-2.88 (m, 1H), 1.42 (d, 6H) and 1.06 (s, 6H).

[1081] LCMS m/z 452.4 (M+H).sup.+ (ES.sup.+); 450.2 (MH).sup. (ES.sup.).

Example 7: N-((4-Fluoro-2-iso-propyl-6-(isoxazol-4-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1082] ##STR00325##

[1083] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(isoxazol-4-yl)aniline (Intermediate A7) to afford the title compound (23 mg, 57%) as a white solid.

[1084] .sup.1H NMR (DMSO-d.sub.6) 11.26 (s, 1H), 9.05 (s, 1H), 8.83 (s, 1H), 8.14 (s, 1H), 7.94 (d, 1H), 7.32 (dd, 1H), 7.15 (dd, 1H), 6.64 (d, 1H), 4.60 (sept, 1H), 3.06-2.95 (m, 1H), 1.43 (d, 6H) and 1.08 (br s, 6H).

[1085] LCMS 436.5 (M+H).sup.+ (ES.sup.+); 434.3 (MH).sup. (ES.sup.).

Example 8: N-((3-Cyano-5-fluoro-3-iso-propyl-[1,1-biphenyl]-2-yl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, sodium salt

[1086] ##STR00326##

[1087] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 2-amino-5-fluoro-3-isopropyl-[1,1-biphenyl]-3-carbonitrile (Intermediate A8) to afford the title compound (14.6 mg, 14%) as a colourless powder.

[1088] .sup.1H NMR (DMSO-d.sub.6) 7.78 (s, 1H), 7.75 (d, 1H), 7.66 (d, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 7.42 (t, 1H), 7.09 (dd, 1H), 6.96 (dd, 1H), 6.16 (d, 1H), 4.48 (sept, 1H), 3.23-3.11 (m, 1H), 1.40 (d, 6H) and 1.08 (d, 6H).

[1089] LCMS m/z 470 (M+H).sup.+ (ES.sup.+); 468 (MH).sup. (ES.sup.).

Example 9: N-((4-Cyano-5-fluoro-3-iso-propyl-[1,1-biphenyl]-2-yl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, sodium salt

[1090] ##STR00327##

[1091] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 2-amino-5-fluoro-3-isopropyl-[1,1-biphenyl]-4-carbonitrile (Intermediate A9) to afford the title compound (47.4 mg, 48%) as a colourless powder.

[1092] .sup.1H NMR (DMSO-d.sub.6) 7.72 (s, 1H), 7.67 (d, 2H), 7.52 (d, 2H), 7.39 (s, 1H), 7.11 (dd, 1H), 6.93 (dd, 1H), 6.24 (d, 1H), 4.51 (sept, 1H), 3.19 (br s, 1H), 1.42 (d, 6H) and 1.09 (d, 6H).

[1093] LCMS m/z 470 (M+H).sup.+ (ES.sup.+); 468 (MH).sup. (ES.sup.).

Example 10: N-((4-Fluoro-2-iso-propyl-6-(pyridin-4-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1094] ##STR00328##

[1095] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(pyridin-4-yl)aniline (Intermediate A10) to afford the title compound (24 mg, 36%) as a white solid.

[1096] .sup.1H NMR (DMSO-d.sub.6) 8.55-8.34 (m, 2H), 7.89 (s, 1H), 7.79 (s, 1H), 7.31 (d, 2H), 7.21 (dd, 1H), 7.03 (dd, 1H), 6.49 (s, 1H), 4.57 (sept, 1H), 3.12-2.95 (m, 1H), 1.43 (d, 6H) and 1.09 (d, 6H). One exchangeable signal as a very broad singlet 11.25-10.00 ppm.

[1097] LCMS m/z 446.4 (M+H).sup.+ (ES.sup.+); 444.1 (MH).sup. (ES.sup.).

Example 11: N-((2-(1,3-Dimethyl-1H-pyrazol-5-yl)-4-fluoro-6-iso-propylphenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1098] ##STR00329##

[1099] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 2-(1,3-dimethyl-1H-pyrazol-5-yl)-4-fluoro-6-isopropylaniline (Intermediate A11) to afford the title compound (41 mg, 57%) as a white solid.

[1100] .sup.1H NMR (DMSO-d.sub.6) 7.84 (s, 1H), 7.53 (s, 1H), 7.19 (dd, 1H), 6.97 (dd, 1H), 6.45 (s, 1H), 5.94 (s, 1H), 4.55 (sept, 1H), 3.45 (s, 3H), 3.10-2.95 (m, 1H), 2.13 (s, 3H), 1.43 (d, 6H) and 1.08 (d, J=6.8 Hz, 6H); one exchangeable signal not observed.

[1101] LCMS m/z 463.4 (M+H).sup.+ (ES.sup.+); 461.3 (MH).sup. (ES.sup.).

Example 12: N-((4-Fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1102] ##STR00330##

[1103] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(2-methoxy-pyridin-4-yl)aniline (Intermediate A12) to afford the title compound (32 mg, 44%) as a white solid.

[1104] .sup.1H NMR (DMSO-d.sub.6) 7.99 (d, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 7.11 (dd, 1H), 6.93 (dd, 1H), 6.83 (d, 1H), 6.70 (s, 1H), 6.40 (s, 1H), 4.48 (sept, 1H), 3.80 (s, 3H), 3.02-2.82 (m, 1H), 1.35 (d, 6H) and 1.00 (d, 6H); one exchangeable signal not observed.

[1105] LCMS m/z 476.4 (M+H).sup.+ (ES.sup.+); 474.3 (MH).sup. (ES.sup.).

Example 13: N-((4-Fluoro-2-iso-propyl-6-(2-methylpyridin-4-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1106] ##STR00331##

[1107] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(2-methylpyridin-4-yl)aniline (Intermediate A13) to afford the title compound (37 mg, 53%) as a white solid.

[1108] .sup.1H NMR (DMSO-d.sub.6) 8.33 (d, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 7.21 (s, 1H), 7.17 (dd, 1H), 7.11 (d, 1H), 7.05-6.89 (m, 1H), 6.44 (s, 1H), 4.54 (sept, 1H), 3.15-2.96 (m, 1H), 2.45 (s, 3H), 1.42 (d, 6H) and 1.08 (d, 6H); one exchangeable signal not observed.

[1109] LCMS m/z 460.5 (M+H).sup.+ (ES.sup.+); 458.4 (MH).sup. (ES.sup.).

Example 14: N-((4-Fluoro-2-iso-propyl-6-(2-methylpyridin-3-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1110] ##STR00332##

[1111] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(2-methylpyridin-3-yl)aniline (Intermediate A14) to afford the title compound (8 mg, 11%) as a white solid.

[1112] .sup.1H NMR (DMSO-d.sub.6) 8.39 (dd, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 7.46-7.32 (m, 1H), 7.21-7.03 (m, 2H), 7.02-6.79 (m, 1H), 6.34 (s, 1H), 4.54 (sept, 1H), 3.16-2.93 (m, 1H), 2.19 (s, 3H), 1.43 (d, 6H) and 1.17-1.04 (m, 6H); one exchangeable signal not observed.

[1113] LCMS m/z 460.5 (M+H).sup.+ (ES.sup.+); 458.4 (MH).sup. (ES.sup.).

Example 15: N-((4-Fluoro-2-iso-propyl-6-(6-methylpyridin-3-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1114] ##STR00333##

[1115] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(6-methylpyridin-3-yl)aniline (Intermediate A15) to afford the title compound (21 mg, 30%) as a white solid.

[1116] .sup.1H NMR (DMSO-d.sub.6) 8.38 (s, 1H), 7.84 (s, 1H), 7.66 (s, 1H), 7.61 (d, 1H), 7.19 (d, 1H), 7.13 (dd, 1H), 6.99 (dd, 1H), 6.44 (s, 1H), 4.56 (sept, 1H), 3.14-2.88 (m, 1H), 2.50 (s, 3H), 1.42 (d, 6H) and 1.07 (d, 6H); one exchangeable signal not observed.

[1117] LCMS m/z 460.5 (M+H).sup.+ (ES.sup.+); 458.3 (MH).sup. (ES.sup.).

Example 16: N-((2-(5-Chloropyridin-3-yl)-4-fluoro-6-iso-propylphenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1118] ##STR00334##

[1119] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 2-(5-chloropyridin-3-yl)-4-fluoro-6-isopropylaniline (Intermediate A16) to afford the title compound (43.2 mg, 58%) as a white solid.

[1120] .sup.1H NMR (DMSO-d.sub.6) 8.57 (d, 1H), 8.46 (s, 1H), 7.98-7.79 (m, 3H), 7.21 (dd, 1H), 7.11 (dd, 1H), 6.45 (d, 1H), 4.56 (sept, 1H), 3.07-2.92 (m, 1H), 1.42 (d, 6H) and 1.09 (d, 6H).

[1121] LCMS m/z 480.4/482.4 (M+H).sup.+ (ES.sup.+); 478.3/480.3 (MH).sup. (ES.sup.).

Example 17: N-((4-Fluoro-2-iso-propyl-6-(5-methoxypyridin-3-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1122] ##STR00335##

[1123] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(5-methoxy-pyridin-3-yl)aniline (Intermediate A17) to afford the title compound (44.6 mg, 60%) as a white solid.

[1124] .sup.1H NMR (DMSO-d.sub.6) 8.24 (d, 1H), 8.09 (d, 1H), 7.93-7.75 (m, 2H), 7.38 (s, 1H), 7.18 (dd, 1H), 7.06 (dd, 1H), 6.50 (s, 1H), 4.57 (sept, 1H), 3.82 (s, 3H), 3.06-2.89 (m, 1H), 1.43 (d, 6H) and 1.08 (d, 6H).

[1125] LCMS m/z 476.4 (M+H).sup.+ (ES.sup.+); 474.5 (MH).sup. (ES.sup.).

Example 18: N-((4-Fluoro-2-iso-propyl-6-(pyrimidin-5-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1126] ##STR00336##

[1127] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)aniline (Intermediate A18) to afford the title compound (24.7 mg, 25%) as a colourless solid.

[1128] .sup.1H NMR (DMSO-d.sub.6) 11.06 (s, 1H), 9.13 (s, 1H), 8.75 (s, 2H), 8.01 (s, 1H), 7.90 (s, 1H), 7.25 (dd, 1H), 7.18 (dd, 1H), 6.49 (s, 1H), 4.59 (sept, 1H), 3.04 (sept, 1H), 1.44 (d, 6H) and 1.10 (d, 6H).

[1129] LCMS m/z 447 (M+H).sup.+ (ES.sup.+); 445 (MH).sup. (ES.sup.).

Example 19: N-((4-Fluoro-2-iso-propyl-6-(6-methoxypyridin-3-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1130] ##STR00337##

[1131] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(6-methoxy-pyridin-3-yl)aniline (Intermediate A19) to afford the title compound (29 mg, 53%) as a white solid.

[1132] .sup.1H NMR (DMSO-d.sub.6) 10.90 (s, 1H), 8.10 (d, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.63 (dd, 1H), 7.15 (dd, 1H), 7.01 (dd, 1H), 6.74 (d, 1H), 6.55 (s, 1H), 4.59 (sept, 1H), 3.89 (s, 3H), 3.07-2.86 (m, 1H), 1.43 (d, 6H) and 1.08 (d, 6H).

[1133] LCMS m/z 476.5 (M+H).sup.+ (ES.sup.+); 474.4 (MH).sup. (ES.sup.).

Example 20: N-((4-Fluoro-2-iso-propyl-6-(4-methylpyridin-3-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1134] ##STR00338##

[1135] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(4-methylpyridin-3-yl)aniline (Intermediate Ago) to afford the title compound (23 mg, 40%) as a white solid.

[1136] .sup.1H NMR (DMSO-d.sub.6) 8.40-8.34 (m, 1H), 8.32 (s, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.16 (dd, 1H), 7.02 (dd, 1H), 6.45 (s, 1H), 4.55 (sept, 1H), 3.12-2.93 (m, 1H), 2.29 (s, 3H), 1.42 (d, 6H) and 1.08 (d, 6H); one exchangeable signal not observed.

[1137] LCMS m/z 460.6 (M+H).sup.+ (ES.sup.+); 458.4 (MH).sup. (ES.sup.).

Example 21: N-((4-Fluoro-2-(5-fluoropyridin-3-yl)-6-isopropylphenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1138] ##STR00339##

[1139] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-(5-fluoropyridin-3-yl)-6-isopropylaniline (Intermediate A21) to afford the title compound (14.1 mg, 21%) as a colourless solid.

[1140] .sup.1H NMR (DMSO-d.sub.6) 8.51 (d, 1H), 8.41 (s, 1H), 7.81-7.63 (m, 3H), 7.17 (dd, 1H), 7.07 (dd, 1H), 6.31 (s, 1H), 4.51 (sept, 1H), 3.21-3.04 (m, 1H), 1.41 (d, 6H) and 1.09 (d, 6H); one exchangeable signal not observed.

[1141] LCMS m/z 464 (M+H).sup.+ (ES.sup.+); 462 (MH).sup. (ES.sup.).

Example 22: N-((4-Fluoro-2-iso-propyl-6-(3-methylpyridin-4-yl)phenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1142] ##STR00340##

[1143] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(3-methylpyridin-4-yl)aniline (Intermediate A22) to afford the title compound (27.9 mg, 41%) as a colourless powder.

[1144] .sup.1H NMR (DMSO-d.sub.6) 10.75 (s, 1H), 8.42 (s, 1H), 8.28 (d, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 7.22 (dd, 1H), 7.02 (s, 1H), 6.93 (dd, 1H), 6.49 (s, 1H), 4.60 (sept, 1H), 2.98 (sept, 1H), 2.00 (s, 3H), 1.45 (d, 6H) and 1.11 (d, 6H).

[1145] LCMS m/z 460 (M+H).sup.+ (ES.sup.+); 458 (MH).sup. (ES.sup.).

Example 23: N-((2-(2-Aminopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1146] ##STR00341##

[1147] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-(2-amino-5-fluoro-3-isopropylphenyl) pyridin-2-amine (Intermediate A23) to afford the title compound (19 mg, 27%) as a white solid.

[1148] .sup.1H NMR (DMSO-d.sub.6) 10.90 (br s, 1H), 7.95 (d, 1H), 7.78 (dd, 1H), 7.70 (s, 1H), 7.18 (dd, 1H), 6.93 (dd, 1H), 6.58 (d, 1H), 6.41-6.35 (m, 1H), 6.32 (s, 1H), 5.95 (br s, 2H), 4.60 (sept, 1H), 3.06-2.83 (m, 1H), 1.44 (d, 6H) and 1.07 (d, 6H).

[1149] LCMS m/z 461.5 (M+H).sup.+ (ES.sup.+); 459.3 (MH).sup. (ES.sup.).

Example 24: N-((2-(2-Ethoxypyridin-4-yl)-4-fluoro-6-iso-propylphenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1150] ##STR00342##

[1151] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 2-(2-ethoxypyridin-4-yl)-4-fluoro-6-isopropylaniline (Intermediate A24) to afford the title compound (20 mg, 27%) as a white solid.

[1152] .sup.1H NMR (DMSO-d.sub.6) 10.94 (s, 1H), 8.06 (d, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.20 (dd, 1H), 7.02 (dd, 1H), 6.93-6.79 (m, 1H), 6.73 (d, 1H), 6.55 (s, 1H), 4.59 (sept, 1H), 4.32 (q, 2H), 3.07-2.88 (m, 1H), 1.43 (d, 6H), 1.34 (t, 3H) and 1.20-0.88 (m, 6H).

[1153] LCMS m/z 490.5 (M+H).sup.+ (ES.sup.+); 488.3 (MH).sup. (ES.sup.).

Example 25: N-((4-Fluoro-2-(2-hydroxypyridin-4-yl)-6-iso-propylphenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1154] ##STR00343##

[1155] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-(2-amino-5-fluoro-3-isopropylphenyl) pyridin-2-ol (Intermediate A25) to afford the title compound (10.5 mg, 15%) as a colourless powder.

[1156] .sup.1H NMR (DMSO-d.sub.6) 11.89 (s, 1H), 7.75 (br s, 2H), 7.23 (d, 1H), 7.13 (dd, 1H), 6.92 (dd, 1H), 6.45 (s, 1H), 6.18 (s, 1H), 6.07 (d, 1H), 4.54 (sept, 1H), 3.21-3.02 (m, 1H), 1.40 (d, 6H) and 1.08 (d, 6H); one exchangeable signal not observed.

[1157] LCMS m/z 462 (M+H).sup.+ (ES.sup.+); 460 (MH).sup. (ES.sup.).

Example 26: N-((4-Fluoro-2-iso-propyl-6-(2-methoxy-6-methylpyridin-4-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1158] ##STR00344##

[1159] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(2-methoxy-6-methylpyridin-4-yl)aniline (Intermediate A26) to afford the title compound (16.7 mg, 23%) as a colourless powder.

[1160] .sup.1H NMR (DMSO-d.sub.6) 7.74 (s, 1H), 7.57 (s, 1H), 7.13 (dd, 1H), 6.94 (dd, 1H), 6.82 (s, 1H), 6.60 (s, 1H), 6.35 (s, 1H), 4.51 (sept, 1H), 3.85 (s, 3H), 3.19-3.02 (m, 1H), 2.36 (s, 3H), 1.41 (d, 6H) and 1.08 (d, 6H).

[1161] LCMS m/z 490 (M+H).sup.+ (ES.sup.+); 488 (MH).sup. (ES.sup.).

Example 27: N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-iso-propyl-phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1162] ##STR00345##

[1163] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-(2-isopropoxy-pyridin-4-yl)-6-isopropylaniline (Intermediate A27) to afford the title compound (31.6 mg, 42%) as a colourless powder.

[1164] .sup.1H NMR (DMSO-d.sub.6) 8.04 (d, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.18 (dd, 1H), 7.01 (dd, 1H), 6.86 (d, 1H), 6.70 (s, 1H), 6.50 (s, 1H), 5.27 (sept, 1H), 4.57 (sept, 1H), 3.14-2.89 (m, 1H), 1.43 (d, 6H), 1.32 (d, 6H) and 1.08 (d, 6H).

[1165] LCMS m/z 504 (M+H).sup.+ (ES.sup.+); 502 (MH).sup. (ES.sup.).

Example 28: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-iso-propylphenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1166] ##STR00346##

[1167] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-(2-amino-5-fluoro-3-isopropylphenyl)-picolinonitrile (Intermediate A28) to afford the title compound (18.5 mg, 26%) as a colourless powder.

[1168] .sup.1H NMR (DMSO-d.sub.6) 11.07 (s, 1H), 8.67 (d, 1H), 8.06-8.01 (m, 2H), 7.85 (d, 1H), 7.67 (dd, 1H), 7.27 (dd, 1H), 7.15 (dd, 1H), 6.43 (s, 1H), 4.56 (sept, 1H), 3.18-2.96 (m, 1H), 1.43 (d, 6H) and 1.11 (d, 6H).

[1169] LCMS m/z 471 (M+H).sup.+ (ES+); 469 (MH) (ES).

Example 29: N-((2-(2-Ethylpyridin-4-yl)-4-fluoro-6-iso-propylphenyl) carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1170] ##STR00347##

[1171] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 2-(2-ethylpyridin-4-yl)-4-fluoro-6-isopropylaniline (Intermediate A29) to afford the title compound (27.8 mg, 39%) as a colourless powder.

[1172] .sup.1H NMR (DMSO-d.sub.6) 10.92 (s, 1H), 8.41 (dd, 1H), 7.95 (d, 1H), 7.88 (s, 1H), 7.26-7.20 (m, 2H), 7.11 (dd, 1H), 7.06 (dd, 1H), 6.58 (d, 1H), 4.60 (sept, 1H), 2.97 (sept, 1H), 2.75 (q, 2H), 1.44 (d, 6H), 1.25 (t, 3H) and 1.09 (br s, 6H).

[1173] LCMS m/z 474 (M+H).sup.+ (ES.sup.+); 472 (MH).sup. (ES.sup.).

Example 30: 3-(N-((4-Fluoro-2-iso-propyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt

[1174] ##STR00348##

[1175] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P4) and 4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)aniline (Intermediate A30) to afford the title compound (5 mg, 5%) as a solid.

[1176] .sup.1H NMR (DMSO-d.sub.6) 7.39 (s, 1H), 6.81 (td, 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) and 1.04 (d, 6H).

[1177] LCMS m/z 496.5 (M+H).sup.+ (ES.sup.+); 494.3 (MH).sup. (ES.sup.).

Example 31: N-((4-Fluoro-2-iso-propyl-6-(1-methyl-1H-pyrazol-4-yl) phenyl)carbamoyl)-1-iso-propyl-1H-imidazole-4-sulfonamide

[1178] ##STR00349##

[1179] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-imidazol-4-yl)sulfonyl)amide (Intermediate P6) and 4-fluoro-2-isopropyl-6-(1-methyl-1H-pyrazol-4-yl)aniline (Intermediate A2) to afford the title compound (24.9 mg, 37%) as a white solid.

[1180] .sup.1H NMR (DMSO-d.sub.6) 7.95 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.68 (s, 1H), 7.68-7.64 (m, 1H), 7.14 (dd, 1H), 6.94 (dd, 1H), 4.44 (sept, 1H), 3.87 (s, 3H), 3.14-2.87 (m, 1H), 1.38 (d, 6H) and 1.04 (d, 6H); one exchangeable signal not observed.

[1181] LCMS m/z 449.4 (M+H).sup.+ (ES.sup.+); 447.2 (MH).sup. (ES.sup.).

Example 32: 3-(N-((4-Fluoro-2-iso-propyl-6-(pyrimidin-5-yl)phenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt

[1182] ##STR00350##

[1183] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P4) and 4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)aniline (Intermediate A18) to afford the title compound (31 mg, ii %) as a white solid.

[1184] .sup.1H NMR (DMSO-d.sub.6) 9.03 (s, 1H), 8.76 (s, 2H), 7.30 (br s, 1H), 7.11 (dd, 1H), 7.03 (dd, 1H), 6.43 (s, 1H), 3.85 (s, 3H), 3.26 (sept, 1H), 3.04 (s, 6H) and 1.14 (d, 6H).

[1185] LCMS m/z 490.4 (M+H).sup.+ (ES.sup.+).

Example 33: 3-(N-((4-Fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt

[1186] ##STR00351##

[1187] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P4) and 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A1) to afford the title compound (23 mg, 9%) as a white solid.

[1188] .sup.1H NMR (DMSO-d.sub.6) 8.55 (m, 1H), 8.45 (dd, 1H), 7.77 (dt, 1H), 7.25 (ddd, 1H), 7.06 (dd, 1H), 6.91 (dd, 1H), 6.44 (s, 1H), 3.84 (s, 3H), 3.26 (sept, 1H), 3.04 (s, 6H) and 1.13 (d, 6H).

[1189] LCMS m/z 489.4 (M+H).sup.+ (ES+).

Example 34: 3-(N-((4-Fluoro-2-iso-propyl-6-(1-methyl-1H-pyrazol-4-yl) phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt

[1190] ##STR00352##

[1191] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P4) and 4-fluoro-2-isopropyl-6-(1-methyl-1H-pyrazol-4-yl)aniline (Intermediate A2) to afford the title compound (40 mg, 21%) as a white solid.

[1192] .sup.1H NMR (DMSO-d.sup.6) 7.95 (s, 1H), 7.76 (s, 1H), 7.25 (s, 1H), 7.10 (dd, 1H), 6.86 (dd, 1H), 6.58 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.20 (m, 1H), 2.99 (s, 6H) and 1.06 (d, 6H).

[1193] LCMS m/z 492.4 (M+H).sup.+ (ES.sup.+); 490.3 (MH).sup. (ES.sup.).

Example 35: N-((4-Fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[1194] ##STR00353##

[1195] Prepared from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P5) and 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A1) to afford the title compound (7 mg, 13%) as a white solid.

[1196] .sup.1H NMR (DMSO-d.sub.6) 10.93 (br s, 1H), 8.55 (dd, 1H), 8.49 (d, 1H), 7.89 (s, 1H), 7.73 (dt, 1H), 7.38 (ddd. 1H), 7.22 (dd, 1H), 7.07 (dd, 1H), 6.56 (s, 1H), 4.00 (s, 3H), 3.11-2.99 (m, 1H), 2.99 (s, 3H), 1.51 (s, 6H) and 1.19-1.00 (br s, 6H).

[1197] LCMS m/z 490.4 (M+H).sup.+ (ES.sup.+).

Example 36: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1198] ##STR00354##

[1199] 4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (Intermediate A12; 0.1 g, 0.384 mmol) was dissolved in dry tetrahydrofuran (2 mL). Triethylamine (0.06 ml, 0.430 mmol) and a solution of triphosgene (0.108 g, 0.365 mmol) in tetrahydrofuran (1 mL) was added. The thick, opaque mixture was stirred overnight and then filtered through a phase cartridge washing with toluene (30 mL). After concentration in vacuo, 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine was isolated as an oil. 5-((Dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P1; 0.042 g, 0.192 mmol) was dissolved in dry tetrahydrofuran (1 mL). Sodium tert-butoxide (2 M in tetrahydrofuran; 0.1 ml, 0.200 mmol) was added and the mixture was stirred at room temperature for 1 hour. A solution of the previously prepared isocyanate (0.192 mmol) in tetrahydrofuran (1 mL) was added via syringe and the mixture was stirred overnight. The volatiles were removed in vacua and the residue was dissolved in dimethylsulfoxide (1 mL) and then purified by preparative HPLC (basic 6.5 minutes run, 10-40% acetonitrile in 10 mM aqueous ammonium bicarbonate) to afford the title compound (15.2 mg, 16%) as a colourless powder.

[1200] .sup.1H NMR (DMSO-d.sub.6) 10.87 (s, 1H), 8.09 (dd, 1H), 7.85 (s, 1H), 7.22 (dd, 1H), 7.04 (dd, 1H), 6.89 (dd, 1H), 6.77 (s, 1H), 6.51 (s, 1H), 3.88 (s, 6H), 3.49 (s, 2H), 3.02 (sept, 1H), 2.17 (s, 6H) and 1.09 (d, 6H).

[1201] LCMS m/z 505 (M+H).sup.+ (ES.sup.+); 503 (MH).sup. (ES.sup.).

Example 37: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1202] ##STR00355##

[1203] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P2) and 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (Intermediate A12) to afford the title compound (44.1 mg, 43%) as a colourless powder.

[1204] .sup.1H NMR (DMSO-d.sub.6) 10.92 (s, 1H), 8.09 (dd, 1H), 7.87 (s, 1H), 7.22 (dd, 1H), 7.04 (dd, 1H), 6.92 (dd, 1H), 6.79 (s, 1H), 6.48 (s, 1H), 4.81 (sept, 1H), 3.88 (s, 3H), 3.48 (s, 2H), 2.98 (sept, 1H), 2.15 (s, 6H), 1.37 (d, 6H) and 1.08 (d, 6H).

[1205] LCMS m/z 533 (M+H).sup.+ (ES.sup.+); 531 (MH) (ES.sup.).

Example 38: N-((3-Cyano-5-fluoro-3-iso-propyl-[1,1-biphenyl]-2-yl)carbamoyl)-5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1206] ##STR00356##

[1207] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediates P1) and 2-amino-5-fluoro-3-isopropyl-[1,1-biphenyl]-3-carbonitrile (Intermediate A8) to afford the title compound (37.3 mg, 34%) as a colourless powder.

[1208] .sup.1H NMR (DMSO-d.sub.6) 10.86 (s, 1H), 7.90 (s, 1H), 7.84-7.78 (m, 2H), 7.65-7.60 (m, 1H), 7.53 (t, 1H), 7.21 (dd, 1H), 7.06 (dd, 1H), 6.45 (s, 1H), 3.87 (s, 3H), 3.49 (s, 2H), 3.04 (sept, 1H), 2.17 (s, 6H) and 1.10 (br s, 6H).

[1209] LCMS m/z 499 (M+H).sup.+ (ES.sup.+); 497 (MH).sup. (ES.sup.).

Example 39: N-((3-Cyano-5-fluoro-3-iso-propyl-[1,1-biphenyl]-2-yl)carbamoyl)-5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1210] ##STR00357##

[1211] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P2) and 2-amino-5-fluoro-3-isopropyl-[1,1-biphenyl]-3-carbonitrile (Intermediate A8) to afford the title compound (27.6 mg, 24%) as a colourless powder.

[1212] .sup.1H NMR (DMSO-d.sub.6) 10.92 (s, 1H), 7.93 (s, 1H), 7.82 (dt, 2H), 7.66 (dt, 1H), 7.57-7.51 (m, 1H), 7.21 (dd, 1H), 7.07 (dd, 1H), 6.42 (s, 1H), 4.79 (sept, 1H), 3.48 (s, 2H), 3.00 (sept, 1H), 2.15 (s, 6H), 1.37 (d, 6H) and 1.09 (s, 6H).

[1213] LCMS m/z 527 (M+H).sup.+ (ES.sup.+); 525 (MH) (ES.sup.).

Example 40: 5-((Dimethylamino)methyl)-N-((5-fluoro-3-iso-propyl-[1,1-biphenyl]-2-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1214] ##STR00358##

[1215] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P1) and 5-fluoro-3-isopropyl-[1,1-biphenyl]-2-amine (Intermediate A4) to afford the title compound (14.2 mg, 14%) as a colourless solid.

[1216] .sup.1H NMR (DMSO-d.sub.6) 10.73 (s, 1H), 7.68 (s, 1H), 7.42-7.30 (m, 3H), 7.31-7.24 (m, 2H), 7.16 (dd, 1H), 6.96 (dd, 1H), 6.54 (s, 1H), 3.90 (s, 3H), 3.50 (s, 2H), 2.99 (sept, 1H), 2.17 (s, 6H) and 1.09 (d, 6H).

[1217] LCMS m/z 474 (M+H).sup.+ (ES.sup.+); 472 (MH).sup. (ES.sup.).

Example 41: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide

[1218] ##STR00359##

[1219] 5-((Dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P2; 0.020 g, 0.081 mmol) and N,N-dimethylaminopyridine (0.030 g, 0.244 mmol) were dissolved in dry acetonitrile (1 mL) at room temperature and stirred for 10 minutes, after which time the mixture had become homogeneous. Diphenyl carbonate (0.019 g, 0.089 mmol) was then added as a solid and the slightly turbid reaction mixture was stirred at room temperature overnight. This was repeated 4 times at different temperatures. The crude reaction mixtures were combined and added to 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A1; 36.4 mg, 0.158 mmol). The mixture was then heated to 70 C. for 2 hours, evaporated to dryness in vacuo and the brown residue obtained triturated with 1:4 ethyl acetate:dichloromethane (4 mL). The filtrate was then purified by preparative HPLC [Gilson apparatus, basic procedure (0.1% ammonium bicarbonate), basic Waters X-Bridge Prep-C18, 5 m, 1950 mm column, 5-95% acetonitrile in water with 10 mM ammonium bicarbonate) to afford the title compound (26 mg, 30%) as a white solid.

[1220] .sup.1H NMR (DMSO-d.sub.6) 10.91 (br s, 1H), 8.60-8.39 (m, 2H), 7.86 (s, 1H), 7.73 (dt, 1H), 7.36 (ddd, 1H), 7.21 (dd, 1H), 7.07 (dd, 1H), 6.44 (s, 1H), 4.80 (sept, 1H), 3.48 (s, 2H), 3.04-2.93 (m, 1H), 2.15 (s, 6H), 1.38 (d, 6H) and 1.09 (d, 6H).

[1221] LCMS m/z 503.6 (M+H).sup.+ (ES.sup.+); 501.4 (MH).sup. (ES.sup.).

Example 42: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1222] ##STR00360##

[1223] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P1) and 4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)aniline (Intermediate A18) to afford the title compound (13.7 mg, 10%) as a colourless powder.

[1224] .sup.1H NMR (DMSO-d6) 10.93 (s, 1H), 9.15 (s, 1H), 8.73 (s, 2H), 8.02 (s, 1H), 7.27 (dd, J=10.0, 3.0 Hz, 1H), 7.19 (dd, J=8.8, 3.0 Hz, 1H), 6.48 (s, 1H), 3.90 (s, 3H), 3.53 (s, 2H), 3.06 (hept, J=6.9 Hz, 1H), 2.19 (s, 6H), 1.11 (d, J=6.7 Hz, 6H).

[1225] LCMS m/z 476 (M+H).sup.+ (ES.sup.+); 474 (MH).sup. (ES.sup.).

Example 43: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1226] ##STR00361##

[1227] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P2) and 4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)aniline (Intermediate A18) to afford the title compound (17.4 mg, 12%) as a colourless powder.

[1228] .sup.1H NMR (DMSO-d6) 11.02 (s, 1H), 9.13 (s, 1H), 8.76 (s, 2H), 8.04 (s, 1H), 7.26 (dd, J=10.0, 3.0 Hz, 1H), 7.20 (dd, J=8.8, 3.0 Hz, 1H), 6.44 (s, 1H), 4.81 (sept, J=6.6 Hz, 1H), 3.51 (s, 2H), 3.03 (sept, J=7.0 Hz, 1H), 2.17 (s, 6H), 1.38 (d, J=6.6 Hz, 6H), 1.10 (d, J=6.8 Hz, 6H).

[1229] LCMS m/z 504 (M+H).sup.+ (ES.sup.+); 502 (MH).sup. (ES.sup.).

Example 44: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1230] ##STR00362##

[1231] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P1) and 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A1) to afford the title compound (35.8 mg, 34%) as a colourless powder.

[1232] .sup.1H NMR (DMSO-d6) 10.84 (s, 1H), 8.57-8.52 (m, 1H), 8.49 (s, 1H), 7.83 (s, 1H), 7.73-7.67 (m, 1H), 7.35 (dd, J=8.0, 4.9 Hz, 1H), 7.21 (dd, J=10.1, 3.0 Hz, 1H), 7.06 (dd, J=8.9, 3.0 Hz, 1H), 6.47 (s, 1H), 3.89 (s, 3H), 3.49 (s, 2H), 3.04 (sept, J=6.4 Hz, 1H), 2.17 (s, 6H), 1.10 (d, J=6.6 Hz, 6H).

[1233] LCMS m/z 475 (M+H).sup.+ (ES.sup.+); 473 (MH).sup. (ES.sup.).

Example 45: N-((1,3-Dimethyl-1H-pyrazol-5-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1234] ##STR00363##

[1235] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-methyl-1H-Pyrazole-3-sulfonamide (Intermediate P1) and 2-(1,3-dimethyl-1H-pyrazol-5-yl)-4-fluoro-6-isopropylaniline (Intermediate A11) to afford the title compound (15.9 mg, 22%) as a colourless powder.

[1236] .sup.1H NMR (DMSO-d6) 10.84 (s, 1H), 7.68 (s, 1H), 7.24 (dd, J=10.1, 3.0 Hz, 1H), 7.04 (dd, J=8.7, 3.0 Hz, 1H), 6.52 (s, 1H), 5.93 (s, 1H), 3.89 (s, 3H), 3.50 (s, 2H), 3.45 (s, 3H), 3.08-2.92 (m, 1H), 2.17 (s, 6H), 2.14 (s, 3H), 1.09 (d, J=6.8 Hz, 6H).

[1237] LCMS m/z 492 (M+H).sup.+ (ES.sup.+); 490 (MH).sup. (ES.sup.).

Example 46: 5-((Dimethylamino)methyl)-N-((5-fluoro-3-isopropyl-[1,1-biphenyl]-2-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1238] ##STR00364##

[1239] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P2) and 5-fluoro-3-isopropyl-[1,1-biphenyl]-2-amine (Intermediate A4) to afford the title compound (35.8 mg, 32%) as a colourless powder.

[1240] .sup.1H NMR (DMSO-d6) 10.77 (s, 1H), 7.70 (s, 1H), 7.39-7.27 (m, 5H), 7.16 (dd, J=10.1, 3.0 Hz, 1H), 6.97 (dd, J=8.9, 3.0 Hz, 1H), 6.51 (s, 1H), 4.83 (hept, J=6.6 Hz, 1H), 3.50 (s, 2H), 2.95 (hept, J=7.9 Hz, 1H), 2.17 (s, 6H), 1.39 (d, J=6.5 Hz, 6H), 1.09 (d, J=6.8 Hz, 6H).

[1241] LCMS m/z 502 (M+H).sup.+ (ES.sup.+); 500 (MH).sup. (ES.sup.).

Example 47: N-((4-Fluoro-2-isopropyl-6-(2-(trifluoromethyl)pyridin-4-yl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1242] ##STR00365##

[1243] Prepared according to the general procedure for N-((4-fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide (Example 1) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(2-(trifluoromethyl)pyridin-4-yl)aniline (Intermediate A31) to afford the title compound (21.9 mg, 28%) as a colourless powder.

[1244] .sup.1H NMR (DMSO-d6) 11.04 (s, 1H), 8.70 (d, J=5.0 Hz, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.64 (d, J=4.6 Hz, 1H), 7.28 (dd, J=9.9, 3.0 Hz, 1H), 7.19 (dd, J=8.8, 3.0 Hz, 1H), 6.48 (s, 1H), 4.57 (sept, J=6.5 Hz, 1H), 3.06 (sept, J=6.4 Hz, 1H), 1.42 (d, J=6.7 Hz, 6H), 1.10 (d, J=6.8 Hz, 6H).

[1245] LCMS m/z 514 (M+H).sup.+ (ES.sup.+); 512 (MH).sup. (ES.sup.).

Example 48: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1246] ##STR00366##

[1247] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P1) and 4-(2-amino-5-fluoro-3-isopropylphenyl)picolino-nitrile (Intermediate A28) to afford the title compound (7.9 mg, 7%) as a colourless powder.

[1248] .sup.1H NMR (DMSO-d6) 10.91 (s, 1H), 8.66 (d, J=5.1 Hz, 1H), 8.07-7.97 (m, 2H), 7.73-7.61 (m, 1H), 7.27 (dd, J=9.9, 3.0 Hz, 1H), 7.15 (dd, J=8.8, 2.9 Hz, 1H), 6.33 (s, 1H), 3.86 (s, 3H), 3.48 (s, 2H), 3.12 (sept, J=6.5 Hz, 1H), 2.17 (s, 6H), 1.12 (d, J=6.8 Hz, 6H).

[1249] LCMS m/z 500.5 (M+H).sup.+ (ES.sup.+); 498.4 (MH).sup. (ES.sup.).

Example 49: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide

[1250] ##STR00367##

[1251] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate P7) and 4-(2-amino-5-fluoro-3-isopropylphenyl)picolino-nitrile (Intermediate A28) to afford the title compound (6.9 mg, 6%) as a colourless powder.

[1252] .sup.1H NMR (DMSO-d6) 8.65 (d, J=5.0 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H), 7.97 (s, 1H), 7.73-7.65 (m, 1H), 7.26 (dd, J=10.0, 3.0 Hz, 1H), 7.15 (dd, J=8.8, 3.0 Hz, 1H), 6.29 (s, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.46 (s, 2H), 3.21-3.02 (m, 1H), 2.16 (s, 6H), 1.33 (t, J=7.2 Hz, 3H), 1.11 (d, J=6.8 Hz, 6H).

[1253] LCMS m/z 514.6 (M+H).sup.+ (ES.sup.+); 512.4 (MH).sup. (ES.sup.).

Example 50: N-((2-(2-(Dimethylamino)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1254] ##STR00368##

[1255] Prepared according to the general procedure for N-((4-fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide (Example 1) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-(2-amino-5-fluoro-3-isopropylphenyl)-N,N-dimethylpyridin-2-amine (Intermediate A32) to afford the title compound (23.7 mg, 32%) as a colourless powder.

[1256] .sup.1H NMR (DMSO-d6) 8.01 (d, J=5.1 Hz, 1H), 7.85 (s, 1H), 7.62 (s, 1H), 7.15 (dd, J=10.1, 3.0 Hz, 1H), 6.98 (dd, J=9.0, 2.9 Hz, 1H), 6.58 (s, 1H), 6.54-6.43 (m, 2H), 4.56 (sept, J=6.7 Hz, 1H), 3.02 (s, 6H), 3.02 (m, 1H), 1.43 (d, J=6.7 Hz, 6H), 1.07 (d, J=6.8 Hz, 6H), one exchangeable proton not visible.

[1257] LCMS m/z 489.6 (M+H).sup.+ (ES.sup.+); 487.5 (MH).sup. (ES.sup.).

Example 51: N-((4-Fluoro-2-isopropyl-6-(2-(prop-1-yn-1-yl)pyridin-4-yl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1258] ##STR00369##

[1259] Prepared according to the general procedure for N-((4-fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide (Example 1) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 4-fluoro-2-isopropyl-6-(2-(prop-1-yn-1-yl)pyridin-4-yl)aniline (Intermediate A33) to afford the title compound (21.2 mg, 29%) as a colourless powder.

[1260] .sup.1H NMR (DMSO-d6) 10.94 (br s, 1H), 8.41 (d, J=5.1 Hz, 1H), 7.86 (s, 2H), 7.41 (s, 1H), 7.28-7.23 (m, 1H), 7.21 (dd, J=10.0, 3.0 Hz, 1H), 7.05 (dd, J=8.8, 2.9 Hz, 1H), 6.46 (s, 1H), 4.56 (sept, J=6.7 Hz, 1H), 3.12-2.95 (m, 1H), 2.09 (s, 3H), 1.43 (d, J=6.7 Hz, 6H), 1.09 (d, J=6.8 Hz, 6H).

[1261] LCMS m/z 484.4 (M+H).sup.+ (ES.sup.+); 482.3 (MH).sup. (ES.sup.).

Example 52: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[1262] ##STR00370##

[1263] Prepared according to the general procedure of 5-((dimethylamino)methyl)-N-((4-fluoro-2-iso-propyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 36) from 5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P8) and 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (Intermediate A12) to afford the title compound (22.5 mg, 22%) as a colourless powder.

[1264] .sup.1H NMR (DMSO-d6) 11.08 (s, 1H), 8.12 (d, J=5.3 Hz, 1H), 7.89 (s, 1H), 7.23 (dd, J=10.1, 2.9 Hz, 1H), 7.05 (dd, J=8.8, 2.9 Hz, 1H), 6.99 (s, 1H), 6.92 (dd, J=5.4, 1.5 Hz, 1H), 6.79 (s, 1H), 4.86 (d, J=7.4 Hz, 2H), 4.79 (d, J=7.3 Hz, 2H), 3.75 (s, 3H), 3.34 (s, 3H), 3.04 (sept, J=7.0 Hz, 1H), 2.95 (s, 3H), 1.09 (br s, 6H).

[1265] LCMS m/z 534.4 (M+H).sup.+ (ES.sup.+); 532.2 (MH) (ES.sup.).

Example 53: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-isopropyl-1H-imidazole-4-sulfonamide

[1266] ##STR00371##

[1267] Prepared according to the general procedure for N-((4-fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide (Example 1) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-imidazol-4-yl)sulfonyl)amide (Intermediate P6) and 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (Intermediate A12) to afford the title compound (20 mg, 28%) as a white solid.

[1268] .sup.1H NMR (DMSO-d6) 10.55 (bs, 1H), 8.09 (d, J=5.3 Hz, 1H), 7.95 (s, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 7.21 (dd, J=10.0, 3.0 Hz, 1H), 7.03 (dd, J=8.9, 3.0 Hz, 1H), 6.83 (d, J=5.3 Hz, 1H), 6.74 (s, 1H), 4.48 (sept, J=6.1 Hz, 1H), 3.88 (s, 3H), 3.02-2.93 (m, 1H), 1.41 (d, J=6.7 Hz, 6H), 1.16-0.95 (m, 6H).

[1269] LCMS m/z 476.6 (M+H).sup.+ (ES.sup.+).

Example 54: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-isopropyl-1H-imidazole-4-sulfonamide

[1270] ##STR00372##

[1271] Prepared according to the general procedure for N-((4-fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide (Example 1) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl) ((1-isopropyl-1H-imidazol-4-yl)sulfonyl)amide (Intermediate P6) and 4-(2-amino-5-fluoro-3-isopropylphenyl)picolino-nitrile (Intermediate A28) to afford the title compound (19 mg, 27%) as a white solid.

[1272] .sup.1H NMR (DMSO-d6) 10.78 (bs, 1H), 8.68 (d, J=5.1 Hz, 1H), 8.02 (s, 2H), 7.89 (s, 1H), 7.82 (s, 1H), 7.63 (d, J=5.0 Hz, 1H), 7.28 (dd, J=10.1, 3.0 Hz, 1H), 7.16 (dd, J=8.8, 3.0 Hz, 1H), 4.46 (sept, J=6.9 Hz, 1H), 3.13-3.01 (m, 1H), 1.41 (d, J=6.7 Hz, 6H), 1.10 (d, J=6.2 Hz, 6H).

[1273] LCMS m/z 471.2 (M+H).sup.+ (ES.sup.+).

Example 55: N-((7-Fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1274] ##STR00373##

[1275] Prepared according to the general procedure for N-((4-fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide (Example 1) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A34) to afford the title compound (23.7 mg, 34%) as a colourless powder.

[1276] .sup.1H NMR (DMSO-d6) 10.92 (s, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.89 (s, 1H), 7.01 (d, J=9.2 Hz, 1H), 6.89 (dd, J=5.3, 1.5 Hz, 1H), 6.75 (s, 1H), 6.61 (s, 1H), 4.60 (sept, J=6.7 Hz, 1H), 3.89 (s, 3H), 2.94 (t, J=7.4 Hz, 2H), 2.66 (t, J=7.5 Hz, 2H), 2.03 (p, J=7.5 Hz, 2H), 1.44 (d, J=6.7 Hz, 6H).

[1277] LCMS m/z 474.4 (M+H).sup.+ (ES.sup.+); 472.3 (MH).sup. (ES.sup.).

Example 56: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

[1278] ##STR00374##

[1279] Prepared according to the general procedure for N-((4-fluoro-2-iso-propyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonamide (Example 1) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl) ((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P3) and 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35) to afford the title compound (20.7 mg, 30%) as a colourless powder.

[1280] .sup.1H NMR (DMSO-d6) 10.86 (s, 1H), 8.12 (d, J=5.4 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.90 (s, 1H), 7.21 (d, J=7.7 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.87 (dd, J=5.3, 1.4 Hz, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 4.60 (sept, J=6.3 Hz, 1H), 3.88 (s, 3H), 20.91 (t, J=7.4 Hz, 2H), 2.62 (t, J=7.4 Hz, 2H), 1.97 (p, J=7.4 Hz, 2H), 1.44 (d, J=6.7 Hz, 6H).

[1281] LCMS m/z 456.4 (M+H).sup.+ (ES.sup.+); 454.3 (MH).sup. (ES.sup.).

Example 57: 1-(2-(Dimethylamino)ethyl)-N-((4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1H-pyrazole-3-sulfonamide

[1282] ##STR00375##

[1283] To a solution of 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A1) (0.5 g, 2.17 mmol, 1 eq) and triethylamine (439 mg, 4.34 mmol, 604.43 L, 2 eq) in THF (10 mL) was added triphosgene (257 mg, 868.51 mol, 0.4 eq) in portions at 5 C. Then the reaction mixture was heated to 70 C. and stirred for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and the resulting mixture was filtered. The filtrate was concentrated in vacuo to give 3-(5-fluoro-2-isocyanato-3-isopropylphenyl)pyridine (0.2 g, crude) as a yellow oil. To a solution of 1-(2-(dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P9) (100 mg, 458.14 mol, 1 eq) in THF (10 mL) was added MeONa (29 mg, 549.76 mol, 1.2 eq) and the previously prepared 3-(5-fluoro-2-isocyanato-3-isopropylphenyl)pyridine (129 mg, 503.95 mol, 1.1 eq). Then the solution was stirred at 70 C. for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by preparative reversed phase HPLC (see Experimental Methods, preparative reversed phase HPLC method 3) to give the title compound (19.52 mg, 40.72 mol, 9% yield, 99% purity) as a yellow solid.

[1284] .sup.1H NMR (DMSO-d.sub.6) 8.51-8.48 (m, 2H), 7.70 (s, 2H), 7.49 (s, 1H), 7.28-7.26 (m, 1H), 7.10 (dd, 1H), 6.97 (dd, 1H), 6.28 (s, 1H), 4.20 (t, 2H), 3.14-3.12 (m, 1H), 2.67-2.62 (m, 2H), 2.18 (s, 6H) and 1.08 (dd, 6H).

[1285] LCMS: m/z 475 (M+H).sup.+ (ES.sup.+).

Example 58: 3-(Diethylamino)-N-((4-fluoro-2-isopropyl-6-(pyridin-3-yl) phenyl)carbamoyl)propane-1-sulfonamide

[1286] ##STR00376##

[1287] To a solution of 3-(diethylamino)propane-1-sulfonamide (Intermediate P32) (200 mg, 1.03 mmol, 1 eq) in THF (5 mL) was added NaOMe (56 mg, 1.03 mmol, 1 eq) and 3-(5-fluoro-2-isocyanato-3-isopropylphenyl)pyridine (Intermediate A41) (263.80 mg, 1.03 mmol, 1 eq). The reaction mixture was stirred at 70 C. for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini, 250 mm*25 mm*5 m; mobile phase: [A: water (0.04% ammonium hydroxide v/v); B: MeCN]; B %: 18%-39%, 10 min) to give the title compound (58.2 mg, 11% yield, 100% purity on LCMS) as a brown solid.

[1288] .sup.1H NMR (DMSO-d.sub.6): 8.59 (br s, 1H), 8.50 (dd, 1H), 7.83-7.81 (m, 1H), 7.38 (dd 2H), 7.12 (dd, 1H), 6.97 (d, 1H), 3.29-3.25 (m, 1H), 2.75-2.73 (m, 2H), 2.49-2.43 (m, 6H), 1.64-1.60 (m, 2H), 1.16 (d, 6H) and 0.97 (t, 6H).

[1289] LCMS: m/z 451.2 (M+H).sup.+ (ES.sup.+).

Example 61: 1-(2-(Dimethylamino)ethyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

[1290] ##STR00377##

[1291] 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35) (100 mg, 0.416 mmol) was dissolved in dry THF (5 mL). Triethylamine (70 L, 0.502 mmol) was added, followed by a solution of bis(trichloromethyl) carbonate (123 mg, 0.416 mmol) in THF (1 mL). The slurry was stirred at room temperature for two hours before being filtered. The solid was washed with THF (5 mL) and DCM (5 mL) and then the filtrate was concentrated in vacua to give 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine as a pale yellow solid that was used without further purification. 1-(2-(Dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide (45 mg, 0.206 mmol) (Intermediate P9) was dissolved in dry THF (2 mL). Sodium tert-butoxide (2 M in THF) (104 L, 0.208 mmol) was added and the mixture was stirred at room temperature for 30 minutes. A solution of 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (55 mg, 0.205 mmol) in DMF (2 mL) was added and the mixture was stirred overnight. The THF was removed in vacua. DMSO (1 mL) was added and the resulting solution was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (16 mg, 16%) as a colourless powder.

[1292] .sup.1H NMR (DMSO-d6) 10.70 (br s, 1H), 8.12 (dd, J=5.3, 0.7 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.86 (s, 1H), 7.20 (d, J=7.7 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.87 (dd, J=5.3, 1.5 Hz, 1H), 6.73-6.71 (m, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.31 (t, J=6.5 Hz, 2H), 3.89 (s, 3H), 2.91 (t, J=7.5 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 2.23 (s, 6H), 1.99 (p, J=7.5 Hz, 2H).

[1293] LCMS; m/z 485.4 (M+H)+ (ES+); 483.3 (MH) (ES).

Example 64: 5-((Dimethylamino)methyl)-1-ethyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

[1294] ##STR00378##

[1295] Prepared according to the general procedure of 1-(2-(dimethylamino)ethyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 61) from 5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate P7) and 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35) to afford the title compound (29 mg, 28%) as a colourless powder.

[1296] .sup.1H NMR (DMSO-d6) 10.81 (s, 1H), 8.13 (dd, J=5.3, 0.7 Hz, 1H), 7.92 (s, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.87 (dd, J=5.3, 1.5 Hz, 1H), 6.73-6.71 (m, 1H), 6.56 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.89 (s, 3H), 3.50 (s, 2H), 2.91 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.17 (s, 6H), 1.96 (p, J=7.5 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).

[1297] LCMS; m/z 499.4 (M+H)+ (ES+); 497.3 (MH) (ES).

[1298] The compounds of examples 59, 60, 62, 63 and 65-69 were synthesised by methods analogous to those outlined above and below.

TABLE-US-00002 TABLE 1 .sup.1H NMR and MS data Ex Structure and Name 1H NMR spectrum MS MW 59 [00379] N-((7-Fluoro-5-(pyridin-3-yl)-2,3- 1H NMR (400 MHz, DMSO-d6) 10.94 (s, 1H), 8.56 (dd, J = 4.8, 1.7 Hz, 1H), 8.48 (s, 1H), 7.84 (s, 1H), 7.75-7.70 (m, 1H), 7.43 (dd, J = 7.9, 4.9 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.96 (s, 1H), 4.89 (d, J = 7.3 Hz, 2H), 4.80 (d, J = 7.4 Hz, 2H), 3.76 (s, 3H), 2.98 (s, 3H) 2.95 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.04 (p, J = 7.6 Hz, 2H). m/z 502.4 (M + H)+ (ES+); 500.3 (M H) (ES) 501.53 dihydro-1H-inden-4-yl)carbamoyl)-5- (3-methoxyoxetan-3-yl)-1-methyl-1H- pyrazole-3-sulfonamide 60 [00380] 1H NMR (400 MHz, DMSO-d6) 8.52-8.48 (m, 2H), 7.75-7.70 (m, 3H), 7.34-7.32 (m, 1H), 7.18-7.15 (m, 1H), 7.03- 7.02 (m, 1H), 6.43 (s, 1H), 5.05 (s, 1H), 4.11-3.96 (m, 3H), 3.07-3.05 (m, 1H), 1.09 (d, J = 6.4 Hz, 6H), 1.04 (d, J = 6.4 Hz, 3H). m/z 462.2 (M + H)+ 461.51 (R)-N-((4-Fluoro-2-isopropyl-6- (pyridin-3-yl)phenyl)carbamoyl)-1-(2- hydroxypropyl)-1H-pyrazole-3- sulfonamide 61 [00381] 1-(2-(Dimethylamino)ethyl)-N-((5-(2- 1H NMR (500 MHz, DMSO-d6) 10.70 (br s, 1H), 8.12 (dd, J = 5.3, 0.7 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.87 (dd, J = 5.3, 1.5 Hz, 1H), 6.73-6.71 (m, 1H), 6.58 (d, J = 2.4 Hz, 1H), 4.31 (t, J = 6.5 Hz, 2H), 3.89 (s, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.23 (s, 6H), 1.99 (p, J = 7.5 Hz, 2H). m/z 485.4 (M + H)+ (ES+); 483.3 (M H) (ES) 484.57 methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 62 [00382] 1-(2-(Dimethylamino)ethyl)-N-((7- 1H NMR (400 MHz, DMSO-d6) 8.55 (dd, J = 4.8, 1.7 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.83 (s, 1H), 7.73-7.68 (m, 1H), 7.40 (dd, J = 7.9, 4.9 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 4.33 (t, J = 6.5 Hz, 2H), 2.96 (t, J = 7.4 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.26 (s, 6H), 2.06 (p, J = 7.4 Hz, 2H); NH not observed. m/z 473.4 (M + H)+ (ES+); 471.0 (M H) (ES) 472.54 fluoro-5-(pyridin-3-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 63 [00383] 1H NMR (400 MHz, DMSO-d6) 10.60 (s, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.85 (s, 1H), 7.00 (d, J = 9.2 Hz, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 4.32 (t, J = 6.5 Hz, 2H), 3.89 (s, 3H), 2.95 (t, J = 7.4 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.26 (s, 6H), 2.05 (p, J = 7.6 Hz, 2H). m/z 503.5 (M + H)+ (ES+); 501.2 (M H) (ES) 502.56 1-(2-(Dimethylamino)ethyl)-N-((7- fluoro-5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 64 [00384] 5-((Dimethylamino)methyl)-1-ethyl-N- 1H NMR (500 MHz, DMSO-d6) 10.81 (s, 1H), 8.13 (dd, J = 5.3, 0.7 Hz, 1H), 7.92 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.87 (dd, J = 5.3, 1.5 Hz, 1H), 6.73-6.71 (m, 1H), 6.56 (s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 3.50 (s, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.17 (s, 6H), 1.96 (p, J = 7.5 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). m/z 499.4 (M + H)+ (ES+); 497.3 (M H) (ES) 498.6 ((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 65 [00385] 5-((Dimethylamino)methyl)-1-ethyl-N- 1H NMR (400 MHz, DMSO-d6) 10.83 (s, 1H), 8.56 (dd, J = 4.8, 1.6 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 7.90 (s, 1H), 7.72- 7.68 (m, 1H), 7.43-7.39 (m, 1H), 7.03 (d, J = 9.2 Hz, 1H), 6.54 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.51 (s, 2H), 2.95 (t, J = 7.4 Hz, 2H), 2.68 (t, J = 7.3 Hz, 2H), 2.18 (s, 6H), 2.03 (p, J = 7.6 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). m/z, 487.5 (M + H)+ (ES+); 485.3 (M H) (ES) 486.56 ((7-fluoro-5-(pyridin-3-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1H-pyrazole- 3-sulfonamide 66 [00386] 5-((Dimethylamino)methyl)-1-ethyl-N- 1H NMR (400 MHz, DMSO-d6) 10.85 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.90 (s, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.75 (s, 1H), 6.56 (s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 3.51 (s, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.66 (t, J = 7.1 Hz, 2H), 2.18 (s, 6H), 2.02 (p, J = 7.6 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H). m/z 517.4 (M + H)+ (ES+); 515.3 (M H) (ES) 516.59 ((7-fluoro-5-(2-methoxypyridin-4-yl)- 2,3-dihydro-1H-inden-4-yl)carbamoyl)- 1H-pyrazole-3-sulfonamide 67 [00387] 1H NMR (400 MHz, DMSO-d6) 10.86 (s, 1H), 8.53 (d, J = 5.0 Hz, 1H), 8.16 (d, J = 2.7 Hz, 1H), 7.96 (s, 2H), 7.69 (s, 1H), 7.49 (dd, J = 5.1, 1.8 Hz, 1H), 7.25 (dd, J = 10.1, 3.0 Hz, 1H), 7.10 (dd, J = 8.8, 2.9 Hz, 1H), 6.41 (s, 1H), 3.86 (s, 3H), 3.47 (s, 2H), 3.17-2.96 (m, 1H), 2.16 (s, 6H), 1.11 (br s, 6H). m/z 518.4 (M + H)+ (ES+); 516.3 (M H) (ES) 517.58 4-(2-(3-((5-((Dimethylamino)methyl)-1- methyl-1H-pyrazol-3- yl)sulfonyl)ureido)-5-fluoro-3- isopropylphenyl)picolinamide 68 [00388] N-((5-(3-Cyanophenyl)-2,3-dihydro-1H- .sup.1H NMR (DMSO-d6) 10.82 (s, 1H), 7.94 (s, 1H), 7.82-7.79 (m, 1H), 7.73- 7.72 (m, 1H), 7.63-7.53 (m, 2H), 7.23 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 6.52 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.49 (s, 2H), 2.92 (t, J = 7.4 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 2.17 (s, 6H), 1.98 (p, J = 7.5 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H). m/z 493.0 (M + H)+ (ES+); 491.3 (M H) (ES). 492.6 inden-4-yl)carbamoyl)-5- ((dimethylamino)methyl)-1-ethyl-1H- pyrazole-3-sulfonamide 69 [00389] 1-(1-(Dimethylamino)-2-methylpropan- 1H NMR (DMSO-d6) 10.84 (s, 1H), 8.15 (dd, J = 5.3, 0.7 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.92 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.73-6.72 (m, 1H), 6.64 (d, J = 2.4 Hz, 1H), 3.89 (s, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.58 (s, 2H), 1.97 (p, J = 7.6 Hz, 2H), 1.92 (s, 6H), 1.53 (s, 6H). m/z 513.5 (M + H)+ (ES+) 512.62 2-yl)-N-((5-(2-methoxypyridin-4-yl)- 2,3-dihydro-1H-inden-4-yl)carbamoyl)- 1H-pyrazole-3-sulfonamide

Example 70: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1299] ##STR00390##

[1300] 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35) (0.30 g, 1.25 mmol) was dissolved in THF (10 mL). TEA (0.20 mL, 1.43 mmol) was added, followed by a solution of bis(trichloromethyl) carbonate (0.35 g, 1.18 mmol) in THF (2 mL). The mixture was stirred at room temperature for 1 hour, then concentrated in vacua and dried for 30 minutes to afford the intermediate 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine as a pale yellow solid which was used without further purification.

[1301] 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P12) (45 mg, 0.21 mmol) was dissolved in dry THF (2 mL). NaOtBu (2 M in THF) (0.125 ml, 0.250 mmol) was added and the mixture was stirred at room temperature for 1 hour. A solution of 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (prepared above) (55 mg) in THF (2 mL) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in DMSO (2 mL) and purified by basic prep-HPLC to afford the title compound (41 mg, 40%) as a colourless powder. .sup.1H NMR (DMSO-d6) 10.76 (s, 1H), 8.13 (d, J=2.6 Hz, 1H), 8.03 (dd, J=5.3, 0.7 Hz, 1H), 7.91 (s, 1H), 7.60 (dd, J=9.5, 2.6 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.83 (dd, J=5.3, 1.5 Hz, 1H), 6.65 (s, 1H), 6.47 (d, J=9.6 Hz, 1H), 4.99 (sept, J=6.8 Hz, 1H), 3.84 (s, 3H), 2.91 (t, J=7.5 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 1.98 (p, J=7.4 Hz, 2H), 1.29 (d, J=6.8 Hz, 6H).

[1302] LCMS: m/z 483.3 (M+H).sup.+ (ES.sup.+); 481.5 (MH).sup. (ES.sup.).

Example 71: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide, sodium salt

Step A: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1303] ##STR00391##

[1304] Prepared according to the general procedure of 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 70) from 4-(4-amino-2,3-dihydro-1H-inden-5-yl)picolinonitrile (Intermediate A36) (0.03 g, 0.123 mmol) and 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P12) (0.027 g, 0.123 mmol) and purified by reversed phase flash C18 chromatography (12 g column, 0-60% MeCN/10 mM ammonium bicarbonate) to afford the title compound (35 mg, 30%) as a flocculent white solid.

[1305] .sup.1H NMR (DMSO-d6) 8.56 (d, J=50.1 Hz, 1H), 7.93 (d, J=2.6 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.75 (br s, 1H), 7.59 (dd, J=5.1, 1.8 Hz, 1H), 7.51 (dd, J=9.5, 2.5 Hz, 1H), 7.17-7.12 (m, 2H), 6.32 (d, J=9.4 Hz, 1H), 4.96 (sept, J=6.7 Hz, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.4 Hz, 2H), 1.98 (p, J=7.5 Hz, 2H), 1.25 (d, J=6.8 Hz, 6H). One exchangeable proton not observed.

[1306] LCMS: m/z 478.3 (M+H).sup.+ (ES.sup.+); 476.2 (MH).sup. (ES.sup.).

Step B: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide, sodium salt

[1307] ##STR00392##

[1308] N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (0.025 g, 0.052 mmol) was treated with 0.1 M NaOH solution (520 L) and the resultant solution was freeze-dried to afford the title compound (26 mg, 99%) as a white solid.

[1309] .sup.1H NMR (DMSO-d6) 8.54 (dd, J=5.1, 0.8 Hz, 1H), 7.91-7.89 (m, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.60 (dd, J=5.1, 1.8 Hz, 1H), 7.54-7.46 (m, 2H), 7.13-7.09 (m, 2H), 6.27 (d, J=9.4 Hz, 1H), 4.97 (sept, J=6.7 Hz, 1H), 2.89 (t, J=7.5 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 1.96 (p, J=7.5 Hz, 2H), 1.25 (d, J=6.8 Hz, 6H).

[1310] LCMS: m/z 478.3 (M+H).sup.+ (ES.sup.+); 476.2 (MH).sup. (ES.sup.).

Example 72: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide, sodium salt

Step A: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide

[1311] ##STR00393##

[1312] Prepared according to the general procedure of 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 70) from 4-(4-amino-2,3-dihydro-1H-inden-5-yl)picolinonitrile (Intermediate A36) (0.03 g, 0.123 mmol) and 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (Intermediate P13) (0.027 g, 0.123 mmol) and purified by reversed phase flash C18 chromatography (12 g column, 0-60% MeCN/10 mM ammonium bicarbonate) to afford the title compound (0.023 g, 19%) as a flocculent yellow solid.

[1313] .sup.1H NMR (DMSO-d6) 8.58 (d, J=5.1 Hz, 1H), 7.93 (s, 2H), 7.89 (d, J=1.7 Hz, 1H), 7.76 (br s, 1H), 7.59 (dd, J=5.2, 1.7 Hz, 1H), 7.19-7.12 (m, 2H), 4.84 (p, J=6.8 Hz, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 1.99 (p, J=7.5 Hz, 2H), 1.28 (d, J=6.8 Hz, 6H).

[1314] LCMS: m/z 479.3 (M+H).sup.+ (ES.sup.+); 477.2 (MH).sup. (ES.sup.).

Step B: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide, sodium salt

[1315] ##STR00394##

[1316] N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (0.015 g, 0.031 mmol) was treated with 0.1 M NaOH solution (310 L) and the resultant solution was freeze-dried to afford the title compound (16 mg, quant. yield) as a yellow solid.

[1317] .sup.1H NMR (DMSO-d6) 8.56 (d, J=5.1 Hz, 1H), 7.89 (t, J=1.6 Hz, 2H), 7.84 (d, J=1.1 Hz, 1H), 7.67-7.56 (m, 2H), 7.13-7.09 (m, 2H), 4.85 (sept, J=6.8 Hz, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.77 (t, J=7.3 Hz, 2H), 1.98 (p, J=7.5 Hz, 2H), 1.28 (d, J=6.8 Hz, 6H).

[1318] LCMS: m/z 479.3 (M+H).sup.+ (ES.sup.+); 477.1 (MH).sup. (ES.sup.).

Example 73: 4-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-oxo-4,5-dihydropyrazine-2-sulfonamide, partial ammonium salt

[1319] ##STR00395##

[1320] Prepared according to the general procedure of 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 70) from 4-isopropyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (Intermediate P13) (26 mg, 0.12 mmol) and 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35) (50 mg, 0.21 mmol) to afford the title compound (13.2 mg, 23%).

[1321] .sup.1H NMR (DMSO-d6) 8.09 (s, 1H), 8.05 (d, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.71 (s, 1H), 7.16 (d, J=7.7 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.86 (d, J=5.3 Hz, 1H), 6.65 (s, 1H), 4.86 (sept, J=7.2, 6.7 Hz, 1H), 3.86 (s, 3H), 2.90 (t, J=7.4 Hz, 2H), 2.69 (t, J=7.5 Hz, 2H), 1.98 (p, J=7.4 Hz, 2H), 1.30 (d, J=6.7 Hz, 6H).

[1322] LCMS: m/z 484.3 (M+H).sup.+ (ES.sup.+).

Example 74: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-isopropylazetidine-3-sulfonamide

[1323] ##STR00396##

[1324] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P14) (70 mg, 392.70 mol, 1 eq) in THF (2 mL) was added t-BuONa (37 mg, 392.70 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A37) (110 mg, 392.70 mol, 1 eq) was added. The reaction mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 12%-42%, 11.5 min) to give the title compound (80.02 mg, 43% yield, 96% purity on LCMS) as a white solid.

[1325] .sup.1H NMR (DMSO-d.sub.6) 8.75 (d, 1H), 8.06 (s, 1H), 7.77-7.66 (m, 2H), 7.21 (dd, 1H), 7.12 (dd, 1H), 3.78-3.49 (m, 4H), 3.26-3.22 (d, 2H), 2.83-2.79 (m, 1H), 1.15 (d, 6H) and 0.95 (d, 6H). One exchangeable proton not observed.

[1326] LCMS: m/z 460.2 (M+H).sup.+ (ES.sup.+).

Example 75: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-isopropylazetidine-3-sulfonamide

[1327] ##STR00397##

[1328] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P14) (70 mg, 392.70 mmol, 1 eq) in THF (2 mL) was added t-BuONa (38 mg, 392.70 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) (112 mg, 392.70 mol, 1 eq) was added. The mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 12%-42%, 11.5 min) to give the title compound (87.88 mg, 48% yield, 99% purity on LCMS) as a white solid.

[1329] .sup.1H NMR (DMSO-d.sub.6) 8.11 (d, 1H), 7.17 (br s, 1H), 7.11 (d, 1H), 7.01 (s, 1H), 6.93 (d, 1H), 6.85 (s, 1H), 3.86 (s, 3H), 3.81-3.77 (m, 1H), 3.26-3.22 (m, 1H), 3.18-3.15 (m, 2H), 3.03-3.00 (m, 2H), 2.22-1.98 (m, 1H), 1.16-1.12 (m, 6H) and 0.80 (d, 6H). One exchangeable proton not observed.

[1330] LCMS: m/z 465.2 (M+H).sup.+ (ES.sup.+).

Example 76: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)azetidine-3-sulfonamide

[1331] ##STR00398##

[1332] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P14) (70 mg, 392.70 mol, 1 eq) in THF (2 mL) was added t-BuONa (38 mg, 392.70 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (104 mg, 392.70 mol, 1 eq) was added. The mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (56.2 mg, 32% yield, 100% purity on LCMS) as a white solid.

[1333] .sup.1H NMR (DMSO-d.sub.6) 8.13 (d, 1H), 7.49 (br s, 1H), 7.12 (d, 1H), 7.07 (d, 1H), 6.98 (d, 1H), 6.79 (s, 1H), 4.00-3.94 (m, 1H), 3.87 (s, 3H), 3.70-3.64 (m, 2H), 3.58-3.54 (m, 2H), 2.91 (t, 2H), 2.83 (t, 2H), 2.76-2.73 (m, 1H), 2.04-1-97 (m, 2H) and 0.94 (d, 6H). One exchangeable proton not observed.

[1334] LCMS: m/z 445.2 (M+H).sup.+ (ES.sup.+).

Example 77: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-isopropylazetidine-3-sulfonamide

[1335] ##STR00399##

[1336] A mixture of 1-isopropylazetidine-3-sulfonamide (Intermediate P14) (50 mg, 280.50 mol, 1 eq) and t-BuONa (27 mg, 280.50 mol, 1 eq) in THF (2 mL) was stirred at 25 C. for 10 minutes. 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A40) (71 mg, 280.50 mol, 1 eq) was added and the resulting mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 12%-42%, 10 min) to give the title compound (7.96 mg, 7% yield, 100% purity on LCMS) as a white solid.

[1337] .sup.1H NMR (DMSO-d.sub.6) 8.55 (d, 2H), 7.4-7.38 (m, 3H), 6.95 (d, 1H), 3.94-3.88 (m, 1H), 3.70-3.67 (m, 2H), 3.61-3.58 (m, 2H), 2.95 (t, 2H), 2.86 (t, 2H), 2.82-2.75 (m, 1H), 2.10-2.02 (m, 2H) and 0.96 (d, 6H). One exchangeable proton not observed.

[1338] LCMS: m/z 433.2 (M+H).sup.+ (ES.sup.+).

Example 78: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-cyclobutylazetidine-3-sulfonamide

[1339] ##STR00400##

[1340] A solution of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P15) (30 mg, 157.68 mol, 1 eq) and t-BuONa (15 mg, 157.68 mol, 1 eq) in THF (1 mL) was stirred at 25 C. for 10 minutes. 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A37) (44 mg, 157.68 mol, 1 eq) was added and the resulting mixture was stirred at 25 C. for 10 minutes. Then the reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (Column: Waters Xbridge C18, 150 mm*25 mm*5% m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (6.35 mg, 8% yield, 97% purity on LCMS) as a white solid.

[1341] .sup.1H NMR (DMSO-d.sub.6) 8.75 (d, 1H), 8.05 (s, 1H), 7.77-7.75 (m, 1H), 7.67-7.65 (m, 1H), 7.23-7.18 (m, 1H), 7.12 (d, 1H), 3.95-3.68 (m, 2H), 3.67-3.56 (m, 2H), 3.55-3.42 (m, 2H), 3.25-3.21 (m, 1H), 1.99-1.97 (m, 2H), 1.86-1.84 (m, 2H), 1.71-1.62 (m, 2H) and 1.16 (d, 6H). One exchangeable proton not observed.

[1342] LCMS: m/z 472.2 (M+H).sup.+ (ES.sup.+).

Example 79: 1-Cyclobutyl-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)azetidine-3-sulfonamide

[1343] ##STR00401##

[1344] To a solution of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P15) (25 mg, 131.40 mol, 1 eq) in THF (1 mL) was added t-BuONa (13 mg, 131.40 mol, 1 eq). The reaction mixture was stirred at 20 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) (38 mg, 131.40 mol, 1 eq) was added and the resulting mixture was stirred at 20 C. for 20 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 15%-45%, 10 min) to give the title compound (41.16 mg, 66% yield, 100% purity on LCMS) as a white solid.

[1345] .sup.1H NMR (DMSO-d.sub.6) 8.16 (d, 1H), 7.61 (br s, 1H), 7.16 (d, 1H), 7.03-6.96 (m, 2H), 6.83 (s, 1H), 4.02-3.92 (m, 1H), 3.88 (s, 3H), 3.75-3.48 (m, 4H), 3.22-3.02 (m, 2H), 2.15-1.95 (m, 2H), 1.94-1.76 (m, 2H), 1.74-1.56 (m, 2H) and 1.14 (d, 6H). One exchangeable proton not observed.

[1346] LCMS: m/z 477.2 (M+H).sup.+ (ES.sup.+).

Example 80: 1-Cyclobutyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)azetidine-3-sulfonamide

[1347] ##STR00402##

[1348] A mixture of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P15) (40 mg, 210.24 mol, 1 eq) and t-BuONa (20 mg, 210.24 mol, 1 eq) in THF (2 mL) was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (56 mg, 210.24 mol, 1 eq) was added and the resulting mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 10%-40%, 10 min) to give the title compound (20.06 mg, 21% yield, 100% purity on LCMS) as a white solid.

[1349] .sup.1H NMR (DMSO-d.sub.6) 8.13 (d, 1H), 7.40 (br s, 1H), 7.12 (d, 1H), 7.06 (d, 1H), 6.96 (d, 1H), 6.77 (s, 1H), 4.06-3.98 (m, 1H), 3.87 (s, 3H), 3.49-3.44 (m, 3H), 3.38-3.35 (m, 2H), 2.91 (t, 2H), 2.82 (t, 2H), 2.03-1.99 (m, 2H), 1.98-1.94 (m, 2H), 1.85-1.81 (m, 2H) and 1.71-1.62 (m, 2H). One exchangeable proton not observed.

[1350] LCMS: m/z 457.3 (M+H).sup.+ (ES.sup.+).

Example 81: 1-Cyclobutyl-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)azetidine-3-sulfonamide

[1351] ##STR00403##

[1352] A mixture of 1-cyclobutylazetidine-3-sulfonamide (Intermediate P15) (37 mg, 194.47 mol, 1 eq) and t-BuONa (19 mg, 194.47 mol, 1 eq) in THF (2 mL) was stirred at 25 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A40) (49 mg, 194.47 mol, 1 eq) was added and the resulting mixture was stirred at 25 C. for 10 minutes. Then the reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 0%-30%, 10 min) to give the title compound (18.09 mg, 20% yield, 97% purity on LCMS) as a yellow solid.

[1353] .sup.1H NMR (DMSO-d.sub.6) 8.57 (d, 2H), 7.57 (br s, 1H), 7.39 (d, 2H), 6.97 (d, 1H), 4.02-3.95 (m, 1H), 3.70-3.66 (m, 3H), 3.57-3.54 (m, 1H), 3.37-3.27 (m, 1H), 2.96 (t, 2H), 2.86 (t, 2H), 2.11-2.00 (m, 4H), 1.92-1.87 (m, 2H) and 1.72-1.65 (m, 2H). One exchangeable proton not observed.

[1354] LCMS: m/z 445.2 (M+H).sup.+ (ES.sup.+).

Example 82: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-ethylazetidine-3-sulfonamide

[1355] ##STR00404##

[1356] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P16) (40 mg, 243.57 mol, 1 eq) in THF (1 mL) was added t-BuONa (23 mg, 243.57 mol, 1 eq). The mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-picolinonitrile (Intermediate A37) (68 mg, 243.57 mol, 1 eq) was added and the mixture was stirred at 70 C. for 10 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (48.97 mg, 45% yield, 100% purity on LCMS) as a white solid.

[1357] .sup.1H NMR (DMSO-d.sub.6) 8.75 (d, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.22-7.18 (m, 1H), 7.12-7.09 (m, 1H), 3.83-3.76 (m, 5H), 3.24-3.20 (m, 1H), 2.93-2.88 (m, 2H), 1.16 (d, 6H) and 0.99 (t, 3H). One exchangeable proton not observed.

[1358] LCMS: m/z 446.2 (M+H).sup.+ (ES.sup.+).

Example 83: 1-Ethyl-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) phenyl)carbamoyl)azetidine-3-sulfonamide

[1359] ##STR00405##

[1360] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P16) (40 mg, 243.57 mol, 1 eq) in THF (1 mL) was added t-BuONa (23 mg, 243.57 mol, 1 eq). The mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) (69 mg, 243.57 mol, 1 eq) was added and the mixture was stirred at 75 C. for another 10 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (46.05 mg, 42% yield, 100% purity on LCMS) as a white solid.

[1361] .sup.1H NMR (DMSO-d.sub.6) 8.15 (d, 1H), 7.48 (s, 1H), 7.17-7.12 (m, 1H), 7.03-6.94 (m, 2H), 6.84 (s, 1H), 3.99-3.77 (m, 8H), 3.24-3.20 (m, 1H), 2.95-2.92 (m, 2H), 1.15 (d, 6H) and 1.00 (t, 3H). One exchangeable proton not observed.

[1362] LCMS: m/z 451.2 (M+H).sup.+ (ES.sup.+).

Example 84: 1-Ethyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)azetidine-3-sulfonamide

[1363] ##STR00406##

[1364] To a solution of 1-ethylazetidine-3-sulfonamide (Intermediate P16) (40 mg, 243.57 mol, 1 eq) in THF (1 mL) was added t-BuONa (23 mg, 243.57 mol, 1 eq). The mixture was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (64 mg, 243.57 mol, 1 eq) was added and the mixture was stirred at 70 C. for 10 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (52.99 mg, 51% yield, 100% purity on LCMS) as a white solid.

[1365] .sup.1H NMR (DMSO-d.sub.6) 8.13 (d, 1H), 7.43 (br s, 1H), 7.12 (d, 1H), 7.06 (d, 1H), 6.97 (dd, 1H), 6.79 (s, 1H), 4.08-4.00 (m, 1H), 3.88 (s, 3H), 3.85-3.80 (m, 2H), 3.77-3.72 (m, 2H), 2.91 (t, 2H), 2.87-2.80 (m, 4H), 2.04-1.96 (m, 2H) and 0.98 (t, 3H). One exchangeable proton not observed.

[1366] LCMS: m/z 431.2 (M+H).sup.+ (ES.sup.+).

Example 85: 1-Ethyl-N-((7-fluoro-5(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)azetidine-3-sulfonamide

[1367] ##STR00407##

[1368] A solution of 1-ethylazetidine-3-sulfonamide (Intermediate P16) (50 mg, 304.46 mol, 1 eq) and t-BuONa (29 mg, 304.46 mol, 1 eq) in THF (1 mL) was stirred at 25 C. for 10 minutes. Then a solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl) pyridine (Intermediate A40) (77 mg, 304.46 mol, 1 eq) in THF (2 mL) was added and the reaction mixture was stirred at 25 C. for 10 minutes. Then the reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (9.59 mg, 8% yield, 100% purity on LCMS) as a white solid.

[1369] .sup.1H NMR (DMSO-d.sub.6) 8.57 (d, 2H), 7.43 (br s, 1H), 7.40 (d, 2H), 6.96 (d, 1H), 4.01-3.88 (m, 5H), 2.98-2.93 (m, 4H), 2.86 (t, 2H), 2.11-2.03 (m, 2H) and 1.01 (t, 3H). One exchangeable proton not observed.

[1370] LCMS: m/z 419.2 (M+H).sup.+ (ES.sup.+).

Example 86: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide

[1371] ##STR00408##

[1372] A solution of 1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (Intermediate P17) (50 mg, 219.99 mol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A37) (68 mg, 241.99 mol, 1.1 eq) and t-BuONa (25 mg, 263.99 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %: 15%-45%, 12 min) to give the title compound (10 mg, 9%) as a white solid.

[1373] .sup.1H NMR (DMSO-d.sub.6) 8.74 (d, 1H), 8.50-8.47 (m, 2H), 8.05 (s, 1H), 8.00 (br s, 1H), 7.73 (d, 1H), 7.68 (d, 1H), 7.39-7.35 (m, 1H), 7.29-7.25 (m, 1H), 7.16 (d, 1H), 4.03-3.97 (m, 1H), 3.73-3.68 (m, 2H), 3.45-3.38 (m, 4H), 3.19-3.15 (m, 1H) and 1.14 (d, 6H). One exchangeable proton not observed.

[1374] LCMS: m/z 509.3 (M+H).sup.+ (ES.sup.+).

Example 87: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide

[1375] ##STR00409##

[1376] A solution of 1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (Intermediate P17) (50 mg, 219.99 mol, 1 eq), 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (64 mg, 241.99 mol, 1.1 eq) and t-BuONa (25 mg, 263.99 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %: 15%-45%, 12 min) to give the title compound (37 mg, 34%) as a white solid.

[1377] .sup.1H NMR (DMSO-d.sub.6) 8.49-8.45 (m, 2H), 8.12 (d, 1H), 7.79 (br s, 1H), 7.67 (d, 1H), 7.38-7.33 (m, 1H), 7.18 (d, 1H), 7.09 (d, 1H), 6.92 (d, 1H), 6.73 (s, 1H), 4.19-4.15 (m, 1H), 3.80 (s, 3H), 3.66 (s, 2H), 3.50-3.43 (m, 2H), 3.38-3.34 (m, 2H), 2.91 (t, 2H), 2.78 (t, 2H) and 2.04-1.98 (m, 2H). One exchangeable proton not observed.

[1378] LCMS: m/z 494.2 (M+H).sup.+ (ES.sup.+).

Example 88: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide

[1379] ##STR00410##

[1380] To a solution of 1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (Intermediate P17) (54 mg, 235.98 mol, 1 eq) in THF (5 mL) was added t-BuONa (27 mg, 283.18 mol, 1.2 eq) and a solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A40) (60 mg, 235.98 mol, 1 eq) in THF (5 mL) and DCM (5 mL). The reaction mixture was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %: 5%-50%, 10 min) to give the title compound (35.53 mg, 31% yield, 99.4% purity on LCMS) as a white solid.

[1381] .sup.1H NMR (DMSO-do) 8.56-8.54 (m, 2H), 8.49-8.47 (m, 2H), 7.76 (br s, 1H), 7.68 (d, 1H), 7.36 (dd, 3H), 7.00 (d, 1H), 4.17-4.12 (m, 1H), 3.68 (s, 2H), 3.47 (t, 2H), 3.40 (t, 2H), 2.96 (t, 2H), 2.84 (t, 2H) and 2.11-2.03 (m, 2H). One exchangeable proton not observed.

[1382] LCMS: m/z 482.2 (M+H).sup.+ (ES.sup.+).

Example 89: N-((2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1383] ##STR00411##

[1384] A solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P12) (60 mg, 225.09 mol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-picolinonitrile (Intermediate A37) (70 mg, 247.60 mol, 1.1 eq) and t-BuONa (26 mg, 270.11 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %: 15%-45%, 12 min) to give the title compound (30 mg, 26%) as a white solid.

[1385] .sup.1H NMR (DMSO-d.sub.6) 8.57 (d, 1H), 7.99-7.92 (m, 3H), 7.64-7.62 (m, 1H), 7.47-7.45 (m, 1H), 7.25-7.22 (m, 1H), 7.14-7.11 (m, 1H), 6.36 (d, 1H), 4.99-4.91 (m, 1H), 3.10-3.05 (m, 1H), 1.25 (d, 6H) and 1.09 (d, 6H). One exchangeable proton not observed.

[1386] LCMS: m/z 498.3 (M+H).sup.+ (ES.sup.+).

Example 90: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1387] ##STR00412##

[1388] A solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P12) (60 mg, 225.09 mol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) (71 mg, 247.60 mol, 1.1 eq) and t-BuONa (26 mg, 270.11 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 2%-32%, 10 min) to give the title compound (61 mg, 54%) as a white solid.

[1389] .sup.1H NMR (DMSO-d.sub.6) 7.97 (d, 2H), 7.51 (d, 2H), 7.13 (dd, 1H), 6.96-6.89 (m, 2H), 6.73 (s, 1H), 6.35 (d, 1H), 5.00-4.95 (m, 1H), 3.83 (s, 3H), 3.09-3.04 (m, 1H), 1.25 (d, 6H) and 1.05 (d, 6H). One exchangeable proton not observed.

[1390] LCMS: m/z 503.2 (M+H).sup.+ (ES.sup.+).

Example 91: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[1391] ##STR00413##

[1392] A solution of 1-isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P12) (50 mg, 187.58 mol, 1 eq), 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A40) (52 mg, 206.34 mol, 1.1 eq) and t-BuONa (22 mg, 225.10 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %:12%-42%, 12 min) to give the title compound (6 mg, 7% yield, 99.17% purity on LCMS) as a white solid.

[1393] .sup.1H NMR (DMSO-d.sub.6) 8.46 (d, 2H), 8.08 (s, 1H), 7.83 (br s, 1H), 7.58 (dd, 1H), 7.26 (d, 2H), 6.99 (d, 1H), 6.45 (d, 1H), 5.02-4.94 (m, 1H), 2.94 (t, 2H), 2.71 (t, 2H), 2.07-2.01 (m, 2H) and 1.28 (d, 6H). One exchangeable proton not observed.

[1394] LCMS: m/z 471.2 (M+H).sup.+ (ES.sup.+).

Example 92: N-((4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-isopropylazetidine-3-sulfonamide

[1395] ##STR00414##

[1396] To a solution of 1-isopropylazetidine-3-sulfonamide (Intermediate P14) (200 mg, 1.12 mmol, 1 eq) in THF (5 mL) was added MeONa (60 mg, 1.12 mmol, 1 eq). The reaction mixture was stirred at 25 C. for 30 minutes. Then 3-(5-fluoro-2-isocyanato-3-isopropylphenyl)pyridine (Intermediate A41) (431 mg, 1.68 mmol, 1.5 eq) was added and the resulting mixture was stirred at 70 C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (column: Welch Ultimate XB_C18, 35 mm*235 mm*20/35 m, mobile phase: [A: water (0.05% ammonium hydroxide); B: MeCN]; B %: 0%-40%, 10 min) to give the title compound (33 mg, 7% yield, 100% purity on LCMS) as a white solid.

[1397] .sup.1H NMR (DMSO-d.sub.6) 8.60-8.51 (m, 2H), 7.92-7.77 (m, 1H), 7.57 (s, 1H), 7.44-7.40 (m, 1H), 7.14 (d, 1H), 7.00 (d, 1H), 3.92-3.74 (m, 3H), 3.29-2.95 (m, 4H), 1.26-1.10 (m, 6H) and 1.02 (d, 6H). One exchangeable proton not observed.

[1398] LCMS: m/z 435.2 (M+H).sup.+ (ES.sup.+).

Example 93: N-((4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-isopropylpiperidine-4-sulfonamide

[1399] ##STR00415##

[1400] To a solution of 1-isopropylpiperidine-4-sulfonamide (Intermediate P18) (720 mg, 3.49 mmol, 1 eq) in THF (10 mL) was added NaOMe (226 mg, 4.19 mmol, 1.2 eq) and 3-(5-fluoro-2-isocyanato-3-isopropylphenyl)pyridine (Intermediate A41) (805 mg, 3.14 mmol, 0.9 eq). Then the reaction mixture was stirred at 70 C. for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 250 mm*50 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 15%-45%, 10 min) to give the title compound (69.36 mg, 4% yield, 100% purity on LCMS) as a white solid.

[1401] .sup.1H NMR (DMSO-d.sub.6) 8.57 (s, 1H), 8.48 (d, 1H), 7.87-7.80 (m, 1H), 7.36-7.32 (m, 1H), 7.25 (s, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 6.09 (s, 1H), 2.95-2.85 (m, 1H), 2.79-2.76 (m, 2H), 2.70-2.63 (m, 2H), 1.98-1.85 (m, 2H), 1.65-1.61 (m, 2H), 1.42-1.38 (m, 2H), 1.14 (d, 6H) and 0.94 (d, 6H). One exchangeable proton not observed.

[1402] LCMS: m/z 463.4 (M+H).sup.+ (ES.sup.+).

Example 94: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide

[1403] ##STR00416##

[1404] A solution of 1-(pyridin-3-ylmethyl)azetidine-3-sulfonamide (Intermediate P17) (50 mg, 219.99 mol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) (69 mg, 241.99 mol, 1.1 eq) and t-BuONa (25 mg, 263.99 mol, 1.2 eq) in THF (1.5 mL) was stirred at 16 C. for 0.5 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (44 mg, 38%) as a white solid.

[1405] .sup.1H NMR (DMSO-d.sub.6) 8.47 (s, 2H), 8.12 (d, 1H), 7.67 (d, 2H), 7.35 (dd, 1H), 7.19 (d, 1H), 7.01-6.95 (m, 2H), 6.80 (s, 1H), 4.04-3.98 (m, 1H), 3.78 (s, 3H), 3.64 (s, 2H), 3.43-3.36 (m, 4H), 3.16-3.12 (m, 1H) and 1.12 (d, 6H). One exchangeable proton not observed.

[1406] LCMS: m/z 514.3 (M+H).sup.+ (ES.sup.+).

Example 95: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-oxo-1,2-dihydropyrimidine-5-sulfonamide, sodium salt

[1407] ##STR00417##

[1408] A suspension of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (0.033 g, 0.137 mmol) (Intermediate A35) and (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-2-oxo-1,2-dihydropyrimidin-5-yl)sulfonyl)amide (Intermediate P19) (0.069 g, 0.123 mmol) in dry MeCN (2 mL) was stirred at 50 C. for 2 hours. Then the reaction mixture was concentrated in vacua and the crude product was purified by prep-HPLC (column: Waters Xbridge C18, 19 mm*15 mm*5 m; mobile phase: [A: water (0.1% NH.sub.4HCO.sub.3); B: MeCN]; B %: 10%-40%) to afford 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-oxo-1,2-dihydropyrimidine-5-sulfonamide (0.031 g, 52%) as a flocculent white solid. The free acid (0.024 g, 0.050 mmol) was treated with 0.1 M NaOH (aq) (0.500 ml, 0.05 mmol) and the resultant solution was freeze-dried to afford the title compound (0.025 g, 99%) as a white solid.

[1409] .sup.1H NMR (DMSO-d6) 8.65 (d, J=3.0 Hz, 1H), 8.35 (d, J=3.1 Hz, 1H), 7.98 (d, J=5.2 Hz, 1H), 7.24 (br s, 1H), 7.08 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.88 (dd, J=5.3, 1.4 Hz, 1H), 6.70 (t, J=1.0 Hz, 1H), 4.76 (sept, J=6.7 Hz, 1H), 3.82 (s, 3H), 2.88 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.4 Hz, 2H), 1.94 (1), J=7.5 Hz, 2H), 1.30 (d, J=6.8 Hz, 6H).

[1410] LCMS: m/z 484.1 (M+H).sup.+ (ES.sup.+); 482.1 (MH).sup. (ES.sup.).

Example 96: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-oxo-1,2-dihydropyridine-4-sulfonamide, sodium salt

[1411] ##STR00418##

[1412] To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35) (0.156 g, 0.65 mmol) in DCM (5 mL) and saturated aqueous NaHCO.sub.3 (5 mL) was added a solution of bis(trichloromethyl) carbonate (0.079 g, 0.264 mmol) in toluene (1 mL) to the DCM layer without stirring. The reaction mixture was stirred for 1 hour, passed through a phase separator, dried (MgSO.sub.4), filtered and concentrated in vacuo to afford crude isocyanate intermediate as an orange oil which was used without further purification. The crude isocyanate intermediate was dissolved in dry THF (11 mL).

[1413] A solution of 1-isopropyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (Intermediate P20) (0.050 g, 0.224 mmol) in dry THF (3 mL) was treated with sodium tert-butoxide (2 M in THF) (0.120 ml, 0.24 mmol). The reaction mixture was stirred at room temperature for 1 hour, treated with a solution of the crude isocyanate intermediate in dry THF (4 mL) and then stirred at room temperature for 22 hours. The reaction mixture was concentrated in vacuo and the residue purified by reversed phase flash C18 chromatography (liquid load) (12 g cartridge, 5-50% MeCN/10 mM ammonium bicarbonate) to afford 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-oxo-1,2-dihydropyridine-4-sulfonamide (0.079 g, 70%) as a flocculent white solid. The free acid (0.071 g, 0.141 mmol) was treated with 0.1 M NaOH (aq) (1.410 ml, 0.141 mmol) and the mixture was freeze-dried to afford the title compound (0.073 g, 102%) as a white solid.

[1414] .sup.1H NMR (DMSO-d6) 8.06 (dd, J=5.3, 0.7 Hz, 1H), 7.87 (dd, J=6.9, 2.1 Hz, 1H), 7.76 (dd, J=7.0, 2.1 Hz, 1H), 7.30 (br s, 1H), 7.06 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 6.94 (dd, J=5.3, 1.5 Hz, 1H), 6.76 (t, J=1.0 Hz, 1H), 6.30 (t, J=6.9 Hz, 1H), 5.14 (sept, J=6.8 Hz, 1H), 3.85 (s, 3H), 2.85 (t, J=7.4 Hz, 2H), 2.67 (t, J=7.4 Hz, 2H), 1.90 (p, J=7.5 Hz, 2H), 1.30 (d, J=6.8 Hz, 6H).

[1415] LCMS: m/z 483.1 (M+H).sup.+ (ES.sup.+); 481.0 (MH).sup. (ES.sup.).

Example 97: 1-Ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt

[1416] ##STR00419##

[1417] To a solution of 1-ethylpiperidine-4-sulfonamide (Intermediate P11; 90 mg, 0.37 mmol) in THF (5 mL) was added potassium tert-butoxide (49 mg, 0.44 mmol). The mixture was stirred at room temperature for 45 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A42; 90 mg, 0.32 mmol) was added and the mixture was stirred for 2 hours room temperature. The reaction mixture was concentrated in vacua and DMSO (0.5-1 mL) was added. The mixture (filtered over cotton wool when solids were present) was submitted for purification by reversed phase column chromatography (see Experimental Methods, preparative reversed phase HPLC method 4) to afford the title compound (18 mg, 10%) as a white solid.

[1418] .sup.1H NMR (methanol-d.sub.4) 8.10 (d, 1H), 7.03 (d, 1H), 6.87 (s, 1H), 6.84 (s, 1H), 3.92 (s, 3H), 3.23 (m, 2H), 3.07 (m, 1H), 3.00 (m, 4H), 2.68 (m, 2H), 2.32-2.08 (m, 4H), 2.03 (m, 2H), 1.86 (m, 2H), 1.18 (t, 3H).

[1419] LCMS: m/z 477 (M+H).sup.+ (ES.sup.+); 475 (MH).sup. (ES.sup.).

Example 98: 1-Ethyl-N-((5(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt

[1420] ##STR00420##

[1421] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 97) using 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) and 1-ethylpiperidine-4-sulfonamide (Intermediate Pu) to afford the title compound (54 mg, 30%) as a white solid.

[1422] .sup.1H NMR (methanol-d.sub.4) 8.08 (d, 1H), 7.25-7.08 (m, 2H), 7.03 (dd, 1H), 6.86 (s, 1H), 3.92 (s, 3H), 3.39-3.17 (m, 3H), 2.95 (m, 4H), 2.71 (q, 2H), 2.33 (t, 2H), 2.22-1.97 (m, 4H), 1.97-1.72 (m, 2H), 1.18 (t, 3H).

[1423] LCMS: m/z 459 (M+H).sup.+ (ES.sup.+); 457 (MH).sup. (ES.sup.).

Example 99: N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-ethylpiperidine-4-sulfonamide, potassium salt

[1424] ##STR00421##

[1425] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 97) using 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)picolinonitrile (Intermediate A43) and 1-ethylpiperidine-4-sulfonamide (Intermediate P11) to afford the title compound (18 mg, 18%) as a white solid.

[1426] .sup.1H NMR (methanol-d.sub.4) 8.66 (dd, 1H), 7.95 (d, 1H), 7.73 (dd, 1H), 7.20 (q, 2H), 3.55 (m, 1H), 3.09 (q, 2H), 2.98 (m, 4H), 2.85 (m, 4H), 2.13 (m, 2H), 2.1-1.97 (m, 4H), 1.31 (t, 3H).

[1427] LCMS: m/z 454 (M+H).sup.+ (ES.sup.+); 452 (MH).sup. (ES.sup.).

Example 100 1-Ethyl-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) phenyl)carbamoyl)piperidine-4-sulfonamide, potassium salt

[1428] ##STR00422##

[1429] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 97) using 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) and 1-ethylpiperidine-4-sulfonamide (Intermediate P11) to afford the title compound (23 mg, 14%) as a white solid.

[1430] .sup.1H NMR (methanol-d.sub.4) 8.09 (d, 1H), 7.06 (dd, 2H), 6.88 (m, 2H), 3.92 (s, 3H), 3.72 (m, 1H), 3.19 (m, 1H), 3.08 (m, 2H), 2.49 (d, 2H), 1.87 (m, 6H), 1.23 (d, 6H), 1.12 (t, 3H).

[1431] LCMS: m/z 479 (M+H).sup.+ (ES.sup.+); 477 (MH).sup. (ES.sup.).

Example 101: 1-Ethyl-N-((5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)piperidine-4-sulfonamide, potassium salt

[1432] ##STR00423##

[1433] Prepared as described for 1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)piperidine-4-sulfonamide, potassium salt (Example 97) using 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A44) and 1-ethylpiperidine-4-sulfonamide (Intermediate P11) to afford the title compound (11 mg, 13%) as a white solid.

[1434] .sup.1H NMR (methanol-d.sub.4) 8.55-8.42 (m, 2H), 7.58-7.44 (m, 2H), 7.24-7.05 (m, 2H), 3.22 (d, 2H), 3.07 (m, 1H), 2.97 (m, 4H), 2.65 (t, 2H), 2.23 (t, 2H), 2.10 (m, 2H), 2.04-1.67 (m, 4H), 1.18 (t, 3H).

[1435] LCMS: m/z 429 (M+H).sup.+ (ES.sup.+); 427 (MH).sup. (ES.sup.).

Example 102: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-6-(dimethylamino)pyrazine-2-sulfonamide

[1436] ##STR00424##

[1437] To a solution of 6-(dimethylamino)pyrazine-2-sulfonamide (intermediate P21) (65 mg, 321.41 mol, 1 eq) in THF (2 mL) was added with t-BuONa (30 mg, 321.41 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A37) (90 mg, 321.41 mol, 1 eq) was added and the resulting mixture was stirred at 70 C. for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 18%-48%, 11.5 min) to give the title compound (75.35 mg, 48% yield, 100% purity on LCMS) as a white solid.

[1438] .sup.1H NMR (DMSO-d.sub.6): 8.57 (d, 1H), 8.05 (s, 1H), 7.96 (s, 1H), 7.64 (br s, 1H), 7.20-7.14 (m, 4H), 3.19-3.15 (m, 1H), 3.07 (s, 6H) and 1.08 (d, 6H).

[1439] LCMS: m/z 484.2 (M+H).sup.+ (ES.sup.+).

Example 103: 6-(Dimethylamino)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)pyrazine-2-sulfonamide

[1440] ##STR00425##

[1441] To a solution of 6-(dimethylamino) pyrazine-2-sulfonamide (intermediate P21) (65 mg, 321.41 mol, 1 eq) in THF (2 mL) was added with t-BuONa (30 mg, 321.41 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A38) (92 mg, 321.41 mol, 1 eq) was added. The mixture was stirred at 70 C. for 10 minutes and then concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 20%-50%, 11.5 min) to give the title compound (41.48 mg, 26% yield, 100% purity on LCMS) as a white solid.

[1442] .sup.1H NMR (DMSO-d.sub.6): 8.27 (s, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.74 (br s, 1H), 7.14 (d, 1H), 6.97 (d, 1H), 6.91 (s, 1H), 6.76 (s, 1H), 3.87 (s, 3H), 3.11 (s, 6H), 3.04-2.95 (m, 1H) and 1.25-1.02 (m, 6H).

[1443] LCMS: m/z 489.2 (M+H).sup.+ (ES.sup.+).

Example 104: 6-(Dimethylamino)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

[1444] ##STR00426##

[1445] To a solution of 6-(dimethylamino) pyrazine-2-sulfonamide (intermediate P21) (65 mg, 321.41 mol, 1 eq) in THF (2 mL) was added with t-BuONa (30 mg, 321.41 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A39) (85 mg, 321.41 mol, 1 eq) was added. The mixture was stirred at 70 C. for 10 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 18%-48%, 11.5 min) to give the title compound (96.47 mg, 64% yield, 100% purity on LCMS) as a white solid.

[1446] .sup.1H NMR (DMSO-d.sub.6): 8.23 (s, 1H), 8.14 (s, 1H), 8.06 (d, 1H), 7.65 (br s, 1H), 7.13 (d, 1H), 7.06 (d, 1H), 6.90 (d, 1H), 6.74 (s, 1H), 3.87 (s, 3H), 3.09 (s, 6H), 2.89 (t, 2H), 2.71-2.67 (m, 2H) and 2.00-1.91 (m, 2H).

[1447] LCMS: m/z 469.2 (M+H).sup.+ (ES.sup.+).

Example 105: 6-(Dimethylamino)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

[1448] ##STR00427##

[1449] A mixture of 6-(dimethylamino)pyrazine-2-sulfonamide (intermediate P21) (60 mg, 296.69 mol, 1 eq) and t-BuONa (29 mg, 296.69 mol, 1 eq) in THF (2 mL) was stirred at 25 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A40) (75 mg, 296.69 mol, 1 eq) was added. The mixture was stirred at 25 C. for 10 minutes and then concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (10 mg, 7% yield, 100% purity on LCMS) as a white solid.

[1450] .sup.1H NMR (DMSO-d.sub.6): 11.13 (br s, 1H), 8.50 (d, 2H), 8.30 (s, 1H), 8.15 (s, 1H), 7.83 (br s, 7.30 (d, 2H), 6.98 (d, 1H), 3.11 (s, 6H), 2.94 (t, 2H), 2.73-2.69 (m, 2H) and 2.08-2.00 (m, 2H).

[1451] LCMS: m/z 457.2 (M+H).sup.+ (ES.sup.+).

Example 106: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-5-(dimethylamino)pyrazine-2-sulfonamide

[1452] ##STR00428##

[1453] To a solution of 5-(dimethylamino)pyrazine-2-sulfonamide (intermediate P22) (60 mg, 296.69 mol, 1 eq) in THF (4 mL) was added t-BuONa (29 mg, 296.69 mol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A37) (83 mg, 296.69 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 11.5 min) to give the title compound (49 mg, 34% yield, 100% purity on LCMS) as a white solid.

[1454] .sup.1H NMR (DMSO-d.sub.6): 8.58 (d, 1H), 8.24 (s, 7.99 (s, 7.92 (s, 7.78 (br s, 1H), 7.60 (s, 1H), 7.20 (dd, 1H), 7.06 (dd, 1H), 3.18 (s, 6H), 3.14-1.09 (m, 1H) and 1.10 (d, 6H).

[1455] LCMS: m/z 484.2 (M+H).sup.+ (ES.sup.+).

Example 107: 5-(Dimethylamino)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)pyrazine-2-sulfonamide

[1456] ##STR00429##

[1457] To a solution of 5-(dimethylamino)pyrazine-2-sulfonamide (intermediate P22) (71 mg, 349.28 mol, 1 eq) in THF (5 mL) was added t-BuONa (34 mg, 349.28 mol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A38) (100 mg, 349.28 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 0%-30%, 10 min) to give the title compound (30 mg, 18% yield, 100% purity on LCMS) as a white solid.

[1458] .sup.1H NMR (DMSO-d.sub.6): 8.40 (s, 1H), 8.12 (s, 1H), 8.06 (d, 1H), 7.73 (br s, 1H), 7.16 (dd, 1H), 6.99-6.96 (m, 1H), 6.82 (d, 1H), 6.72 (s, 1H), 3.87 (s, 3H), 3.18 (s, 6H), 2.95-2.91 (m, 1H) and 1.12-0.95 (m, 6H).

[1459] LCMS: m/z 489.3 (M+H).sup.+ (ES.sup.+).

Example 108: 5-(Dimethylamino)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

[1460] ##STR00430##

[1461] To a solution of 5-(dimethylamino)pyrazine-2-sulfonamide (intermediate P22) (70 mg, 346.13 mol, 1 eq) in THF (5 mL) was added t-BuONa (33 mg, 346.13 mol, 1 eq) and 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A39) (92 mg, 346.13 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 2%-32%, 11.5 min) to give the title compound (40 mg, 24% yield, 98.92% purity on LCMS) as a white solid.

[1462] .sup.1H NMR (DMSO-d.sub.6): 8.46-8.41 (m, 1H), 8.09-8.07 (t, 2H), 7.60 (br s, 1H), 7.13 (d, 1H), 7.05 (d, 1H), 6.82 (d, 1H), 6.68 (s, 1H), 3.86 (s, 3H), 3.16 (s, 6H), 2.88 (t, 2H), 2.65 (t, 2H) and 1.99-1.91 (m, 2H).

[1463] LCMS: m/z 469.3 (M+H).sup.+ (ES.sup.+).

Example 109: 5-(Dimethylamino)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

[1464] ##STR00431##

[1465] To a mixture of 5-(dimethylamino)pyrazine-2-sulfonamide (intermediate P22) (80 mg, 393.30 mol, 1 eq) in THF (5 mL) was added t-BuONa (41 mg, 432.63 mol, 1.1 eq) in one portion at 15 C. Then the reaction mixture was stirred for 15 minutes. Then a solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A40) (100 mg, 393.30 mol, 1 eq) in THF (2 mL) was added. The resulting mixture was stirred at 15 C. for 30 minutes and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, to min) to give the title compound (72.57 mg, 40%) as an off-white solid.

[1466] .sup.1H NMR (DMSO-d.sub.6): 8.49 (d, 2H), 8.40 (s, 1H), 8.07 (s, 1H), 7.54 (br s, 1H), 7.28 (d, 2H), 6.93 (d, 1H), 3.16 (s, 6H), 2.93 (t, 2H), 2.74 (t, 2H) and 2.07-1.99 (m, 2H).

[1467] LCMS: m/z 457.2 (M+H).sup.+ (ES.sup.+).

Example 110: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-3-(difluoromethyl)pyrazine-2-sulfonamide

[1468] ##STR00432##

[1469] To a solution of 3-(difluoromethyl)pyrazine-2-sulfonamide (intermediate P23) (74 mg, 355.5 mol, 1 eq) in THF (4 mL) was added t-BuONa (34 mg, 355.51 mol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A37) (0.1 g, 355.51 mol, 1 eq). The mixture was stirred at 25 C. for 10 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3); B: MeCN]; B %: 20%-50%, 12 min) to give the title compound (13.20 mg, 7% yield, 98.3% purity on LCMS) as a white solid.

[1470] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): 8.75-8.61 (m, 2H), 8.45 (d, 1H), 7.95-7.59 (m, 2H), 7.48 (d, 1H), 7.19-7.13 (m, 1H), 7.12-6.95 (m, 1H), 3.20-3.04 (m, 1H) and 1.19-0.93 (m, 6H).

[1471] LCMS: m/z 491.2 (M+H).sup.+ (ES.sup.+).

Example 111: 3-(Difluoromethyl)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)pyrazine-2-sulfonamide

[1472] ##STR00433##

[1473] To a solution of 3-(difluoromethyl)pyrazine-2-sulfonamide (intermediate P23) (73 mg, 349.28 mol, 1 eq) in THF (4 mL) was added t-BuONa (34 mg, 349.28 mol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A38) (100 mg, 349.28 mol, 1 eq). The mixture was stirred at 25 C. for 10 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3); B: MeCN]; B %: 17%-47%, 12 min) to give the title compound (14.57 mg, 8% yield, 98.6% purity on LCMS) as a white solid.

[1474] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): 8.82-8.76 (m, 2H), 7.98-7.65 (m, 2H), 7.15-7.00 (m, 1H), 6.88-6.86 (m, 1H), 6.79 (d, 1H), 6.61 (s, 1H), 3.82-3.79 (m, 3H), 3.19-2.93 (m, 1H) and 1.21-0.97 (m, 6H).

[1475] LCMS: m/z 496.2 (M+H).sup.+ (ES.sup.+).

Example 112: 3-(Difluoromethyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

[1476] ##STR00434##

[1477] To a solution of 3-(difluoromethyl)pyrazine-2-sulfonamide (intermediate P23) (75 mg, 358.55 mol, 1 eq) in THF (5 mL) was added t-BuONa (34 mg, 358.55 mol, 1 eq) and 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A39) (95 mg, 358.55 mol, 1 eq). The mixture was stirred at 10 C. for 1 hour and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 15%-45%, 12 Min) to give the title compound (24.17 mg, 14% yield, 100% purity on LCMS) as a white solid.

[1478] .sup.1H NMR (DMSO-d.sub.6): 8.78 (s, 2H), 8.15-7.87 (m, 2H), 7.07 (d, 1H), 7.00 (d, 1H), 6.85-6.83 (m, 1H), 6.67 (s, 1H), 6.06 (br s, 1H), 3.85 (s, 3H), 2.88-2.84 (m, 2H), 2.68-2.63 (m, 2H) and 1.96-1.90 (m, 2H).

[1479] LCMS: m/z 476.2 (M+H).sup.+ (ES.sup.+).

Example 113: 3-(Difluoromethyl)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

[1480] ##STR00435##

[1481] To a solution of 3-(difluoromethyl)pyrazine-2-sulfonamide (intermediate P23) (82.27 mg, 393.30 mol, 1 eq) in THF (5 mL) was added t-BuONa (42 mg, 432.63 mol, 1.1 eq) and a solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A40) (100 mg, 393.30 mol, 1 eq) in THF (5 mL) and DCM (5 mL). The reaction mixture was stirred at 16 C. for 0.5 hour and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3); B: MeCN]; B %: 15%-45%, 10 min) to give the title compound (25.31 mg, 14%) as a light yellow solid.

[1482] .sup.1H NMR (DMSO-d6+D.sub.2O): 8.89 (s, 1H), 8.85 (d, 1H), 8.49 (d, 2H), 7.76 (t, 1H), 7.45-7.25 (m, 2H), 6.96 (d, 1H), 2.92 (t, 2H), 2.72-2.67 (m, 2H) and 2.05-2.01 (m, 2H).

[1483] LCMS: m/z 464.1 (M+H).sup.+ (ES.sup.+).

Example 114: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-4,6-dimethylpyrimidine-2-sulfonamide

[1484] ##STR00436##

[1485] To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P24) (65 mg, 347.19 mol, 1 eq) in THF (5 mL) was added t-BuONa (33 mg, 347.19 mol, 1 eq) in one portion at 25 C. under N.sub.2. Then the reaction mixture was stirred for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A37) (98 mg, 347.19 mol, 1 eq) was added. The resulting mixture was heated to 70 C. and stirred for 10 minutes. The reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 12%-42%, 10 min) to give the title compound (19.94 mg, 12% yield, 100% purity on LCMS) as a white solid.

[1486] .sup.1H NMR (DMSO-d.sub.6): 8.69-8.68 (m, 1H), 8.02 (s, 1H), 7.71-7.69 (m, 1H), 7.35-7.33 (m, 1H), 7.25-7.20 (m, 1H), 7.13-7.09 (m, 2H), 3.33-3.16 (m, 1H), 2.43 (s, 6H) and 1.10 (d, 6H).

[1487] LCMS: m/z 469.2 (M+H).sup.+ (ES.sup.+).

Example 115: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4,6-dimethylpyrimidine-2-sulfonamide

[1488] ##STR00437##

[1489] To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P24) (65 mg, 349.28 mol, 1 eq) in THF (5 mL) was added t-BuONa (34 mg, 349.28 mol, 1 eq) in one portion at 25 C. under N.sub.2. Then the reaction mixture was stirred for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A38) (100 mg, 349.28 mol, 1 eq) was added. The reaction mixture was heated to 70 C. and stirred for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 11.5 min) to give the title compound (60.47 mg, 37% yield, 100% purity on LCMS) as a white solid.

[1490] .sup.1H NMR (DMSO-d.sub.6): 8.11-8.07 (m, 1H), 7.85 (br s, 1H), 7.42-7.39 (m, 1H), 7.18-7.12 (m, 1H), 7.05-6.94 (m, 2H), 6.76 (s, 1H), 3.90 (s, 3H), 3.12-3.08 (m, 1H), 2.46 (s, 6H) and 1.14-1.07 (m, 6H).

[1491] LCMS: m/z 474.2 (M+H).sup.+ (ES.sup.+).

Example 116: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4,6-dimethylpyrimidine-2-sulfonamide

[1492] ##STR00438##

[1493] To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P24) (70 mg, 375.52 mol, 1 eq) in THF (5 mL) was added t-BuONa (36 mg, 375.52 mol, 1 eq) in one portion at 25 C. under N.sub.2. Then the reaction mixture was stirred for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A39) (100 mg, 375.52 mol, 1 eq) was added. The reaction mixture was heated to 70 C. and stirred for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 2%-32%, 11.5 min) to give the title compound (41.33 mg, 24% yield, 98.29% purity on LCMS) as a white solid.

[1494] .sup.1H NMR (DMSO-d.sub.6): 8.10 (d, 1H), 7.32-7.30 (m, 1H), 7.11 (d, 1H), 7.05 (d, 1H), 6.98 (d, 1H), 6.76 (s, 1H), 3.86 (s, 3H), 2.87 (t, 2H), 2.76-2.73 (m, 2H), 2.49 (s, 6H) and 1.98-1.93 (m, 2H).

[1495] LCMS: m/z 454.2 (M+H).sup.+ (ES.sup.+).

Example 117: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4,6-dimethylpyrimidine-2-sulfonamide

[1496] ##STR00439##

[1497] To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P24) (50 mg, 267.07 mol, 1 eq) in THF (3 mL) was added t-BuONa (26 mg, 267.07 mol, 1 eq) in one portion at 25 C. under N.sub.2. Then the reaction mixture was stirred for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A40) (68 mg, 267.07 mol, 1 eq) was added. The reaction mixture was stirred at 25 C. for 10 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (22.84 mg, 19% yield, 97.11% purity on LCMS) as a white solid.

[1498] .sup.1H NMR (DMSO-d.sub.6): 8.56 (d, 2H), 7.75 (br s, 1H), 7.39-7.36 (m, 3H), 6.98 (d, 1H), 2.93 (t, 2H), 2.85-2.75 (m, 2H), 2.49 (s, 6H) and 2.06-2.02 (m, 2H).

[1499] LCMS: m/z 442.1 (M+H).sup.+ (ES.sup.+).

Example 118: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-5-(dimethylamino)pyridazine-3-sulfonamide

[1500] ##STR00440##

[1501] To a mixture of 5-(dimethylamino)pyridazine-3-sulfonamide (intermediate P25) (70 mg, 346.13 mol, 1 eq) in THF (2 mL) was added t-BuONa (33 mg, 346.13 mol, 1 eq) in one portion at 25 C. under N.sub.2. Then the reaction mixture was stirred for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A37) (97 mg, 346.13 mol, 1 eq) was added. The reaction mixture was stirred at 25 C. for 10 minutes and then concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (65.88 mg, 39% yield, 99.38% purity on LCMS) as a white solid.

[1502] .sup.1H NMR (DMSO-d.sub.6): 8.77 (d, 1H), 8.61-8.59 (m, 1H), 7.94 (s, 1H), 7.87-7.84 (m, 1H), 7.59-7.58 (m, 1H), 7.20-7.17 (m, 1H), 7.07 (dd, 1H), 6.96 (s, 1H), 3.21-3.17 (m, 1H), 3.09 (s, 6H) and 1.15-1.08 (m, 6H).

[1503] LCMS: m/z 484.2 (M+H).sup.+ (ES.sup.+).

Example 119: 5-(Dimethylamino)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl) pyridazine-3-sulfonamide

[1504] ##STR00441##

[1505] To a mixture of 5-(dimethylamino)pyridazine-3-sulfonamide (intermediate P25) (40 mg, 197.79 mol, 1 eq) in THF (5 mL) was added t-BuONa (19 mg, 197.79 mol, 1 eq) in one portion at 25 C. under N.sub.2. Then the reaction mixture was stirred for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A38) (57 mg, 197.79 mol, 1 eq) was added. The resulting mixture was heated to 70 C. and stirred for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 13%-43%, 10 min) to give the title compound (49.52 mg, 51% yield, 98.93% purity on LCMS) as a white solid.

[1506] .sup.1H NMR (DMSO-d.sub.6): 8.90-8.85 (m, 1H), 8.09-8.05 (m, 1H), 7.92-7.87 (m, 1H), 7.18-7.15 (m, 1H), 7.07 (d, 1H), 6.98 (d, 1H), 6.84 (d, 1H), 6.73 (s, 1H), 3.85 (s, 3H), 3.07 (s, 6H), 3.06-3.01 (m, 1H) and 1.09-0.94 (m, 6H).

[1507] LCMS: m/z 489.2 (M+H).sup.+ (ES.sup.+).

Example 120: 5-(Dimethylamino)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl) pyridazine-3-sulfonamide

[1508] ##STR00442##

[1509] To a mixture of 5-(dimethylamino)pyridazine-3-sulfonamide (intermediate P25) (35 mg, 173.07 mol, 1 eq) in THF (2 mL) was added t-BuONa (17 mg, 173.07 mol, 1 eq) in one portion at 25 C. under N.sub.2. Then the reaction mixture was stirred for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A39) (46 mg, 173.07 mol, 1 eq) was added. The reaction mixture was heated to 25 C. and stirred for 20 minutes. The reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (21.73 mg, 27% yield, 99.14% purity on LCMS) as a white solid.

[1510] .sup.1H NMR (DMSO-d.sub.6): 8.83 (d, 1H), 8.06 (d, 1H), 7.75-7.74 (m, 1H), 7.13 (d, 1H), 7.07-7.05 (m, 2H), 6.86 (d, 1H), 6.71 (s, 1H), 3.88 (s, 3H), 3.06 (s, 6H), 2.86 (t, 2H), 2.68 (t, 2H) and 1.99-1.93 (m, 2H).

[1511] LCMS: m/z 469.2 (M+H).sup.+ (ES.sup.+).

Example 121: 5-(Dimethylamino)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl) pyridazine-3-sulfonamide

[1512] ##STR00443##

[1513] To a mixture of 5-(dimethylamino)pyridazine-3-sulfonamide (intermediate P25) (50 mg, 247.24 mol, 1 eq) in THF (3 mL) was added t-BuONa (24 mg, 247.24 mol, 1 eq) in one portion at 25 C. under N.sub.2. Then the reaction mixture was stirred for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A40) (63 mg, 247.24 mol, 1 eq) was added. The reaction mixture was stirred at 25 C. for 10 minutes. The reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (22.81 mg, 20% yield, 98.41% purity on LCMS) as a white solid.

[1514] .sup.1H NMR (DMSO-d.sub.6): 8.83 (d, 1H), 8.51 (d, 2H), 7.71 (br s, 1H), 7.31-7.30 (m, 2H), 7.04 (d, 1H), 6.95 (d, 1H), 3.06 (s, 6H), 2.92 (t, 2H), 2.78-2.75 (m, 2H) and 2.05-2.00 (m, 2H).

[1515] LCMS: m/z 457.0 (M+H).sup.+ (ES.sup.+).

Example 122: 3-(N-Methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea

[1516] ##STR00444##

[1517] To a cooled (0 C.) solution of chlorosulfonyl isocyanate (59 mg, 0.41 mmol) in DCM (5 mL) was added 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35; 100 mg, 0.41 mmol). The mixture was stirred for 10 minutes at 0 C. N,1-dimethylpyrrolidin-3-amine (95 mg, 0.83 mmol) in DCM (5 mL) was added and the reaction was allowed to reach room temperature over 30 minutes. The mixture was evaporated to dryness in vacua and purified by reversed phase chromatography to afford the title compound (9 mg; 5%) as a white solid.

[1518] .sup.1H NMR (CD.sub.3OD) 8.12 (d, 1H), 7.19 (d, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 6.83 (s, 1H), 4.48 (m, 1H), 3.92 (s, 3H), 2.92 (m, 6H), 2.82 (m, 2H), 2.71 (s, 3H), 2.50 (s, 3H), 2.10 (m, 3H) and 1.92 (m, 1H).

[1519] LCMS: m/z 460 (M+H).sup.+ (ES.sup.+); 458 (MH).sup. (ES.sup.).

Example 123: 3-(N-Methyl-N-((1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea

[1520] ##STR00445##

[1521] Prepared as described for 3-(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea (Example 122), using chlorosulfonyl isocyanate (59 mg, 0.41 mmol), 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A35; 100 mg, 0.41 mmol) and N-methyl-1-(1-methylpyrrolidin-2-yl)methanamine (107 mg, 0.83 mmol) to afford the title compound (2 mg; 1%) as a white solid.

[1522] .sup.1H NMR (CD.sub.3OD) 8.12 (d, 1H), 7.19 (m, 2H), 7.09 (d, 1H), 6.93 (s, 1H), 3.92 (s, 3H), 3.88 (m, 1H), 3.65 (m, 1H), 3.09 (m, 1H), 2.98 (m, 6H), 2.79 (s, 3H), 2.69 (s, 3H), 2.10 (m, 3H), 1.97 (m, 2H) and 1.60 (m, 1H).

[1523] LCMS: m/z 474 (M+H).sup.+ (ES.sup.+).

Example 124: 3-(N-Methyl-N-((1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea

[1524] ##STR00446##

[1525] Prepared as described for 3-(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea (Example 122), using chlorosulfonyl isocyanate (55 mg, 0.38 mmol), 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A34; 100 mg, 0.38 mmol) and N,1-dimethylpyrrolidin-3-amine (95 mg, 0.83 mmol) to afford the title compound (12 mg; 10%) as a white solid.

[1526] .sup.1H NMR (CD.sub.3OD) 8.14 (d, 1H), 7.08 (d, 1H), 6.98 (m, 2H), 4.48 (m, 1H), 3.92 (s, 3H), 2.98 (m, 8H), 2.71 (s, 3H), 2.60 (s, 3H), 2.10 (m, 3H) and 1.92 (m, 1H).

[1527] LCMS: m/z 479 (M+H).sup.+ (ES.sup.+).

Example 125: 3-(N-Methyl-N-((1-methylpyrrolidin-2-yl)methyl) sulfamoyl)-1-(7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea

[1528] ##STR00447##

[1529] Prepared as described for 3-(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)-1-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)urea (Example 122), using chlorosulfonyl isocyanate (55 mg, 0.38 mmol), 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A34; 100 mg, 0.38 mmol) and N-methyl-1-(1-methylpyrrolidin-2-yl)methanamine (139 mg, 1.16 mmol) to afford the title compound (23 mg; 12%) as a white solid.

[1530] .sup.1H NMR (CD.sub.3OD) 8.12 (d, 1H), 7.00 (d, 1H), 6.90 (d, 1H), 6.83 (s, 1H), 3.92 (s, 3H), 3.78 (m, 1H), 3.55 (m, 1H), 3.00 (m, 7H), 2.79 (s, 3H), 2.67 (s, 3H), 2.19 (m, 3H), 2.01 (m, 2H) and 1.62 (m, 1H).

[1531] LCMS: m/z 492 (M+H).sup.+ (ES.sup.+); 490 (MH).sup. (ES.sup.).

Example 126: (1R,4R)N-((7-Fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonamide

[1532] ##STR00448##

[1533] (1R,4R)-2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (50 mg, 0.18 mmol) and sodium hydride (60%) (150 mg, 3.7 mmol) were refluxed for 1 hour in THF (10 mL). The mixture was cooled to room temperature and filtered over Celite. The filtrate was evaporated to dryness in vacua and the residue was dissolved in DCM (10 mL), after which DABCO was added (20 mg, 0.18 mmol).

[1534] Meanwhile, to a cooled (0 C.) solution of chlorosulfonyl isocyanate (35 mg, 0.25 mmol) in DCM (5 mL) was added 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A34; 66 mg, 0.26 mmol). The mixture was stirred for 10 minutes at 0 C.

[1535] Both DCM mixtures were combined and allowed to reach room temperature after 1 hour. The mixture was evaporated to dryness in vacua and purified by reversed phase chromatography to afford the title compound (4 mg; 5%) as a white solid.

[1536] .sup.1H NMR (CD.sub.3OD) 8.12 (d, 1H), 7.02 (d, 1H), 6.90 (m, 2H), 4.54 (m, 1H), 4.24 (m, 1H), 3.92 (s, 3H), 3.39 (m, 2H), 2.98 (m, 4H), 0.75 (s, 3H), 2.20 (m, 2H), and 1.64 (m, 2H).

[1537] LCMS: m/z 476 (M+H).sup.+ (ES.sup.+); 474 (MH).sup. (ES.sup.).

Example 127: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-phenylmethanesulfonamide

[1538] ##STR00449##

[1539] To a solution of phenylmethanesulfonamide (61 mg, 355.51 mol, 1 eq) in THF (2 mL) was added t-BuONa (34 mg, 355.51 mol, 1 eq) and the mixture was stirred at 25 C. for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A37) (0.1 g, 355.51 mol, 1 eq) was added and the resulting mixture was heated to 70 C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN]; B %: 15%-45%, 11.5 min) to give the title compound (0.038 g, 23% yield, 99% purity on LCMS) as a white solid.

[1540] .sup.1H NMR (DMSO-d.sub.6): 10.59 (br s, 1H), 8.77 (d, 1H), 8.12 (s, 1H), 7.80 (dd, 1H), 7.30-7.10 (m, 7H), 4.30 (s, 2H), 3.24-3.20 (m, 1H) and 1.20 (d, 6H).

[1541] LCMS: m/z 453.3 (M+H).sup.+ (ES.sup.+).

Example 128: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-phenylmethanesulfonamide

[1542] ##STR00450##

[1543] To a solution of phenylmethanesulfonamide (60 mg, 349.28 mol, 1 eq) in THF (2 mL) was added t-BuONa (34 mg, 349.28 mol, 1 eq) and the mixture was stirred at 25 C. for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A38) (0.1 g, 349.28 mol, 1 eq) was added and the resulting mixture was heated to 70 C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN]; B %: 10%-40%, 11.5 min) to give the title compound (0.04 g, 25% yield, 99% purity on LCMS) as a white solid.

[1544] .sup.1H NMR (DMSO-d.sub.6): 8.15 (d, 1H), 7.52 (br s, 1H), 7.34-7.11 (m, 6H), 7.10-6.95 (m, 2H), 6.87 (s, 1H), 4.27 (s, 2H), 3.85 (s, 3H), 3.25-3.19 (m, 1H) and 1.18 (d, 6H).

[1545] LCMS: m/z 458.3 (M+H).sup.+ (ES.sup.+).

Example 129: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-phenylmethanesulfonamide

[1546] ##STR00451##

[1547] To a solution of phenylmethanesulfonamide (64 mg, 375.52 mol, 1 eq) in THF (2 mL) was added t-BuONa (36 mg, 375.52 mol, 1 eq) and the mixture was stirred at 25 C. for 0.5 hour. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A39) (0.1 g, 375.52 mol, 1 eq) was added and the resulting mixture was heated to 70 C. and stirred for 0.1 hour. The mixture was concentrated in vacua.

[1548] The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (90.80 mg, 55% yield, 99% purity on LCMS) as a white solid.

[1549] .sup.1H NMR (DMSO-d.sub.6): 8.14 (d, 1H), 7.50 (br s, 1H), 7.32-7.30 (m, 3H), 7.25-7.24 (m, 2H), 7.17 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 6.80 (s, 1H), 4.37 (s, 2H), 3.87 (s, 3H), 2.94 (t, 2H), 2.85 (t, 2H) and 2.09-1.97 (m, 2H).

[1550] LCMS: m/z 438.2 (M+H).sup.+ (ES.sup.+).

Example 130: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-phenylmethanesulfonamide

[1551] ##STR00452##

[1552] A mixture of phenylmethanesulfonamide (70 mg, 408.84 mol, 1 eq) and t-BuONa (39 mg, 408.84 mol, 1 eq) in THF (2 mL) was stirred at 25 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A40) (104 mg, 408.84 mol, 1 eq) was added. The mixture was stirred at 70 C. for 10 minutes. The reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (16.61 mg, 10% yield, 100% purity on LCMS) as a white solid.

[1553] .sup.1H NMR (DMSO-d.sub.6): 8.54 (d, 2H), 7.41 (d, 2H), 7.26-7.22 (m, 4H), 7.18-7.02 (m, 2H), 6.95 (d, 1H), 4.21 (s, 2H), 2.96 (t, 2H), 2.89 (t, 2H) and 2.12-2.03 (m, 2H).

[1554] LCMS: m/z 426.2 (M+H).sup.+ (ES.sup.+).

Example 131: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-2-methylpropane-1-sulfonamide

[1555] ##STR00453##

[1556] To a solution of 2-methylpropane-1-sulfonamide (49 mg, 355.51 mol, 1 eq) (intermediate P26) in THF (2 mL) were added t-BuONa (34 mg, 355.51 mol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A37) (100 mg, 355.51 mol, 1 eq). The reaction mixture was stirred at 20 C. for 20 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 3%-33%, 12.0 min) to give the title compound (48.16 mg, 32%) as a white solid.

[1557] .sup.1H NMR (DMSO-d.sub.6): 8.72 (d, 1H), 8.07 (s, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.21 (d, 1H), 7.11 (d, 1H), 3.26-3.23 (m, 1H), 2.67-2.63 (m, 2H), 1.77-1.66 (m, 1H), 1.15 (d, 6H) and 0.84 (d, 6H).

[1558] LCMS: m/z 419.2 (M+H).sup.+ (ES.sup.+).

Example 132: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-2-methylpropane-1-sulfonamide

[1559] ##STR00454##

[1560] To a solution of 2-methylpropane-1-sulfonamide (intermediate P26) (48 mg, 349.28 mol, 1 eq) in THF (2 mL) were added t-BuONa (34 mg, 349.28 mol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A38) (100 mg, 349.28 mol, 1 eq). The reaction mixture was stirred at 25 C. for 10 minutes and then was concentrated in vacua. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 15%-45%, 11.5 min) to give the title compound (101.64 mg, 69% yield, 100% purity on LCMS) as a white solid. .sup.1H NMR (DMSO-d.sub.6): 8.17 (d, 1H), 7.91 (s, 1H), 7.27-7.24 (m, 1H), 7.06 (dd, 1H), 6.99 (d, 1H), 6.82 (s, 1H), 3.87 (s, 3H), 3.16-3.09 (m, 1H), 3.00 (d, 2H), 1.91-1.81 (m, 1H), 1.16 (d, 6H) and 0.91 (d, 6H).

[1561] LCMS: m/z 424.2 (M+H).sup.+ (ES.sup.+).

Example 133: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-2-methylpropane-1-sulfonamide

[1562] ##STR00455##

[1563] To a solution of 2-methylpropane-1-sulfonamide (intermediate P26) (55 mg, 401.36 mol, 1 eq) in THF (2 mL) were added t-BuONa (39 mg, 401.36 mol, 1 eq) and 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A39) (167 mg, 401.36 mol, 1 eq). The reaction mixture was stirred at 25 C. for 20 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m, mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN], B %: 18%-48%, 10 min) to give the title compound (16.29 mg, 10%) as a white solid.

[1564] .sup.1H NMR (DMSO-d.sub.6): 8.15 (d, 1H), 7.93 (br s, 1H), 7.22 (d, 1H), 7.12 (d, 1H), 6.94-6.91 (m, 1H), 6.74 (s, 1H), 3.86 (s, 3H), 3.10 (d, 2H), 2.93 (t, 2H), 2.79 (t, 2H), 2.05-1.95 (m, 3H) and 0.95 (d, 6H).

[1565] LCMS: m/z 404.2 (M+H).sup.+ (ES.sup.+).

Example 134: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-2-methylpropane-1-sulfonamide

[1566] ##STR00456##

[1567] To a solution of 2-methylpropane-1-sulfonamide (intermediate P26) (54 mg, 393.30 mol, 1 eq) in THF (2 mL) was added t-BuONa (38 mg, 393.30 mol, 1 eq). Then the mixture was stirred at 25 C. for 10 minutes. A solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A40) (100 mg, 393.30 mol, 1 eq) in THF (2.5 mL) was added. The resulting mixture was stirred at 25 C. for 30 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (Column: Xtimate C18, 250 mm*50 mm*10 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 1%-31%, 10.0 min) to give the title compound (45.33 mg, 29% yield, 100% purity on LCMS) as a white solid.

[1568] .sup.1H NMR (DMSO-d.sub.6): 8.54 (d, 2H), 7.40 (d, 2H), 6.96 (d, 1H), 2.95 (t, 2H), 2.89-2.83 (m, 4H), 2.09-2.03 (m, 2H), 1.96-1.91 (m, 1H) and 0.93 (d, 6H).

[1569] LCMS: m/z 392.2 (M+H).sup.+ (ES.sup.+).

Example 135: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-2-phenylethanesulfonamide

[1570] ##STR00457##

[1571] To a solution of 2-phenylethanesulfonamide (intermediate P27) (66 mg, 355.51 mol, 1 eq) in THF (2 mL) was added t-BuONa (34 mg, 355.51 mol, 1 eq) and the mixture was stirred at 25 C. for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A37) (0.1 g, 355.51 mol, 1 eq) was added and the resulting mixture was heated to 70 C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN]; B %: 12%-42%, 11.5 min) to give the title compound (0.07 g, 42% yield, 99% purity on LCMS) as a white solid.

[1572] .sup.1H NMR (DMSO-d.sub.6): 10.77 (br s, 1H), 8.67 (d, 1H), 8.11 (s, 1H), 7.92 (br s, 1H), 7.80 (d, 1H), 7.31-7.18 (m, 5H), 7.09 (d, 2H), 3.25-3.19 (m, 3H), 2.70-2.51 (m, 2H) and 1.17 (d, 6H).

[1573] LCMS: m/z 467.3 (M+H).sup.+ (ES.sup.+).

Example 136: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-2-phenylethanesulfonamide

[1574] ##STR00458##

[1575] To a solution of 2-phenylethanesulfonamide (intermediate P27) (65 mg, 349.28 mol, 1 eq) in THF (2 mL) was added t-BuONa (34 mg, 349.28 mol, 1 eq) and the mixture was stirred at 25 C. for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A38) (0.1 g, 349.28 mol, 1 eq) was added and the resulting mixture was heated to 70 C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN]; B %: 22%-52%, ii min) to give the title compound (0.0317 g, 19% yield, 99% purity on LCMS) as a white solid.

[1576] .sup.1H NMR (DMSO-d.sub.6): 8.10 (d, 1H), 8.00 (br s, 1H), 7.34-7.22 (m, 4H), 7.16-6.99 (m, 4H), 6.84 (s, 1H), 3.73 (s, 3H), 3.44-3.40 (m, 2H), 3.18-3.13 (m, 1H), 2.80-2.76 (m, 2H) and 1.16 (d, 6H).

[1577] LCMS: m/z 472.2 (M+H).sup.+ (ES.sup.+).

Example 137: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-2-phenylethanesulfonamide

[1578] ##STR00459##

[1579] To a solution of 2-phenylethanesulfonamide (intermediate P27) (70 mg, 375.52 mol, 1 eq) in THF (2 mL) was added t-BuONa (36 mg, 375.52 mol, 1 eq) and the mixture was stirred at 25 C. for 0.5 hour. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A39) (0.1 g, 375.52 mol, 1 eq) was added and the resulting mixture was heated to 70 C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 17%-47%, 11 min) to give the title compound (0.021 g, 12% yield, 100% purity on LCMS) as a white solid.

[1580] .sup.1H NMR (DMSO-d.sub.6): 8.07 (d, 1H), 7.50 (br s, 1H), 7.33-7.26 (m, 2H), 7.19-7.13 (m, 4H), 7.10-7.08 (m, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 3.77 (s, 3H), 3.30-3.23 (m, 2H), 2.92 (t, 2H), 2.86-2.80 (m, 4H) and 2.07-1.98 (m, 2H).

[1581] LCMS: m/z 452.2 (M+H).sup.+ (ES.sup.+).

Example 138: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-2-phenylethanesulfonamide

[1582] ##STR00460##

[1583] A mixture of 2-phenylethanesulfonamide (intermediate P27) (75 mg, 404.87 mol, 1 eq) and t-BuONa (39 mg, 404.87 mol, 1 eq) in THF (2 mL) was stirred at 25 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A40) (103 mg, 404.87 mol, 1 eq) was added. The resulting mixture was stirred at 25 C. for 10 minutes, then warmed to 70 C. and stirred for 10 minutes. The reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (15.1 mg, 8% yield, 100% purity on LCMS) as a white solid.

[1584] .sup.1H NMR (DMSO-d.sub.6): 8.53 (d, 2H), 7.63 (br s, 1H), 7.42 (d, 2H), 7.31 (t, 2H), 7.23-7.16 (m, 3H), 7.00 (d, 1H), 3.39-3.35 (m, 2H), 2.99 (t, 2H), 2.90-2.82 (m, 4H) and 2.10-2.06 (m, 2H).

[1585] LCMS: m/z 440.2 (M+H).sup.+ (ES.sup.+).

Example 139: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-phenylethanesulfonamide

[1586] ##STR00461##

[1587] To a solution of 1-phenylethanesulfonamide (intermediate P28) (50 mg, 269.92 mol, 1 eq) in THF (2 mL) was added t-BuONa (26 mg, 269.92 mol, 1 eq). After stirring at 20 C. for 10 minutes, 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A37) (76 mg, 269.92 mol, 1 eq) was added. The reaction mixture was stirred at 20 C. for 20 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini c18, 150 mm*25 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 22%-52%, 12 min) to give the title compound (14.74 mg, ii % yield, 98% purity on LCMS) as a white solid.

[1588] .sup.1H NMR (DMSO-d.sub.6): 10.53 (br s, 1H), 8.77 (d, 1H), 8.10 (s, 1H), 7.97-7.93 (m, 1H), 7.77 (d, 1H), 7.32-7.24 (m, 4H), 7.23-7.19 (m, 3H), 4.57-4.54 (m, 1H), 3.15-3.12 (m, 1H), 1.46-1.40 (m, 3H) and 1.20-1.08 (m, 6H).

[1589] LCMS: m/z 467.2 (M+H).sup.+ (ES.sup.+).

Example 140: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-phenylethanesulfonamide

[1590] ##STR00462##

[1591] To a solution of 1-phenylethanesulfonamide (intermediate P28) (50 mg, 269.92 mol, 1 eq) in THF (2 mL) was added t-BuONa (26 mg, 269.92 mol, 1 eq). The mixture was stirred at 20 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A38) (77 mg, 269.92 mol, 1 eq) was added. The reaction mixture was stirred at 20 C. for 20 minutes and then concentrated in vacua. The residue was purified by prep-HPLC (column: Xtimate C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 10%-40%, 12 min) to give the title compound (12.98 mg, 10% yield, 100% purity on LCMS) as a white solid.

[1592] .sup.1H NMR (DMSO-d.sub.6): 10.40 (br s, 1H), 8.15 (d, 1H), 7.70 (br s, 1H), 7.32-7.20 (m, 6H), 7.05-7.00 (m, 2H), 6.85 (s, 1H), 4.60-4.56 (m, 1H), 3.86 (s, 3H), 3.16-3.11 (m, 1H), 1.45 (d, 3H) and 1.18 (dd, 6H).

[1593] LCMS: m/z 472.2 (M+H).sup.+ (ES.sup.+).

Example 141: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-phenylethanesulfonamide

[1594] ##STR00463##

[1595] To a solution of 1-phenylethanesulfonamide (intermediate P28) (50 mg, 269.92 mol, 1 eq) in THF (2 mL) was added t-BuONa (26 mg, 269.92 mol, 1 eq). The mixture was stirred at 20 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A39) (72 mg, 269.92 mol, 1 eq) was added and then the resulting mixture was stirred at 20 C. for 20 minutes. The reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Xtimate C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 12 min) to give the title compound (34.56 mg, 28% yield, 99.8% purity on LCMS) as a white solid.

[1596] .sup.1H NMR (DMSO-d.sub.6): 8.12 (d, 1H), 7.60 (br s, 1H), 7.33-7.30 (m, 5H), 7.19 (d, 1H), 7.09 (d, 1H), 6.94-6.92 (m, 1H), 6.77 (s, 1H), 4.69-4.66 (m, 1H), 3.86 (s, 3H), 2.93 (t, 2H), 2.81 (t, 2H), 2.07-2.01 (m, 2H) and 1.54 (d, 3H).

[1597] LCMS: m/z 452.2 (M+H).sup.+ (ES.sup.+).

Example 142: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-phenylethanesulfonamide

[1598] ##STR00464##

[1599] To a solution of 1-phenylethanesulfonamide (intermediate P28) (75 mg, 404.87 mol, 1 eq) in THF (2 mL) was added t-BuONa (39 mg, 404.87 mol, 1 eq). Then the reaction mixture was stirred at 20 C. for 10 minutes. A solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A40) (103 mg, 404.87 mol, 1 eq) in THF (2 mL) was added. The resulting mixture was stirred at 20 C. for 20 minutes and then concentrated in vacua. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 13%-43%, 10 min) to give the title compound (63.22 mg, 35% yield, 99% purity on LCMS) as a light red solid.

[1600] .sup.1H NMR (DMSO-d.sub.6): 8.57 (d, 2H), 7.69 (br s, 1H), 7.37-7.30 (m, 7H), 7.02 (d, 1H), 4.75-4.67 (m, 1H), 2.98 (t, 2H), 2.84 (t, 2H), 2.14-2.08 (m, 2H) and 1.55 (d, 3H).

[1601] LCMS: m/z 440.2 (M+H).sup.+ (ES.sup.+).

Example 143: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)methanesulfonamide

[1602] ##STR00465##

[1603] 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (326 mg, 1.36 mmol) (Intermediate A35) was dissolved in THF (5 mL). Triethylamine (208 l, 1.49 mmol) was added, followed by a solution of bis(trichloromethyl) carbonate (382 mg, 1.29 mmol) in THF (2 mL). The thick reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacua and the solid formed was dried under high vacuum for 1 hour. The solid, 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine, was suspended in THF (8 mL) of which 2 mL were used later. Methanesulfonamide (30 mg, 0.315 mmol) was suspended in THF (2 mL), sodium tert-butoxide (2 M in THF) (175 l, 0.351 mmol) was added, and the mixture was stirred for 30 minutes at room temperature. Then a solution of 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (78 mg, 0.292 mmol) in THF (2 mL), prepared earlier, was added and the mixture was stirred overnight at room temperature. The THF was removed in vacuo and the residue was dissolved in DMSO (2 mL) and then purified by basic prep HPLC to afford the title compound (23.5 mg, 21%) as a colourless solid.

[1604] .sup.1H NMR (DMSO-d.sub.6): 8.17 (d, J=5.3 Hz, 1H), 7.86 (s, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.95 (dd, J=5.3, 1.3 Hz, 1H), 6.77 (s, 1H), 3.88 (s, 3H), 3.01 (s, 3H), 2.94 (t, J=7.4 Hz, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.04 (p, J=7.5 Hz, 2H), NH not observed.

[1605] LCMS; m/z 362.2 (M+H).sup.+ (ES.sup.+); 360.0 (MH).sup. (ES.sup.).

Example 144: 1-Cyclopropyl-N-((6-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-5-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

[1606] ##STR00466##

[1607] To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P29) (50 mg, 267.07 mol, 0.7 eq) in THF (1.5 mL) was added t-BuONa (36 mg, 375.52 mol, 1 eq) and 4-(6-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A45) (100 mg, 375.52 mol, 1 eq). The mixture was stirred at 25 C. for 0.5 hour. Most of the solvent was concentrated to give crude product. The residue was purified by prep-HPLC (column: Xtimate C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 9%-39%, 8 min) to give the title compound (22.39 mg, 13% yield, 98% purity on LCMS) as a white solid.

[1608] .sup.1H NMR (DMSO-d.sub.6): 8.19 (d, 1H), 7.80-7.74 (m, 2H), 7.24 (br s, 1H), 7.01 (s, 1H), 6.91 (d, 1H), 6.72 (s, 1H), 6.42 (s, 1H), 3.89 (s, 3H), 3.76-3.73 (m, 1H), 2.84-2.78 (m, 4H), 2.04-1.98 (m, 2H), and 1.03-0.95 (d, 4H).

[1609] LCMS: m/z 454.3 (M+H).sup.+ (ES.sup.+).

Example 145: 1-Cyclopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide

[1610] ##STR00467##

[1611] To a solution of 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A39) (71 mg, 267.07 mol, 1 eq) in THF (1 mL) was added t-BuONa (26 mg, 267.07 mol, 1 eq) and 1-cyclopropyl-1H-pyrazole-4-sulfonamide (intermediate P30) (50 mg, 267.07 mol, 1 eq). The mixture was stirred at 25 C. for 20 minutes. Most of the solvent was evaporated to give crude product. The crude product was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 12%-42%, 10 min) to give the title compound (12.82 mg, 11% yield, 100% purity on LCMS) as a white solid.

[1612] .sup.1H NMR (DMSO-d.sub.6): 8.16 (s, 1H), 8.04-8.03 (d, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.18-7.16 (d, 1H), 7.09-7.07 (d, 1H), 6.82-6.80 (d, 1H), 6.68 (s, 1H), 3.87 (s, 3H), 3.85-3.78 (m, 1H), 2.92-2.89 (m, 2H), 2.68-2.64 (m, 2H), 2.011.94 (m, 2H), 1.06-1.03 (m, 2H) and 1.01-0.96 (m, 2H).

[1613] LCMS: m/z 454.4 (M+H).sup.+ (ES.sup.+).

Example 146: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-3-(diethylamino)propane-1-sulfonamide

[1614] ##STR00468##

[1615] To a solution of 3-(diethylamino)propane-1-sulfonamide (Intermediate P32) (80 mg, 411.75 mol, 1 eq) in THF (1 mL) was added t-BuONa (40 mg, 411.75 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A37) (116 mg, 411.75 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 12%-42%, 11.5 min) to give the title compound (105.29 mg, 55% yield, 100% purity on LCMS) as a white solid.

[1616] .sup.1H NMR (DMSO-d.sub.6): 8.75 (d, 1H), 8.08 (s, 1H), 7.79-7.73 (m, 2H), 7.23 (d, 1H), 7.13 (d, 1H), 3.09-3.06 (m, 1H), 3.03-2.88 (m, 8H), 1.75-1.72 (m, 2H), 1.16 (d, 6H) and 1.09 (t, 6H).

[1617] LCMS: m/z 476.3 (M+H).sup.+ (ES.sup.+).

Example 147: 3-(Diethylamino)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)propane-1-sulfonamide

[1618] ##STR00469##

[1619] To a solution of 3-(diethylamino)propane-1-sulfonamide (Intermediate P32) (80 mg, 411.75 mol, 1 eq) in THF (1 mL) was added t-BuONa (40 mg, 411.75 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) (118 mg, 411.75 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 18%-48%, 11.5 min) to give the title compound (59.65 mg, 30% yield, 100% purity on LCMS) as a white solid.

[1620] .sup.1H NMR (DMSO-d.sub.6): 8.15 (d, 1H), 7.64 (s, 1H), 7.19 (d, 1H), 7.09-6.95 (m, 2H), 6.85 (s, 1H), 3.87 (s, 3H), 3.23-3.20 (m, 1H), 3.04-2.75 (m, 8H), 1.77-1.72 (m, 2H), 1.16 (d, 6H) and 1.09-1.04 (m, 6H).

[1621] LCMS: m/z 481.3 (M+H).sup.+ (ES.sup.+).

Example 148: 3-(Diethylamino)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)propane-1-sulfonamide

[1622] ##STR00470##

[1623] To a solution of 3-(diethylamino)propane-1-sulfonamide (Intermediate P32) (80 mg, 411.75 mol, 1 eq) in THF (1 mL) was added t-BuONa (40 mg, 411.75 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (171 mg, 411.75 mol, purity: 64% on LCMS, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 15%-45%, 11.5 min) to give the title compound (53.15 mg, 28% yield, 100% purity on LCMS) as a pink solid.

[1624] .sup.1H NMR (DMSO-d.sub.6): 8.13 (d, 1H), 7.64 (br s, 1H), 7.15 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 6.78 (s, 1H), 3.86 (s, 3H), 3.08 (t, 2H), 2.91 (t, 2H), 2.85-2.76 (m, 8H), 2.03-2.00 (m, 2H), 1.82-1.78 (m, 2H) and 1.05 (t, 6H).

[1625] LCMS: m/z 461.3 (M+H).sup.+ (ES.sup.+).

Example 149: 3-(Diethylamino)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)propane-1-sulfonamide

[1626] ##STR00471##

[1627] A mixture of 3-(diethylamino)propane-1-sulfonamide (Intermediate P32) (60 mg, 308.81 mol, 1 eq) and t-BuONa (30 mg, 308.81 mol, 1 eq) in THF (2 mL) was stirred at 25 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A40) (78 mg, 308.81 mol, 1 eq) was added. The resulting mixture was stirred at 25 C. for 10 minutes. The reaction mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 10%-40%, 10 minutes) to give the title compound (18.1 mg, 13% yield, 100% purity on LCMS) as a white solid.

[1628] .sup.1H NMR (DMSO-d.sub.6): 8.58-8.56 (m, 2H), 7.61 (br s, 1H), 7.41 (d, 2H), 6.99 (d, 1H), 3.03 (t, 2H), 2.96 (t, 2H), 2.90-2.78 (m, 8H), 2.11-2.04 (m, 2H), 1.82-1.75 (m, 2H) and 1.07 (t, 6H).

[1629] LCMS: m/z 449.2 (M+H).sup.+ (ES.sup.+).

Example 150: 3-(Benzyl(ethyl)amino)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)propane-1-sulfonamide

[1630] ##STR00472##

[1631] To a solution of 3-(benzyl(ethyl)amino)propane-1-sulfonamide (Intermediate P33) (90 mg, 351.06 mol, 1 eq) in THF (1 mL) was added t-BuONa (34 mg, 351.06 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) (101 mg, 351.06 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 20%-50%, 11.5 min) to give the title compound (66.21 mg, 35% yield, 100% purity on LCMS) as a white solid.

[1632] .sup.1H NMR (DMSO-d.sub.6): 8.13 (d, 1H), 7.72 (s, 1H), 7.32-7.20 (m, 6H), 7.06-7.01 (m, 2H), 6.83 (s, 1H), 3.85 (s, 3H), 3.53 (s, 2H), 3.19-3.15 (m, 1H), 3.04-3.01 (m, 2H), 2.44-2.40 (m, 4H), 1.68-1.64 (m, 2H), 1.15 (d, 6H) and 0.96 (t, 3H).

[1633] LCMS: m/z 543.4 (M+H).sup.+ (ES.sup.+).

Example 151: 3-(Benzyl(ethyl)amino)-N-((2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)propane-1-sulfonamide

[1634] ##STR00473##

[1635] To a solution of 3-(benzyl(ethyl)amino)propane-1-sulfonamide (Intermediate P33) (100 mg, 390.07 mol, 1 eq) in THF (1 mL) was added t-BuONa (37 mg, 390.07 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A37) (no mg, 390.07 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 28%-58%, 11.5 min) to give the title compound (37.69 mg, 18% yield, 100% purity on LCMS) as a white solid.

[1636] .sup.1H NMR (DMSO-d.sub.6): 10.49 (br s, 1H), 8.76 (d, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.76 (dd, 1H), 7.34-7.20 (m, 7H), 3.74 (s, 2H), 3.18-3.09 (m, 3H), 2.47-2.42 (m, 4H), 1.65-1.62 (m, 2H), 1.17 (d, 6H) and 0.96 (t, 3H).

[1637] LCMS: m/z 538.4 (M+H).sup.+ (ES.sup.+).

Example 152: 3-(Benzyl(ethyl)amino)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)propane-1-sulfonamide

[1638] ##STR00474##

[1639] To a solution of 3-(benzyl(ethyl)amino)propane-1-sulfonamide (Intermediate P33) (100 mg, 390.07 mol, 1 eq) in THF (1 mL) was added t-BuONa (37 mg, 390.07 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (146 mg, 390.07 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 18%-48%, 11.5 min) to give the title compound (35.98 mg, 17% yield, 98% purity on LCMS) as a white solid.

[1640] .sup.1H NMR (DMSO-d.sub.6): 10.31 (br s, 1H), 8.16 (d, 1H), 8.00 (s, 1H), 7.32-7.26 (m, 4H), 7.24 (d, 2H), 7.14 (d, 1H), 6.93 (d, 1H), 6.75 (s, 1H), 3.86 (s, 3H), 3.56 (s, 2H), 3.26-3.22 (m, 2H), 2.93 (t, 2H), 2.79 (t, 2H), 2.47-2.40 (m, 4H), 2.02-1.97 (m, 2H), 1.81-1.76 (m, 2H) and 0.96 (t, 3H).

[1641] LCMS: m/z 523.3 (M+H).sup.+ (ES.sup.+).

Example 153: 3-(Benzyl(ethyl)amino)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)propane-1-sulfonamide

[1642] ##STR00475##

[1643] To a solution of 3-(benzyl(ethyl)amino)propane-1-sulfonamide (Intermediate P33) (101 mg, 393.30 mol, 1 eq) in THF (1 mL) was added t-BuONa (38 mg, 393.30 mol, 1 eq). The reaction mixture was stirred at 15 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A40) (100 mg, 393.30 mol, 1 eq) was added. The resulting mixture was stirred at 15 C. for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (67.23 mg, 33% yield, 100% purity on LCMS) as a pink solid.

[1644] .sup.1H NMR (DMSO-d.sub.6): 8.57 (d, 2H), 7.86 (br s, 1H), 7.38 (d, 2H), 7.31 (d, 4H), 7.26-7.23 (m, 1H), 7.03 (d, 1H), 3.56 (s, 2H), 3.18-3.15 (m, 2H), 2.96 (t, 2H), 2.85 (t, 2H), 2.47-2.42 (m, 4H), 2.10-2.03 (m, 2H), 1.76-1.70 (m, 2H) and 0.96 (t, 3H).

[1645] LCMS: m/z 511.3 (M+H).sup.+ (ES.sup.+).

Example 154: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-3-methoxypropane-1-sulfonamide

[1646] ##STR00476##

[1647] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P34) (65 mg, 426.62 mol, 1.2 eq) in THF (1 mL) was added t-BuONa (34 mg, 355.51 mol, 1 eq) and the mixture was stirred at 25 C. for m minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A37) (100 mg, 355.51 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for m minutes. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 11.5 min) to give the title compound (113.93 mg, 74% yield, m0% purity on LCMS) as a white solid.

[1648] .sup.1HNMR (DMSO-d.sub.6): 8.71 (d, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.23-7.18 (m, 1H), 7.10 (d, 1H), 3.29-3.24 (m, 3H), 3.21 (s, 3H), 2.76-2.73 (m, 2H), 1.60-1.57 (m, 2H) and 1.16 (d, 6H).

[1649] LCMS: m/z 435.2 (M+H).sup.+ (ES.sup.+).

Example 155: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-3-methoxypropane-1-sulfonamide

[1650] ##STR00477##

[1651] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P34) (64 mg, 419.14 mol, 1.2 eq) in THF (1 mL) was added t-BuONa (34 mg, 349.28 mol, 1 eq) and the mixture was stirred at 25 C. for m minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) (100 mg, 349.28 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for m minutes. The mixture was concentrated in vacua. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (130.95 mg, 85% yield, 99.7% purity on LCMS) as a white solid.

[1652] .sup.1H NMR (DMSO-d.sub.6): 8.11 (d, 1H), 7.51 (s, 1H), 7.16 (d, 1H), 7.02-6.95 (m, 2H), 6.84 (s, 1H), 3.86 (s, 3H), 3.34-3.27 (m, 3H), 3.21 (s, 3H), 2.90-2.86 (m, 2H), 1.72-1.61 (m, 2H) and 1.15 (d, 6H).

[1653] LCMS: m/z 440.2 (M+H).sup.+ (ES.sup.+).

Example 156: 3-Methoxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)propane-1-sulfonamide

[1654] ##STR00478##

[1655] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P34) (72 mg, 469.98 mol, 1.2 eq) in THF (1 mL) was added t-BuONa (38 mg, 391.65 mol, 1 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (163 mg, 391.65 mol, 1 eq) was added. The resulting mixture was stirred at 70 C. for 10 minutes. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 11.5 min) to give the title compound (15.13 mg, 9% yield, 100% purity on LCMS) as a white solid.

[1656] .sup.1H NMR (DMSO-d.sub.6): 10.34 (br s, 1H), 8.17 (d, 1H), 7.97 (br s, 1H), 7.24 (d, 1H), 7.14 (d, 1H), 6.94 (d, 1H), 6.76 (s, 1H), 3.88 (s, 3H), 3.37 (t, 2H), 3.26-3.20 (m, 5H), 2.95 (t, 2H), 2.81 (t, 2H), 2.06-2.02 (m, 2H) and 1.84-1.78 (m, 2H).

[1657] LCMS: m/z 420.2 (M+H).sup.+ (ES.sup.+).

Example 157: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-3-methoxypropane-1-sulfonamide

[1658] ##STR00479##

[1659] To a solution of 3-methoxypropane-1-sulfonamide (Intermediate P34) (60 mg, 393.30 mol, 1 eq) in THF (1 mL) was added t-BuONa (38 mg, 393.30 mol, 1 eq). The reaction mixture was stirred at 15 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A40) (100 mg, 393.30 mol, 1 eq) was added. The resulting mixture was stirred at 15 C. for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 0%-30%, 10 min) to give the title compound (62.33 mg, 38% yield, 100% purity on LCMS) as a pink solid.

[1660] .sup.1H NMR (DMSO-d.sub.6): 8.57 (d, 2H), 7.63 (br s, 1H), 7.40 (d, 2H), 7.00 (d, 1H), 3.37-3.34 (m, 2H), 3.23 (s, 3H), 3.07-3.04 (m, 2H), 2.97 (t, 2H), 2.87 (t, 2H), 2.11-2.05 (m, 2H) and 1.79-1.72 (m, 2H).

[1661] LCMS: m/z 408.2 (M+H).sup.+ (ES.sup.+).

Example 158: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-(pyridin-3-yl)methanesulfonamide

[1662] ##STR00480##

[1663] To a solution of pyridin-3-ylmethanesulfonamide (70 mg, 406.49 mol, 1 eq) in THF (5 mL) was added t-BuONa (39 mg, 406.49 mol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A37) (114 mg, 406.49 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 11.5 min) to give the title compound (68 mg, 37% yield, 100% purity on LCMS) as a white solid.

[1664] .sup.1H NMR (DMSO-d.sub.6): 8.77 (d, 1H), 8.50 (d, 1H), 8.37 (s, 1H), 8.10 (s, 1H), 7.86 (br s, 1H), 7.79 (d, 1H), 7.61-7.45 (m, 1H), 7.33-7.27 (m, 2H), 7.19-7.02 (m, 1H), 4.31 (s, 2H), 3.24-3.18 (m, 1H) and 1.20-1.06 (m, 6H).

[1665] LCMS: m/z 454.3 (M+H).sup.+ (ES.sup.+).

Example 159: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-(pyridin-3-yl)methanesulfonamide

[1666] ##STR00481##

[1667] To a solution of pyridin-3-ylmethanesulfonamide (60 mg, 348.42 mol, 1 eq) in THF (5 mL) was added t-BuONa (33 mg, 348.42 mol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) (100 mg, 348.42 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (70 mg, 44% yield, 100% purity on LCMS) as a white solid.

[1668] .sup.1H NMR (DMSO-d.sub.6): 8.50 (d, 1H), 8.41 (s, 1H), 8.16 (d, 1H), 7.61 (br s, 1H), 7.50 (d, 1H), 7.33-7.30 (m, 1H), 7.21 (d, 1H), 7.06-7.00 (m, 2H), 6.87 (s, 1H), 4.33 (s, 2H), 3.85 (s, 3H), 3.22-3.17 (t, 1H) and 1.20-1.04 (m, 6H).

[1669] LCMS: m/z 459.3 (M+H).sup.+ (ES.sup.+).

Example 160: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(pyridin-3-yl)methanesulfonamide

[1670] ##STR00482##

[1671] To a solution of pyridin-3-ylmethanesulfonamide (70 mg, 406.49 mol, 1 eq) in THF (5 mL) was added t-BuONa (39 mg, 406.49 mol, 1 eq) and 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (108 mg, 406.49 mol, 1 eq). The mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 11.5 min) to give the title compound (65 mg, 36% yield, 100% purity on LCMS) as a white solid.

[1672] .sup.1H NMR (DMSO-d.sub.6): 8.52 (d, 1H), 8.46 (d, 1H), 8.16 (d, 1H), 7.61 (d, 1H), 7.37-7.34 (m, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 6.97-6.95 (m, 1H), 6.78 (s, 1H), 4.45 (s, 2H), 3.86 (s, 3H), 2.93 (t, 2H), 2.83 (t, 2H) and 2.07-1.98 (m, 2H).

[1673] LCMS: m/z 439.3 (M+H).sup.+ (ES.sup.+).

Example 161: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(pyridin-3-yl)methanesulfonamide

[1674] ##STR00483##

[1675] To a solution of pyridin-3-ylmethanesulfonamide (68 mg, 393.30 mol, 1 eq) in THF (2 mL) was added t-BuONa (38 mg, 393.30 mol, 1 eq). Then the reaction mixture was stirred at 25 C. for 10 minutes. A solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A40) (100 mg, 393.30 mol, 1 eq) in THF (2.5 mL) was added. The resulting mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 m; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 1%-31%, 10 min) to give the title compound (22.34 mg, 13%) as a white solid.

[1676] .sup.1H NMR (DMSO-d.sub.6): 8.57 (d, 2H), 8.49-8.45 (m, 2H), 7.59 (d, 1H), 7.39 (d, 2H), 7.34-7.30 (m, 1H), 6.96 (d, 1H), 4.34 (s, 2H), 2.95 (t, 2H), 2.87 (t, 2H) and 210-2.05 (m, 2H).

[1677] LCMS: m/z 427.2 (M+H).sup.+ (ES.sup.+).

Example 162: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-(1-methylpyrrolidin-3-yl) methanesulfonamide

[1678] ##STR00484##

[1679] A solution of (1-methylpyrrolidin-3-yl)methanesulfonamide (Intermediate P31) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 mL) was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (Intermediate A37) (57 mg, 201.96 mol, 0.2 eq) was added. The resulting mixture was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 10%-40%, 10.0 min) to give the title compound (17.51 mg, 4% yield, 100% purity on LCMS) as a white solid.

[1680] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): 8.70 (d, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.17 (dd, 1H), 7.06 (dd, 1H), 3.26-3.15 (m, 2H), 3.10-3.01 (m, 2H), 2.95-2.80 (m, 2H), 2.77-2.72 (m, 1H), 2.67 (s, 3H), 2.45-2.40 (m, 1H), 2.10-1.98 (m, 1H), 1.62-1.51 (m, 1H) and 1.13 (d, 6H).

[1681] LCMS: m/z 460.2 (M+H).sup.+ (ES.sup.+).

Example 163: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-(1-methylpyrrolidin-3-yl) methanesulfonamide

[1682] ##STR00485##

[1683] A solution of (1-methylpyrrolidin-3-yl)methanesulfonamide (Intermediate P31) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 mL) was stirred at 25 C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (Intermediate A38) (58 mg, 201.96 mol, 0.2 eq) was added. The resulting mixture was stirred at 25 C. for 30 minutes and then concentrated in vacua. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 12%-42%, 10.0 min) to give the title compound (4.92 mg, 1% yield, 100% purity on LCSM) as a white solid.

[1684] .sup.1H NMR (DMSO-d6+D20): 8.12 (d, 1H), 7.14-7.11 (m, 1H), 7.04-7.02 (m, 1H), 6.96-6.93 (m, 1H), 6.85-6.83 (m, 1H), 3.86 (s, 3H), 3.30-3.14 (m, 2H), 3.05-2.98 (m, 3H), 2.92-2.83 (m, 2H), 2.63 (s, 3H), 2.60-2.57 (m, 1H), 2.04-2.00 (m, 1H), 1.61-1.57 (m, 1H) and 1.14 (d, 6H).

[1685] LCMS: m/z 465.2 (M+H).sup.+ (ES.sup.+).

Example 164: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(1-methylpyrrolidin-3-yl) methanesulfonamide

[1686] ##STR00486##

[1687] A solution of (1-methylpyrrolidin-3-yl)methanesulfonamide (Intermediate P31) (180 mg, crude) and t-BuONa (97 mg, 1.01 mmol, 1 eq) in THF (3 mL) was stirred at 25 C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (54 mg, 201.96 mol, 0.2 eq) was added. The resulting mixture was stirred at 25 C. for 30 minutes and then concentrated in vacua. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 10%-40%, 10.0 min) to give the title compound (5.47 mg, 1% yield, 100% purity on LCMS) as a white solid.

[1688] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): 8.09 (d, 1H), 7.11 (d, 1H), 7.04 (d, 1H), 6.98 (d, 1H), 6.78 (s, 1H), 3.84 (s, 3H), 3.28-3.21 (m, 1H), 3.15-3.01 (m, 3H), 2.95-2.90 (m, 1H), 2.89-2.86 (m, 3H), 2.84-2.78 (m, 2H), 2.64 (s, 3H), 2.61-2.55 (m, 1H), 2.11-1.96 (m, 3H) and 1.66-1.55 (m, 1H).

[1689] LCMS: m/z 445.2 (M+H).sup.+ (ES.sup.+).

Example 165: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-(1-methylpyrrolidin-3-yl) methanesulfonamide

[1690] ##STR00487##

[1691] To a solution of (1-methylpyrrolidin-3-yl)methanesulfonamide (Intermediate P31) (180 mg, 1.01 mmol, 5 eq) in THF (2 mL) was added t-BuONa (97 mg, 1.01 mmol, 5 eq) and the mixture was stirred at 25 C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate A40) (51 mg, 201.96 mol, 1 eq) in THF (1.5 mL) was added. The reaction mixture was stirred at 25 C. for 30 minutes. Most of the solvent was evaporated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex Gemini C18, 150 mm*25 mm*5 m, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN), B %: 8%-38%, 10 min) to give the title compound (5.52 mg, 6% yield, 100% purity on LCMS) as a white solid.

[1692] .sup.1H NMR (DMSO-d.sub.6): 8.55 (d, 2H), 7.41 (d, 2H), 7.40 (br s, 1H), 6.95 (d, 1H), 3.12-3.08 (m, 2H), 2.97-2.85 (m, 7H), 2.75-2.71 (m, 1H), 2.58 (s, 3H), 2.53-2.50 (m, 1H), 2.09-2.00 (m, 3H) and 1.59-1.57 (m, 1H).

[1693] LCMS: m/z 433.2 (M+H).sup.+ (ES.sup.+).

Example 166: 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

[1694] ##STR00488##

[1695] A solution of N,N-bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P35) (2.2 g, 6.87 mmol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine (Intermediate A46) (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 m, 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.

[1696] .sup.1H NMR (DMSO-d.sub.6): 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), 3.03-3.00 (m, 1H), 1.30 (d, 6H) and 1.09-1.05 (m, 6H).

[1697] 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

[1698] ##STR00489##

[1699] 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.

[1700] .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), 3.12-3.07 (m, 1H), 1.29 (d, 6H) and 1.20-1.04 (m, 6H).

[1701] LCMS: m/z 635.1 (M+H).sup.+ (ES.sup.+).

Example 167: 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

[1702] ##STR00490##

[1703] A solution of N,N-bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P35) (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-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (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 m, 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.

[1704] .sup.1H NMR (DMSO-d.sub.6): 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).

[1705] 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

[1706] ##STR00491##

[1707] 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.

[1708] .sup.1H NMR (DMSO-d.sub.6): 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).

[1709] LCMS: m/z 587.1 (M+H).sup.+ (ES.sup.+).

Example 168: 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

[1710] ##STR00492##

[1711] To a solution of N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P36) (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 A46) (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 m; 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.

[1712] .sup.1H NMR (DMSO-d.sub.6): 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).

[1713] 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

[1714] ##STR00493##

[1715] 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.

[1716] .sup.1H NMR (DMSO-d.sub.6): 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).

[1717] LCMS: m/z 547.3 (M+H).sup.+ (ES.sup.+).

Example 169: 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

[1718] ##STR00494##

[1719] A solution of N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P36) (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 A39) (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.

[1720] .sup.1H NMR (DMSO-d.sub.6): 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).

[1721] LCMS: m/z 499.3 (M+H).sup.+ (ES.sup.+).

Example 170: 1-Cyclopropyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1722] ##STR00495##

[1723] 7-Fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A34) (60 mg, 0.232 mmol) and ((1-cyclopropyl-1H-pyrazol-3-yl)sulfonyl)(4-(dimethylamino)pyridin-1-ium-1-carbonyl)amide (Intermediate P37) (80 mg, 0.239 mmol) were suspended in MeCN (2 mL) and the mixture was heated to 50 C. for 1 hour. The MeCN was removed in vacuo. The residue was dissolved in DMSO (2 mL) and purified by basic prep-HPLC. After concentration of product containing fractions, the free acid (55 mg, 50%) was isolated as a colourless solid. This solid was dissolved in 0.1 M aq NaOH (1.17 mL, 1 eq) and freeze dried overnight to afford the title compound (50 mg, 43%) as a colourless solid.

[1724] .sup.1H NMR (DMSO-d6) 8.09-8.03 (m, 1H), 7.70 (d, J=9.9 Hz, 1H), 7.32 (s, 1H), 6.94 (s, 1H), 6.90 (d, J=9.3 Hz, 1H), 6.79 (s, 1H), 6.31-6.24 (m, 1H), 3.87 (s, 3H), 3.76-3.66 (m, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.02 (p, J=7.5 Hz, 2H), 1.08-1.00 (m, 2H), 0.99-0.90 (m, 2H).

[1725] LCMS; m/z 472.2 (M+H).sup.+ (ES.sup.+); 470.0 (MH).sup. (ES.sup.).

Example 171: 1-Cyclopropyl-N-((7-cyclopropyl-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1726] ##STR00496##

[1727] Prepared according to the general procedure of 1-cyclopropyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt (Example 170) from ((1-cyclopropyl-1H-pyrazol-3-yl)sulfonyl)(4-(dimethylamino)pyridin-1-ium-1-carbonyl)amide (Intermediate P37) and 7-cyclopropyl-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A47) to afford the title compound (36 mg, 39%) as a white solid.

[1728] .sup.1H NMR (DMSO-d6) 8.01 (d, J=5.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.24 (s, 1H), 6.90 (dd, J=5.3, 1.5 Hz, 1H), 6.74 (d, J=1.3 Hz, 1H), 6.54 (s, 1H), 6.28 (d, J=2.3 Hz, 1H), 3.85 (s, 3H), 3.76-3.67 (m, 1H), 2.95 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 1.98 (p, J=7.6 Hz, 2H), 1.90-1.80 (m, 1H), 1.08-1.01 (m, 2H), 0.98-0.92 (m, 2H), 0.90-0.84 (m, 2H), 0.67-0.59 (m, 2H).

[1729] LCMS; m/z 494.1 (M+H).sup.+ (ES.sup.+).

Example 172: 1-Cyclobutyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1730] ##STR00497##

[1731] 7-Fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A34) (154 mg, 0.596 mmol) was dissolved in DCM (5 mL). Saturated aqueous NaHCO.sub.3 (3 mL) was added, followed by a solution of triphosgene (70 mg, 0.236 mmol) in DCM (1 mL). The biphasic mixture was stirred at room temperature for 1 hour. Then the organic phase was dried by passing through a hydrophobic frit and concentrated in vacua to afford crude 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (85 mg, 50%) as a yellow solid that was used without further purification.

[1732] 1-Cyclobutyl-1H-pyrazole-3-sulfonamide (Intermediate P38) (60 mg, 0.298 mmol) was dissolved in dry THF (2 mL) and sodium tert-butoxide (2 M in THF) (160 l, 0.320 mmol) was added. The mixture was stirred at room temperature for 1 hour, before a solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (85 mg, 0.298 mmol) in THF (1 mL) was added. The mixture was stirred at room temperature overnight. Then the solvent removed in vacuo, the residue dissolved in DMSO (2 mL) and purified by basic prep-HPLC. The free acid was isolated as a colourless solid which was dissolved in 0.1 M aq NaOH (0.8 mL, 0.08 mmol, 1 eq) and the solution freeze dried to afford the title compound (37 mg, 24%) as a colourless solid.

[1733] .sup.1H NMR (DMSO-d6) 8.04 (d, J=5.1 Hz, 1H), 7.77-7.72 (m, 1H), 7.33 (s, 1H), 6.94 (d, J=4.6 Hz, 1H), 6.90 (d, J=9.3 Hz, 1H), 6.80 (s, 1H), 6.32-6.29 (m, 1H), 4.82 (p, J=8.3 Hz, 1H), 3.86 (s, 3H), 2.91 (t, J=7.4 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.49-2.41 (m, 2H), 2.39-2.31 (m, 2H), 2.00 (p, J=7.6 Hz, 2H), 1.83-1.70 (m, 2H).

[1734] LCMS; m/z 486.1 (M+H).sup.+ (ES.sup.+); 484.3 (MH).sup. (ES.sup.).

Example 173: 1-(1-(Azetidin-1-yl)-2-methylpropan-2-yl)-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1735] ##STR00498##

[1736] Prepared according to the general procedure of 1-cyclobutyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt (Example 172) from 1-(1-(azetidin-1-yl)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate P39) and 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A34) to afford the title compound (60 mg, 37%) as a colourless solid.

[1737] .sup.1H NMR (DMSO-d6) 8.07 (d, J=5.5 Hz, 1H), 7.70-7.66 (m, 1H), 7.34 (s, 1H), 6.96 (d, J=4.6 Hz, 1H), 6.90 (d, J=9.3 Hz, 1H), 6.81 (s, 1H), 6.30 (q, J=2.1 Hz, 1H), 3.87 (s, 3H), 2.95 (t, J=7.0 Hz, 4H), 2.91 (t, J=7.5 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 2.64 (s, 2H), 1.99 (p, J=7.6 Hz, 2H), 1.82 (p, J=7.0 Hz, 2H), 1.44 (s, 6H).

[1738] LCMS; m/z 543.1 (M+H).sup.+ (ES.sup.+); 541.0 (MH).sup. (ES.sup.).

Example 174: 2-Isopropoxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethanesulfonamide, sodium salt

[1739] ##STR00499##

[1740] 2-Isopropoxyethanesulfonamide (50 mg, 0.299 mmol) was dissolved in dry THF (2 mL). Sodium tert-butoxide (2M in THF) (160 l, 0.320 mmol) was added and the mixture was stirred at room temperature for 30 minutes. A solution of 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A48) (80 mg, 0.299 mmol) in THF (1 mL) was added and the mixture was stirred for 2 hours at room temperature. The THF was removed in vacuo. The residue was dissolved in DMSO (2 mL) and then purified by basic prep-HPLC to afford to afford 2-isopropoxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethanesulfonamide as a colourless solid. The solid was dissolved in aq NaOH (0.1 M, 0.74 mL, 1 eq) and the solution was freeze dried overnight to afford the title compound (30 mg, 22%) as a colourless solid.

[1741] .sup.1H NMR (DMSO-d6) 8.10 (d, J=5.3 Hz, 1H), 7.13-7.02 (m, 3H), 7.00 (d, J=5.3 Hz, 1H), 6.81 (s, 1H), 3.86 (s, 3H), 3.57-3.48 (m, 3H), 3.14-3.06 (m, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 1.99 (p, J=7.5 Hz, 2H), 1.07 (d, J=6.1 Hz, 6H).

[1742] LCMS; m/z 434.2 (M+H).sup.+ (ES.sup.+); 432.1 (MH).sup. (ES.sup.).

Example 175: 2-Isopropoxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)ethanesulfonamide, sodium salt

[1743] ##STR00500##

[1744] Prepared according to the general procedure of 2-isopropoxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethanesulfonamide, Sodium (Example 174) from 2-isopropoxyethanesulfonamide and 4-(4-isocyanato-2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine (Intermediate A49) and 2-isopropoxyethanesulfonamide to afford the title compound (22 mg, 16%) as a white solid.

[1745] .sup.1H NMR (DMSO-d6) 8.09 (d, J=5.3 Hz, 1H), 7.20 (s, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.96 (dd, J=5.3, 1.4 Hz, 1H), 6.77 (d, J=1.3 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H), 4.54 (t, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.65-3.47 (m, 3H), 3.20-3.09 (m, 4H), 1.07 (d, J=6.1 Hz, 6H).

[1746] LCMS; m/z 436.1 (M+H).sup.+ (ES.sup.+); 434.4 (MH).sup. (ES.sup.).

Example 221: 1-Cyclopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1747] ##STR00501##

[1748] 1-Cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P29) (516 mg, 2.76 mmol) was dissolved in THF (20 mL), and 2 M sodium tert-butoxide in THF (1.52 mL, 3.04 mmol) was added. After 1 hour, 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A39) (810 mg, 3.04 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. Then the reaction mixture was evaporated to dryness, redissolved in DMSO (5 mL) and purified by chromatography on RP Flash C18 (40 g cartridge, 5-50% MeCN/10 mM ammonium bicarbonate) to afford 1-cyclopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (830 mg, 1.83 mmol). The solid was dissolved with 0.1 M aqueous sodium hydroxide (18.30 mL, 1.83 mmol) and the solution obtained was freeze-dried to afford the title compound (837 mg, 63%) as a white solid.

[1749] .sup.1H NMR (DMSO-d6) 8.04 (d, J=5.3 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.34 (s, 1H), 7.07 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.92 (dd, J=5.2, 1.5 Hz, 1H), 6.75 (s, 1H), 6.28 (d, J=2.3 Hz, 1H), 3.86 (s, 3H), 3.71 (tt, J=7.6, 3.9 Hz, 1H), 2.88 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.4 Hz, 2H), 1.95 (p, J=7.5 Hz, 2H), 1.08-0.91 (m, 4H).

[1750] LCMS; m/z 454.3 (M+H).sup.+ (ES.sup.+); 452.1 (MH).sup. (ES.sup.).

[1751] The compounds of examples 176-220 and 222-323 were synthesised by methods analogous to those outlined above.

TABLE-US-00003 TABLE 2 .sup.1H NMR and MS data Ex Structure and Name 1H NMR spectrum MS MW 176 [00502] 6-((Dimethylamino)methyl)-N-((5-(2- 1H NMR (DMSO-d6) 10.25 (s broad, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.11- 8.05 (m, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.43 (s, 1H), 7.10 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 5.3 Hz, 1H), 6.69 (s, 1H), 4.21 (s, 2H), 3.86 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.62 (s, 6H), 1.94 (p, J = 7.5 Hz, 2H). m/z 482.2 (M + H).sup.+ (ES.sup.+). 481.6 methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)pyridine-3- sulfonamide 177 [00503] 2-((Dimethylamino)methyl)-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- 1H NMR (DMSO-d6) 8.46 (dd, J = 5.1, 0.8 Hz, 1H), 8.03 (dd, J = 5.3, 0.7 Hz, 1H), 7.69-7.66 (m, 1H), 7.41 (dd, J = 5.1, 1.6 Hz, 1H), 7.28 (br s, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (d, J = 1.2 Hz, 1H), 3.85 (s, 3H), 3.52 (s, 2H), 2.86 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.19 (s, 6H), 1.93 (p, J = 7.5 Hz, 2H). m/z 482.1 (M + H).sup.+ (ES.sup.+); 480.1 (M H).sup. (ES.sup.). 481.6 inden-4-yl)carbamoyl)pyridine-4- sulfonamide, sodium salt 178 [00504] 1H NMR (DMSO-d6) 8.48 (dd, J = 5.0, 0.8 Hz, 1H), 8.02 (d, J = 5.4 Hz, 1H), 7.48 (s, 1H), 7.36 (dd, J = 5.0, 1.6 Hz, 1H), 7.31 (br s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.89 (dd, J = 5.3, 1.4 Hz, 1H), 6.74 (s, 1H), 3.86 (s, 3H), 3.03 (sept, J = 6.9 Hz, 1H), 2.87 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 1.93 (p, J = 7.5 Hz, 2H), 1.23 (d, J = 6.9 Hz, 6H). m/z 467.3 (M + H).sup.+ (ES.sup.+); 465.2 (M H).sup. (ES.sup.). 466.6 2-Isopropyl-N-((5-(2-methoxypyridin-4- yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)pyridine-4-sulfonamide, sodium salt 179 [00505] .sup.1H NMR (DMSO-d6) 10.9 (br s, 1H), 8.50 (dd, J = 4.8, 1.7 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 7.94 (br s, 1H), 7.77 (br s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.35 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 7.12-7.07 (m, 2H), 6.54 (br s, 1H), 4.60 (app p, J = 6.7 Hz, 1H), 2.75 (br s, 2H), 2.47 (br s, 2H), 1.68 (br s, 4H), 1.44 (d, J = 6.7 Hz, 6H). m/z 440.4 (M + H).sup.+ (ES.sup.+). 439.5 1-Isopropyl-N-((2-(pyridin-3-yl)-5,6,7,8- tetrahydronaphthalen-1-yl)carbamoyl)- 1H-pyrazole-3-sulfonamide 180 [00506] 1H NMR (DMSO-d6) 10.87 (br s, 1H), 8.15 (d, J = 5.3 Hz, 1H), 7.95-7.86 (m, 2H), 7.21 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.91-6.87 (m, 1H), 6.73 (br s, 1H), 6.62 (br s, 1H), 3.89 (s, 3H), 3.75 (p, J = 5.8 Hz, 1H), 3.19 (t, J = 6.8 Hz, 2H), 3.09 (s, 3H), 2.91 (t, J = 7.3 Hz, 2H), 2.75 (s, 2H), 2.72-2.62 (m, 4H), 1.98 (p, J = 7.4 Hz, 2H), 1.49 (s, 6H). m/z 555.2 (M + H)+ (ES+) 554.66 1-(1-(3-Methoxyazetidin-1-yl)-2- methylpropan-2-yl)-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 181 [00507] N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1- 1H NMR (DMSO-d6) 8.57 (d, J = 5.1 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.63 (br s, 1H), 7.61 (dd, J = 5.1, 1.8 Hz, 1H), 7.12 (s, 2H), 6.25 (d, J = 2.4 Hz, 1H), 5.00 (ddt, J = 7.9, 6.1, 3.8 Hz, 1H), 3.99- 3.91 (m, 2H), 3.86 (dd, J = 9.4, 3.7 Hz, 1H), 3.79 (td, J = 8.4, 5.6 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.39-2.33 (m, 1H), 2.22 (m,, 1H), 1.97 (p, J = 7.5 Hz, 2H). m/z 479.3 (M + H)+ (ES+) 478.52 (tetrahydrofuran-3-yl)-1H-pyrazole-3- sulfonamide, sodium salt 182 [00508] 1H NMR (DMSO-d6) 8.56 (d, J = 5.1 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.64 (br s, 1H), 7.60 (dd, J = 5.1, 1.7 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.11 (s, 2H), 6.23 (d, J = 2.2 Hz, 1H), 4.90 (s, 1H), 4.04- 3.90 (m, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.78 (t, J = 7.5 Hz, 2H), 1.98 (p, J = 7.6 Hz, 2H), 1.01 (d, J = 5.9 Hz, 3H). m/z 467.3 (M + H)+ (ES+) 466.51 (R)-N-((5-(2-Cyanopyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1-(2- hydroxypropyl)-1H-pyrazole-3- sulfonamide, sodium salt 183 [00509] 1H NMR (DMSO-d6) 8.58 (d, J = 5.1 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 5.1, 1.7 Hz, 1H), 7.58 (br s, 1H), 7.55 (d, J = 2.3 Hz, 1H), 7.11 (s, 2H), 6.24 (d, J = 2.2 Hz, 1H), 4.68 (s, 1H), 3.99 (s, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 1.97 (p, J = 7.5 Hz, 2H), 1.03 (s, 6H). m/z 481.3 (M + H)+ (ES+) 480.53 N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1-(2-hydroxy- 2-methylpropyl)-1H-pyrazole-3- sulfonamide, sodium salt 184 [00510] (R)-1-(2-Hydroxypropyl)-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- 1H NMR (DMSO-d6) 8.11 (d, J = 5.3 Hz, 1H), 7.80-7.64 (m, 2H), 7.16 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 5.3 Hz, 1H), 6.73 (s, 1H), 6.55- 6.43 (m, 1H), 4.99 (d, J = 5.0 Hz, 1H), 4.09-4.01 (m, 2H), 3.97 (p, J = 5.9 Hz, 1H), 3.88 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 1.98 (p, J = 7.5 Hz, 2H), 1.04 (d, J = 6.2 Hz, 3H). One exchangeable proton not observed. m/z 472.3 (M + H)+ (ES+) 471.53 inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 185 [00511] 1H NMR (DMSO-d6) 8.11 (d, J = 5.2 Hz, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (s, 1H), 6.53 (s, 1H), 4.17 (s, 2H), 3.88 (s, 3H), 3.16 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H), 1.06 (s, 6H). One exchangeable proton not observed. m/z 500.3 (M + H)+ (ES+) 499.58 1-(2-Methoxy-2-methylpropyl)-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 186 [00512] 1H NMR (DMSO-d6) 8.11 (d, J = 5.3 Hz, 1H), 7.84-7.61 (m, 2H), 7.16 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (s, 1H), 6.51 (s, 1H), 4.76 (s, 1H), 4.06 (s, 2H), 3.88 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H), 1.05 (s, 6H). One exchangeable proton not observed sulfonamide m/z 486.3 (M + H)+ (ES+) 485.56 1-(2-Hydroxy-2-methylpropyl)-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 187 [00513] N-((5-(2-Methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1- (tetrahydrofuran-3-yl)-1H-pyrazole-3- 1H NMR (DMSO-d6) 8.10 (d, J = 5.3 Hz, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (s, 1H), 6.55 (s, 1H), 5.13-5.06 (m, 1H), 4.00-3.95 (m, 2H), 3.91- 3.86 (m, 4H), 3.82 (td, J = 8.4, 5.6 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.66 (t, J = 7.4 Hz, 2H), 2.49-2.35 (m, 1H), 2.29-2.19 (m, 1H), 1.97 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. m/z 484.2 (M + H)+ (ES+) 483.54 sulfonamide 188 [00514] 5-(3-Methoxyoxetan-3-yl)-N-((5-(2- 1H NMR (DMSO-d6) 10.90 (s, 1H), 8.14 (d, J = 5.2 Hz, 1H), 7.82 (s, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.96 (s, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.74- 6.72 (m, 1H), 4.87 (d, J = 7.3 Hz, 2H), 4.80 (d, J = 7.3 Hz, 2H), 3.73 (s, 3H), 3.32 (s, 3H), 2.98 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H). m/z 514.3 (M + H)+ (ES+) 513.57 methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1-methyl-1H- pyrazole-3-sulfonamide 189 [00515] .sup.1H NMR (DMSO-d6) 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 2-(3-(N-((5-(2-Methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4- yl)carbamoyl)sulfamoyl)-1H-pyrazol-1- yl)-N,N,2-trimethylpropanamide 190 [00516] .sup.1H NMR (DMSO-d6) 8.07-8.04 (m, 1H), 7.36 (s, 1H), 7.07 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.96-6.92 (m, 1H), 6.76 (s, 1H), 6.28- 6.24 (m, 1H), 3.86 (s, 3H), 3.78-3.74 (m, 2H), 3.63- 3.57 (m, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.30 (d, J = 6.2 Hz, 3H), 2.08-1.99 (m, 1H), 1.94 (p, J = 7.5 Hz, 2H), 1.10-1.04 (m, 2H), 0.97-0.92 (m, 2H). m/z 497.2 (M + H).sup.+ (ES.sup.+); 495.0 (M H).sup. (ES.sup.+). 496.6 1-Cyclopropyl-N-((5-(2-methoxypyridin- 4-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-5-((methylamino)methyl)- 1H-pyrazole-3-sulfonamide, sodium salt 191 [00517] 1-Isopropyl-N-((5-(2-methoxypyridin-4- .sup.1H NMR (DMSO-d6) 8.06 (d, J = 5.3 Hz, 1H), 7.45 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 5.3 Hz, 1H), 6.78 (s, 1H), 6.24 (s, 1H), 4.75 (sept, J = 6.7 Hz, 1H), 3.87 (s, 3H), 3.14-3.08 (m, 1H), 2.86 (t, J = 7.4 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.25-2.19 (m, 2H), 2.17 (s, 3H), 1.89 (p, J = 7.4 Hz, 2H), 1.85-1.58 (m, 4H), 1.38 (d, J = 6.6 Hz, 3H), 1.34 (d, J = 6.5 Hz, 3H). m/z 539.3 (M + H).sup.+ (ES.sup.+); 537.1 (M H).sup. (ES.sup.). 538.7 yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-5-(1-methylpyrrolidin-2- yl)-1H-pyrazole-3-sulfonamide, sodium salt 192 [00518] 5-(1-(Dimethylamino)propyl)-1-isopropyl- N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide .sup.1H NMR (DMSO-d6) 10.84 (s, 1H), 8.15 (dd, J = 5.2, 0.6 Hz, 1H), 7.90 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.4 Hz, 1H), 6.72 (d, J = 1.4 Hz, 1H), 6.57 (s, 1H), 4.86 (sept, J = 6.6 Hz, 1H), 3.88 (s, 3H), 3.75-3.67 (m, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H), 2.14 (s, 6H), 1.92 (p, J = 7.4 Hz, 2H), 1.89- 1.80 (m, 1H), 1.71-1.60 (m, 1H), 1.41 (d, J = 6.5 Hz, 3H), 1.34 (d, J = 6.5 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H). m/z 541.3 (M + H).sup.+ (ES.sup.+); 539.3 (M H).sup. (ES.sup.). 540.7 193 [00519] 5-((Dimethylamino)methyl)-1-isopropyl- .sup.1H NMR (DMSO-d6) 10.85 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.91 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.73-6.71 (m, 1H), 6.55 (s, 1H), 4.81 (sept, J = 6.6 Hz, 1H), 3.88 (s, 3H), 3.50 (s, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.59 (t, J = 7.4 Hz, 2H), 2.16 (s, 6H), 1.95 (p, J = 7.6 Hz, 2H), 1.38 (d, J = 6.6 Hz, 6H). m/z 513.3 (M + H).sup.+ (ES.sup.+); 511.3 (M H).sup. (ES.sup.). 512.6 N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 194 [00520] .sup.1H NMR (DMSO-d6) 10.74 (s, 1H), 7.79 (s, 1H), 7.33-7.28 (m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.95- 6.91 (m, 1H), 6.87-6.79 (m, 2H), 6.61 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.51 (s, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.58 (t, J = 7.4 Hz, 2H), 2.18 (s, 6H), 1.95 (p, J = 7.5 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). m/z 498.4 (M + H).sup.+ (ES.sup.+); 496.1 (M H).sup. (ES.sup.). 497.6 5-((Dimethylamino)methyl)-1-ethyl-N- ((5-(3-methoxyphenyl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 195 [00521] 1-(2-Cyanopropan-2-yl)-N-((5-(2- 1H NMR (DMSO-d6) 8.15 (d, J = 5.3 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 73.2 Hz, 1H), 7.62 (br s, 1H), 7.20 (dd, J = 5.3, 1.5 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 1.5 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.45 (d, J = 2.8 Hz, 1H), 4.51 (t, J = 8.2 Hz, 2H), 3.08 (t, J = 8.2 Hz, 2H), 1.96 (s, 6H). One exchangeable proton not observed. m/z 519.1 (M + H)+ (ES+) 518.49 (difluoromethoxy)pyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 196 [00522] 1H NMR (DMSO-d6) 11.17 (br s, 1H), 8.16 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.95 (br s, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.87 (dd, J = 5.3, 1.4 Hz, 1H), 6.77-6.66 (m, 3H), 4.53 (t, J = 8.7 Hz, 2H), 3.88 (s, 3H), 3.00 (t, J = 8.7 Hz, 2H), 2.00 (s, 6H). m/z 483.2 (M + H)+ (ES+) 482.51 1-(2-Cyanopropan-2-yl)-N-((5-(2- methoxypyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 197 [00523] N-((5-(2-Methoxypyridin-4-yl)-2,3- 1H NMR (DMSO-d6) 8.05 (dd, J = 5.3, 0.7 Hz, 1H), 7.73 (d, J = 2 .4 Hz, 1H), 7.37 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.92 (dd, J = 5.3, 1.5 Hz, 1H), 6.77- 6.75 (m, 1H), 6.32 (d, J = 2.3 Hz, 1H), 3.87 (s, 3H), 2.87 (t, J = 7.4 Hz, 2H), 2.74 (d, J = 7.9 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.17 (d, J = 6.1 Hz, 3H), 1.93 (p, J = 7.5 Hz, 2H), 1.48 (s, 6H), 1.35-1.24 (m, 1H). m/z 499.2 (M + H)+ (ES+) 498.60 dihydro-1H-inden-4-yl)carbamoyl)-1-(2- methyl-1-(methylamino)propan-2-yl)-1H- pyrazole-3-sulfonamide, sodium salt 198 [00524] 1H NMR (DMSO-d6) 8.12-8.06 (m, 1H), 7.72- 7.65 (m, 1H), 7.47-7.37 (m, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.96-6.93 (m, 1H), 6.83 (s, 1H), 6.61 (d, J = 8.4, 3.4 Hz, 1H), 6.35- 6.30 (m, 1H), 4.49 (t, J = 8.8 Hz, 2H), 4.22-4.17 (m, 1H), 3.04 (t, J = 8.8 Hz, 2H), 1.92 (s, 6H), 1.48 (s, 6H), 0.81-0.64 (m, 4H). One CH2 obscured by DMSO peak. m/z 541.2 (M + H)+ (ES+) 540.63 N-((5-(2-Cyclopropoxypyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1-(1- (dimethylamino)-2-methylpropan-2-yl)- 1H-pyrazole-3-sulfonamide, sodium salt 199 [00525] 1H NMR (DMSO-d6) 8.03 (d, J = 5.2 Hz, 1H), 7.74-7.70 (m, 1H), 7.36 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 5.9 Hz, 1H), 6.75 (s, 1H), 6.32- 6.29 (m, 1H), 4.92-4.85 (m, 1H), 3.86 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.83-2.67 (m, 5H), 2.45- 2.39 (m, 1H), 2.39-2.30 (m, 1H), 2.28 (s, 3H), 2.08-1.99 (m, 1H), 1.94 (p, J = 7.6 Hz, 2H). m/z 497.1 (M + H)+ (ES+) 496.58 N-((5-(2-Methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1-(1- methylpyrrolidin-3-yl)-1H-pyrazole-3- sulfonamide, sodium salt 200 [00526] 1H NMR (DMSO-d6) 8.09 (d, J = 5.3 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.37 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.97 (dd, J = 5.2, 1.4 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.20 (tt, J = 6.2, 3.1 Hz, 1H), 2.87 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.53 (s, 2H), 1.98-1.89 (m, 8H), 1.49 (s, 6H), 0.81-0.74 (m, 2H), 0.70-0.64 (m, 2H). m/z 539.1 (M + H)+ (ES+) 538.66 N-((5-(2-Cyclopropoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1-(1- (dimethylamino)-2-methylpropan-2-yl)- 1H-pyrazole-3-sulfonamide, sodium salt 201 [00527] 1-(2-Cyanopropan-2-yl)-N-((5-(2- 1H NMR (DMSO-d6) 8.07 (d, J = 5.3, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.38 (br s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 5.3, 1.4 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 3.87 (s, 3H), 2.88 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 1.97 (s, 6H), 2.73 (p, J = 7.5 Hz, 2H). m/z 481.3 (M + H)+ (ES+) 480.54 methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 202 [00528] 1H NMR (DMSO-d6) 10.93 (br. s, 1H), 8.70 (dd, J = 5.1, 0.8 Hz, 1H), 8.15 (br. s, 1H), 7.96 (dd, J = 1.8, 0.8 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.64 (dd, J = 5.1, 1.8 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 2.94 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.59 (s, 2H), 2.01 (p, J = 7.6 Hz, 2H), 1.92 (s, 6H), 1.52 (s, 6H). m/z 508.4 (M + H)+ (ES+) 507.61 N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1-(1- (dimethylamino)-2-methylpropan-2-yl)- 1H-pyrazole-3-sulfonamide 203 [00529] 1H NMR (DMSO-d6) 10.81 (s, 1H), 8.55 (dd, J = 4.8, 1.7 Hz, 1H), 8.49 (dd, J = 2.3, 0.8 Hz, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.92 (s, 1H), 7.70-7.66 (m, 1H), 7.44-7.40 (m, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 2.92 (t, J = 7.4 Hz, 2H), 2.68-2.61 (m, 2H), 2.59 (s, 2H), 1.98 (p, J = 7.5 Hz, 2H), 1.93 (s, 6H), 1.53 (s, 6H). m/z 483.5 (M + H)+ (ES+) 482.60 1-(1-(Dimethylamino)-2-methylpropan-2- yl)-N-((5-(pyridin-3-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 204 [00530] 1H NMR (DMSO-d6) 11.25 (s, 1H), 7.99-7.81 (m, 2H), 7.68 (s, 1H), 7.45- 7.34 (m, 2H), 7.26-7.13 (m, 2H), 6.98 (s, 1H), 6.59 (s, 1H), 4.61 (hept, J = 6.8 Hz, 1H), 3.09-2.91 (m, 1H), 1.44 (d, J = 6.7 Hz, 6H), 1.09 (d, J = 6.9 Hz, 6H). m/z 417.4 (M + H).sup.+ (ES.sup.+); 415.1 (M H).sup. (ES.sup.) 416.50 N-((2-(1H-Imidazol-1-yl)-6- isopropylphenyl)carbamoyl)-1-isopropyl- 1H-pyrazole-3-sulfonamide 205 [00531] 1H NMR (DMSO-d6) 10.92 (br s, 1H), 8.62- 8.46 (m, 2H), 7.93 (d, J = 2.3 Hz, 1H), 7.88 (br s, 1H), 7.37-7.25 (m, 2H), 7.03 (d, J = 9.2 Hz, 1H), 6.58 (s, 1H), 4.60 (sept, J = 6.7 Hz, 1H), 2.95 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.1 Hz, 2H), 2.04 (p, J = 7.6 Hz, 2H), 1.44 (d, J = 6.7 Hz, 6H). m/z 444.3 (M + H).sup.+ (ES.sup.+); 442.4 (M H).sup. (ES.sup.) 443.49 N-((7-Fluoro-5-(pyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide 206 [00532] N-((7-Fluoro-5-(pyridin-3-yl)-2,3- 1H NMR (DMSO-d6) 10.90 (s, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 8.51 (d, J = 2.3 Hz, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.73- 7.68 (m, 1H), 7.40 (dd, J = 7.9, 4.8 Hz, 1H), 7.02 (d, J = 9.3 Hz, 1H), 6.56 (s, 1H), 4.60 (sept, J = 6.6 Hz, 1H), 2.95 (t, J = 7.4 Hz, 2H), 2.68 (t, J = 7.4 Hz, 2H), 2.04 (p, J = 7.6 Hz, 2H), 1.44 (d, J = 6.7 Hz, 6H). m/z 444.3 (M + H).sup.+ (ES.sup.+); 442.3 (M H).sup. (ES.sup.) 443.49 dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide 207 [00533] 1H NMR (DMSO-d6) 11.13 (s, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.57 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.03-7.97 (m, 2H), 7.95 (s, 1H), 7.90-7.78 (m, 2H), 7.61-7.52 (m, 3H), 7.43 (dd, J = 7.8, 4.8 Hz, 1H), 6.57 (s, 1H), 4.64 (sept, J = 6.7 Hz, 1H), 1.47 (d, J = 6.7 Hz, 6H). m/z 436.4 (M + H).sup.+ (ES.sup.+); 434.3 (M H).sup. (ES.sup.) 435.50 1-Isopropyl-N-((2-(pyridin-3- yl)naphthalen-1-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 208 [00534] 1H NMR (DMSO-d6) 10.88 (s, 1H), 8.58 (d, J = 2.3 Hz, 2H), 8.56 (dd, J = 4.8, 1.6 Hz, 2H), 7.90 (s, 1H), 7.84 (s, 1H), 7.82- 7.76 (m, 2H), 7.38 (dd, J = 7.9, 4.8 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 6.24 (s, 1H), 4.57 (sept, J = 6.7 Hz, 1H), 1.42 (d, J = 6.7 Hz, 6H). m/z 481.3 (M + H).sup.+ (ES.sup.+) 480.51 N-((4-Fluoro-2,6-di(pyridin-3- yl)phenyl)carbamoyl)-1-isopropyl-1H- pyrazole-3-sulfonamide 209 [00535] 1H NMR (DMSO-d6) 11.15 (s, 1H), 8.38 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.62-7.52 (m, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 6.2 Hz, 1H), 6.88 (s, 1H), 6.58 (s, 1H), 4.62 (sept, J = 7.0 Hz, 1H), 3.91 (s, 3H), 1.46 (d, J = 6.7 Hz, 6H). m/z 466.4 (M + H).sup.+ (ES.sup.+); 464.3 (M H).sup. (ES.sup.) 465.52 1-Isopropyl-N-((2-(2-methoxypyridin-4- yl)naphthalen-1-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 210 [00536] N-((2-Cyclopropyl-4-fluoro-6-(2- 1H NMR (DMSO-d6) 10.97 (s, 1H), 8.09 (d, J = 5.3 Hz, 1H), 7.95-7.85 (m, 2H), 7.00 (dd, J = 8.9, 3.0 Hz, 1H), 6.91 (d, J = 5.3 Hz, 1H), 6.83 (dd, J = 10.0, 3.0 Hz, 1H), 6.78 (s, 1H), 6.56 (s, 1H), 4.57 (sept, J = 6.7 Hz, 1H), 3.88 (s, 3H), 1.88-1.79 (m, 1H), 1.42 (d, J = 6.7 Hz, 6H), 0.86-0.77 (m, 2H), 0.70-0.59 (m, 2H). m/z 474.4 (M + H).sup.+ (ES.sup.+); 472.3 (M H).sup. (ES.sup.) 473.52 methoxypyridin-4-yl)phenyl)carbamoyl)- 1-isopropyl-1H-pyrazole-3-sulfonamide 211 [00537] N-((2-Cyclopentyl-4-fluoro-6-(2- 1H NMR (DMSO-d6) 10.94 (s, 1H), 8.09 (d, J = 5.3 Hz, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 7.20 (dd, J = 10.1, 3.0 Hz, 1H), 7.03 (dd, J = 8.9, 3.0 Hz, 1H), 6.91 (dd, J = 5.3, 1.4 Hz, 1H), 6.77 (s, 1H), 6.55 (s, 1H), 4.58 (sept, J = 6.7 Hz, 1H), 3.88 (s, 3H), 3.08-2.98 (m, 1H), 1.95- 1.80 (m, 2H), 1.80-1.69 (m, 2H), 1.59-1.49 (m, 2H), 1.47-1.38 (m, 2H), 1.43 (d, J = 6.7 Hz, 6H). m/z 502.4 (M + H).sup.+ (ES.sup.+); 500.3 (M H).sup. (ES.sup.) 501.57 methoxypyridin-4-yl)phenyl)carbamoyl)- 1-isopropyl-1H-pyrazole-3-sulfonamide 212 [00538] 1-Isopropyl-N-((6-(2-methoxypyridin-4- 1H NMR (DMSO-d6) 11.24 (s, 1H), 8.97-8.94 (m, 1H), 8.46 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 5.3 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.92 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.58 (dd, J = 8.6, 4.2 Hz, 1H), 7.03 (d, J = 5.4 Hz, 1H), 6.89 (d, J = 1.2 Hz, 1H), 6.57 (s, 1H), 4.61 (sept, J = 6.7 Hz, 1H), 3.92 (s, 3H), 1.45 (d, J = 6.7 Hz, 6H). m/z 467.4 (M + H).sup.+ (ES.sup.+); 465.2 (M H).sup. (ES.sup.) 466.51 yl)quinolin-5-yl)carbamoyl)-1H-pyrazole- 3-sulfonamide 213 [00539] .sup.1H NMR (DMSO-d6) 10.9 (br. s, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.93 (br. s, 1H), 7.75 (br. s, 1H), 7.11- 7.06 (m, 2H), 6.84 (d, J = 5.0 Hz, 1H), 6.69 (br. s, 1H), 6.58 (br. s, 1H), 4.59 (app. p, J = 6.7 Hz, 1H), 3.87 (s, 3H), 2.75 (s, 2H), 2.46 (br. s, 2H), 1.67 (br. s, 4H), 1.43 (d, J = 6.7 Hz, 6H). m/z 470.2 (M + H).sup.+ (ES.sup.+) 469.56 1-Isopropyl-N-((2-(2-methoxypyridin-4- yl)-5,6,7,8-tetrahydronaphthalen-1- yl)carbamoyl)-1H-pyrazole-3-sulfonamide 214 [00540] N-((5-(2-Ethoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide .sup.1H NMR (DMSO-d.sub.6) 10.85 (s, 1H), 8.09 (d, J = 5.3 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.83 (dd, J = 5.3, 1.5 Hz, 1H), 6.69- 6.65 (m, 1H), 6.63 (s, 1H), 4.60 (app. p, J = 6.6 Hz, 1H), 4.33 (q, J = 7.0 Hz, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H), 1.43 (d, J = 6.7 Hz, 6H), 1.34 (t, J = 7.0 Hz, 3H). m/z 470.6, 492.2 (M + H, M + Na).sup.+ (ES.sup.+) 469.6 215 [00541] N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1-isopropyl- .sup.1H NMR (DMSO-d.sub.6) 11.05 (br. s, 1H), 8.67 (d, J = 5.1 Hz, 1H), 8.16 (br. s, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 5.1, 1.8 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H), 4.58 (sept, J = 6.6 Hz, 1H), 2.93 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 7.3 Hz, 2H), 1.99 (p, J = 7.5 Hz, 2H), 1.42 (d, J = 6.7 Hz, 6H). m/z 451.0 (M + H).sup.+ (ES.sup.+) 450.5 1H-pyrazole-3-sulfonamide 216 [00542] N-((5-(2-Isopropoxypyridin-4-yl)-2,3- .sup.1H NMR (DMSO-d.sub.6) 10.84 (br. s, 1H), 8.08 (dd, J = 5.2, 0.7 Hz, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.80 (dd, J = 5.3, 1.5 Hz, 1H), 6.63 (dd, J = 1.5, 0.7 Hz, 1H), 6.61 (s, 1H), 5.27 (app. p, J = 6.2 Hz, 1H), 4.59 (sept, J = 6.7 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H), 1.43 (d, J = 6.7 Hz, 6H), 1.31 (d, J = 6.2 Hz, 6H). m/z 484.4 (M + H).sup.+ (ES.sup.+) 483.6 dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide 217 [00543] 1-Isopropyl-N-((7-(2-methoxypyridin-4- .sup.1H NMR (DMSO-d.sub.6) 11.32 (br s, 1H), 9.24 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.40 (br. s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 5.8 Hz, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.05 (dd, J = 5.2, 1.5 Hz, 1H), 6.91-6.82 (m, 1H), 6.51 (d, J = 6.9 Hz, 1H), 4.60 (hept, J = 6.5 Hz, 1H), 3.91 (s, 3H), 1.45 (d, J = 6.7 Hz, 6H). m/z 467.3 (M + H).sup.+ (ES.sup.+) 466.5 yl)isoquinolin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 218 [00544] 1-Isopropyl-N-((5-(2-oxo-1,2- .sup.1H NMR (DMSO-d6) 11.52 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.25 (d, J = 6.8 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.49 (s, 1H), 6.20 (d, J = 1.7 Hz, 1H), 6.15-6.03 (m, 1H), 4.53 (sept, J = 6.7 Hz, 1H), 2.88 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.41 (d, J = 6.7 Hz, 6H). One NH not resolved. m/z 442.1 (M + H).sup.+ (ES.sup.+); 439.9 (M H).sup. (ES.sup.) 441.5 dihydropyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 219 [00545] 1H NMR (DMSO-d6) 10.72 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.86 (s, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (d, J = 1.3 Hz, 1H), 6.60 (s, 1H), 3.89 (s, 3H), 3.32 (br s, 2H), 3.03 (br s, 2H), 2.91 (t, J = 7.4 Hz, 2H), 2.80 (br s, 2H), 2.69-2.61 (m, 2H), 1.97 (p, J = 7.6 Hz, 2H), 1.91- 1.78 (m, 2H), 1.50 (s, 6H). m/z 525.4 (M + H).sup.+ (ES.sup.+); 523.2 (M H).sup. (ES.sup.) 524.6 1-(1-(Azetidin-1-yl)-2-methylpropan-2- yl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 220 [00546] 1H NMR (DMSO-d6) 10.82 (bs, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.70 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.65 (s, 1H), 5.93 (s, 1H), 4.62 (sept, J = 6.6 Hz, 1H), 3.36 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 2.63 (t, J = 7.4 Hz, 2H), 2.17 (s, 3H), 1.97 (p, J = 7.5 Hz, 2H), 1.49-1.42 (m, 6H). m/z 443.3 (M + H).sup.+ (ES.sup.+) 442.5 N-((5-(1,3-Dimethyl-1H-pyrazol-5-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide 221 [00547] 1-Cyclopropyl-N-((5-(2-methoxypyridin- 1H NMR (DMSO-d6) 8.04 (d, J = 5.3 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.34 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.92 (dd, J = 5.2, 1.5 Hz, 1H), 6.75 (s, 1H), 6.28 (d, J = 2.3 Hz, 1H), 3.86 (s, 3H), 3.71 (tt, J = 7.6, 3.9 Hz, 1H), 2.88 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.08-0.91 (m, 4H). m/z 454.3 (M + H).sup.+ (ES.sup.+); 452.1 (M H).sup. (ES.sup.) 453.5 4-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 222 [00548] N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- .sup.1H NMR (DMSO-d6) 8.58 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.63 (br s, 1H), 7.62 (dd, J = 5.2, 1.6 Hz, 1H), 7.12 (s, 2H), 6.21 (d, J = 2.3 Hz, 1H), 3.70 (tt, J = 7.5, 3.9 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 1.98 (p, J = 7.4 Hz, 2H), 1.04-0.91 (m, 4H). m/z 449.3 (M + H).sup.+ (ES.sup.+); 447.2 (M H).sup. (ES.sup.) 448.5 1H-inden-4-yl)carbamoyl)-1-cyclopropyl- 1H-pyrazole-3-sulfonamide, sodium salt 223 [00549] 1H NMR (DMSO-d6) 9.19 (dd, J = 2.4, 1.3 Hz, 1H), 9.07 (dd, J = 5.3, 1.3 Hz, 1H), 7.84-7.58 (m, 2H), 7.55 (dd, J = 5.4, 2.4 Hz, 1H), 7.15 (s, 2H), 6.29 (d, J = 2.3 Hz, 1H), 4.51 (sept, J = 6.7 Hz, 1H), 2.90 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 1.97 (p, J = 7.5 Hz, 2H), 1.41 (d, J = 6.7 Hz, 6H). m/z 427.3 (M + H).sup.+ (ES.sup.+) 426.5 1-Isopropyl-N-((5-(Pyridazin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 224 [00550] .sup.1H NMR (DMSO-d.sub.6) 8.03 (d, J = 5.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.45 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 5.3 Hz, 1H), 6.73 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 4.66-4.36 (m, 3H), 3.86 (s, 3H), 3.03 (t, J = 8.8 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 458.3 (M + H).sup.+ (ES.sup.+) 457.5 1-Isopropyl-N-((5-(2-methoxypyridin-4- yl)-2,3-dihydrobenzofuran-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 225 [00551] 1H NMR (DMSO-d6) 8.66 (d, J = 5.0 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.76 (s, 1H), 7.65 (dd, J = 5.0, 1.6 Hz, 1H), 7.29 (s, 1H), 7.09 (s, 1H), 6.37 (s, 1H), 4.54 (hept, J = 6.7 Hz, 1H), 2.96 (t, J = 7.5 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H), 1.42 (d, J = 6.7 Hz, 6H). One NH not observed. m/z 485.2, 487.2 (M + H).sup.+ (ES.sup.+); 482.7 (M H).sup. (ES.sup.) 485 N-((7-Chloro-5-(2-cyanopyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide, sodium salt 226 [00552] 1H NMR (DMSO-d6) 8.04 (d, J = 5.3 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.44 (s, 1H), 7.10 (s, 1H), 6.91 (d, J = 5.3, Hz, 1H), 6.78 (s, 1H), 6.31 (d, J = 2.3 Hz, 1H), 4.50 (hept, J = 6.7 Hz, 1H), 3.86 (s, 3H), 2.91 (t, J = 7.6 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H), 1.98 (p, J = 7.6 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 489.9, 492.5 (M + H).sup.+ (ES.sup.+); 488.2, 490.2 (M H).sup. (ES.sup.). 489.98 N-((7-Chloro-5-(2-methoxypyridin-4-yl) 2,3-dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide, sodium salt 227 [00553] 1H NMR (DMSO-d6) 8.62 (d, J = 5.1 Hz, 1H), 7.96-7.83 (m, 2H), 7.80 (s, 1H), 7.63 (dd, J = 5.1, 1.8 Hz, 1H), 7.21-7.15 (m, 2H), 6.37 (s, 1H), 4.86 (p, J = 8.5 Hz, 1H), 2.92 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 2.47-2.42 (m, 2H), 2.41-2.37 (m, 2H), 2.00 (p, J = 7.5 Hz, 2H), 1.83-1.74 (m, 2H). NH proton not observed. m/z 463.3 (M + H).sup.+ (ES.sup.+) 462.5 N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1-cyclobutyl- 1H-pyrazole-3-sulfonamide 228 [00554] 1H NMR (DMSO-d6) 8.58 (d, J = 5.1 Hz, 1H), 8.07 (s, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.75-7.56 (m, 2H), 7.16-7.09 (m, 2H) 4.80 (sept, J = 6.8 Hz, 1H), 2.90 (t, J = 7.5 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 1.98 (p, J = 7.5 Hz, 2H), 1.50 (d, J = 6.7 Hz, 6H). m/z 452.3 (M + H).sup.+ (ES.sup.+) 451.5 N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1-isopropyl- 1H-1,2,4-triazole-3-sulfonamide, sodium salt 229 [00555] N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- .sup.1H NMR (DMSO-d6) 8.65 (dd, J = 5.1, 0.8 Hz, 1H), 8.13 (s, 1H), 7.94 (dd, J = 1.8, 0.8 Hz, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 7.60 (dd, J = 5.1, 1.8 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 4.46 (sept, J = 6.8 Hz, 1H), 2.93 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.01 (p, J = 7.5 Hz, 2H), 1.42 (d, J = 6.7 Hz, 6H). One NH not observed. m/z 451.2 (M + H).sup.+ (ES.sup.+) 450.5 1H-inden-4-yl)carbamoyl)-1-isopropyl- 1H-imidazole-4-sulfonamide 230 [00556] .sup.1H NMR (DMSO-d6) 8.58 (d, J = 5.1 Hz, 1H), 8.07 (s, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.75-7.56 (m, 2H), 7.16-7.09 (m, 2H), 4.80 (sept, J = 6.8 Hz, 1H), 2.90 (t, J = 7.5 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 1.98 (p, J = 7.5 Hz, 2H), 1.50 (d, J = 6.7 Hz, 6H). m/z 452.3 (M + H).sup.+ (ES.sup.+) 451.5 N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1-isopropyl- 1H-1,2,3-triazole-4-sulfonamide, sodium salt 231 [00557] .sup.1H NMR (DMSO-d6) 8.54 (dd, J = 5.1, 0.8 Hz, 1H), 7.93-7.87 (m, 1H), 7.82 (s, 1H), 7.60 (dd, J = 5.1, 1.7 Hz, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 7.15- 7.08 (m, 2H), 6.35 (tt, J = 55.0, 3.9 Hz, 1H), 4.59 (td, J = 15.0, 3.8 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.78 (t, J = 7.5 Hz, 2H), 1.98 (p, J = 7.5 Hz, 2H). m/z 473.3 (M + H).sup.+ (ES.sup.+) 472.5 N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1-(2,2- difluoroethyl)-1H-pyrazole-4- sulfonamide, sodium salt 232 [00558] 1H NMR (DMSO-d6) 8.55 (s, 1H), 8.06 (d, J = 5.3 Hz, 1H), 7.50 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 3.9 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 4.62 (sept, J = 6.7 Hz, 1H), 3.86 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.45 (d, J = 6.7 Hz, 6H). m/z 457.3 (M + H).sup.+ (ES.sup.+) 456.5 1-Isopropyl-N-((5-(2-methoxypyridin-4- yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-1,2,4-triazole-3- sulfonamide, sodium salt 233 [00559] 1H NMR (DMSO-d6) 8.11 (d, J = 5.3 Hz, 1H), 7.92-7.80 (m, 3H), 7.18 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 6.70 (s, 1H), 4.48 (sept, J = 6.5 Hz, 1H), 3.88 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.61 (t, J = 7.4 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H), 1.42 (d, J = 6.6 Hz, 6H). One NH not observed. m/z 456.3 (M + H).sup.+ (ES.sup.+) 455.5 1-Isopropyl-N-((5-(2-methoxypyridin-4- yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-imidazole-4- sulfonamide 234 [00560] 1H NMR (DMSO-d6) 8.20 (s, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.41 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 6.7 Hz, 1H), 6.75 (s, 1H), 4.82 (sept, J = 6.7 Hz, 1H), 3.85 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.68 (t, J = 7.4 Hz, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.50 (d, J = 6.7 Hz, 6H). m/z 457.3 (M + H).sup.+ (ES.sup.+) 456.5 1-Isopropyl-N-((5-(2-methoxypyridin-4- yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-1,2,3-triazole-4- sulfonamide, sodium salt 235 [00561] 1H NMR (DMSO-d6) 8.02 (d, J = 5.3 Hz, 1H), 7.90 (s, 1H), 7.59 (s, 1H), 7.21 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.75 (d, J = 1.4 Hz, 1H), 6.35 (tt, J = 54.9, 3.8 Hz, 1H), 4.61 (td, J = 15.1, 3.8 Hz, 2H), 3.85 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H). m/z 478.3 (M + H).sup.+ (ES.sup.+) 477.5 1-(2,2-Difluoroethyl)-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-4- sulfonamide, sodium salt 236 [00562] 1H NMR (DMSO-d6) 8.13 (d, J = 5.3 Hz, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.4 Hz, 1H), 6.74 (s, 1H), 6.53 (s, 1H), 3.89 (s, 3H), 3.20 (s, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.77 (s, 2H), 2.73- 2.55 (m, 4H), 2.35-2.24 (m, 1H), 1.97 (p, J = 7.5 Hz, 2H), 1.48 (s, 6H), 0.93 (d, J = 6.7 Hz, 3H). One NH not observed. m/z 539.3 (M + H).sup.+ (ES.sup.+); 537.1 (M H).sup. (ES.sup.) 538.7 N-((5-(2-Methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1-(2- methyl-1-(3-methylazetidin-1-yl)propan- 2-yl)-1H-pyrazole-3-sulfonamide 237 [00563] N-((5-(2-(Difluoromethoxy)pyridin-4-yl)- 1H NMR (DMSO-d6) 8.11 (d, J = 5.3 Hz, 1H), 7.73 (t, J = 73.1 Hz, 1H), 7.69-7.66 (m, 1H), 7.50 (s, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.13-7.05 (m, 2H), 7.00 (s, 1H), 6.28 (t, J = 1.7 Hz, 1H), 4.49 (sept, J = 6.8 Hz, 1H), 2.89 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 492.3 (M + H).sup.+ (ES.sup.+); 490.0 (M H).sup. (ES.sup.), 491.5 2,3-dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide, sodium salt 238 [00564] 1-Isopropyl-N-((5-(2-methoxy-6- 1H NMR (DMSO-d6) 7.68 (d, J = 2.3 Hz, 1H), 7.33 (s, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.78 (s, 1H), 6.56 (s, 1H), 6.31 (d, J = 2.2 Hz, 1H), 4.48 (sept, J = 6.7 Hz, 1H), 3.84 (s, 3H), 2.87 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.35 (s, 3H), 1.93 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 470.3 (M + H).sup.+ (ES.sup.+); 468.2 (M H).sup. (ES.sup.) 469.6 methylpyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 239 [00565] 4-Fluoro-1-isopropyl-N-((5-(2- .sup.1H NMR (DMSO-d.sub.6) 11.14 (br. s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.08 (s, 1H), 7.79 (br. s,1H), 7.19 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.91- 6.86 (m, 1H), 6.73 (d, J = 1.4 Hz, 1H), 4.53-4.41 (m, 1H), 3.88 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 2.69- 2.63 (m, 2H), 1.97 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 474.3 (M + H).sup.+ (ES.sup.+) 473.5 methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 240 [00566] 1-Isopropyl-N-((5-(1-methyl-1H-imidazol- 1H NMR (DMSO-d6) 7.89 (d, J = 2.4 Hz, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.56 (s, 1H), 4.59 (sept, J = 6.6 Hz, 1H), 3.34 (s, 3H), 2.89 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 1.95 (p, J = 7.4 Hz, 2H), 1.44 (d, J = 6.7 Hz, 6H). Free acid not observed. m/z 429.3 (M + H).sup.+ (ES.sup.+) at 0.83 min, 96% purity (254 nm). 428.5 5-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3-sulfonamide 241 [00567] 1H NMR (DMSO-d6) 9.08 (s, 1H), 8.73 (s, 2H), 7.68 (d, J = 2.3 Hz, 1H), 7.60 (s, 1H), 7.15-7.09 (m, 2H), 6.28 (d, J = 2.3 Hz, 1H), 4.49 (sept, J = 6.7 Hz, 1H), 2.91 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 1.97 (p, J = 7.5 Hz, 2H), 1.41 (d, J = 6.7 Hz, 6H). One NH not observed. m/z 427.2 (M + H).sup.+ (ES.sup.+) 426.5 1-Isopropyl-N-((5-(pyrimidin-5-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 242 [00568] 1H NMR (DMSO-d6) 8.07 (d, J = 5.3 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.09-7.00 (m, 2H), 6.95 (d, J = 5.3 Hz, 1H), 6.78 (s, 1H), 6.29 (d, J = 2.3 Hz, 1H), 5.07-4.86 (m, 1H), 3.87 (s, 3H), 3.29- 3.21 (m, 2H), 3.01-2.90 (m, 2H), 2.87 (t, J = 7.4 Hz, 2H), 2.76 (s, 2H), 2.73 (t, J = 7.7 Hz, 2H), 1.94 (p, J = 7.6 Hz, 2H), 1.46 (s, 6H). One exchangeable proton not observed. m/z 543.3 (M + H)+ (ES+); 541.3 (M H) (ES) 542.63 1-(1-(3-Fluoroazetidin-1-yl)-2- methylpropan-2-yl)-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 243 [00569] 1H NMR (DMSO-d6) 8.06 (d, J = 5.3 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.33 (s, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 5.2 Hz, 1H), 6.76 (s, 1H), 6.30 (d, J = 2.3 Hz, 1H), 3.86 (s, 3H), 2.86 (t, J = 7.5 Hz, 2H), 2.74 (s, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.27-2.20 (m, 4H), 1.92 (p, J = 7.4 Hz, 2H), 1.53- 1.50 (m, 4H), 1.49 (s, 6H). m/z 539.5 (M + H)+ (ES+); 537.8 (M H) (ES) 538.66 N-((5-(2-Methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1-(2- methyl-1-(pyrrolidin-1-yl)propan-2-yl)- 1H-pyrazole-3-sulfonamide, sodium salt 244 [00570] 1-Cyclobutyl-N-((5-(2-methoxypyridin-4- 1H NMR (DMSO-d6) 8.03 (d, J = 5.3 Hz, 1H), 7.76-7.73 (m, 1H), 7.35 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.94-6.90 (m, 1H), 6.76 (s, 1H), 6.33- 6.29 (m, 1H), 4.82 (p, J = 8.4 Hz, 1H), 3.86 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.49-2.40 (m, 2H), 2.40- 2.29 (m, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.83-1.70 (m, 2H). m/z 468.0 (M + H)+ (ES+); 466.4 (M H) (ES) 467.54 yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 245 [00571] 1-Isopropyl-N-((5-(2-methylpyridin-4-yl)- 1H NMR (DMSO-d6) 8.29 (d, J = 5.1 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.38 (s, 1H), 7.18 (s, 1H), 7.13-7.06 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.33 (d, J = 2.3 Hz, 1H), 4.51 (sept, J = 6.6 Hz, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.43 (s, 3H), 1.94 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 440.4 (M + H)+ (ES+) 439.53 2,3-dihydro-1H-inden-4-yl)carbamoyl)- 1H-pyrazole-3-sulfonamide, sodium salt 246 [00572] 2-Isopropyl-N-((5-(2-methoxypyridin-4- 1H NMR (DMSO-d6) 8.06 (d, J = 5.3 Hz, 1H), 7.64-7.60 (m, 1H), 7.30 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.93 (dd, J = 5.3, 1.5 Hz, 1H), 6.77 (s, 1H), 4.79 (sept, J = 6.7 Hz, 1H), 3.86 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.48 (d, J = 6.7 Hz, 6H). m/z 457.3 (M + H)+ (ES+); 455.2 (M H) (ES) 456.52 yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-2H-1,2,3-triazole-4- sulfonamide, sodium salt 247 [00573] 1-(1-((Dimethylamino)methyl)cyclobutyl)- 1H NMR (DMSO-d6) 8.07 (d, J = 5.3 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.32 (s, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.97-6.92 (m, 1H), 6.77 (d, J = 1.5 Hz, 1H), 6.33 (d, J = 2.2, Hz, 1H), 3.87 (s, 3H), 2.07 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.69 (s, 2H), 2.48-2.40 (m, 2H), 2.31-2.23 (m, 2H), 2.00- 1.78 (m, 4H), 1.91 (s, 6H). m/z 525.3 (M + H)+ (ES+); 523.2 (M H) (ES) 524.64 N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 248 [00574] 1-Cyclopropyl-N-((5-(2-methoxypyridin-4- 1H NMR (DMSO-d6) 8.06 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.38 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (d, J = 1.4 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.70 (tt, J = 7.4, 3.9 Hz, 1H), 3.06 (t, J = 8.8 Hz, 2H), 1.06-0.99 (m, 2H), 0.98-0.92 (m, 2H). m/z 456.3 (M + H)+ (ES+) 455.49 3-sulfonamide, sodium salt 249 [00575] 1H NMR (DMSO-d6) 8.05-8.00 (m, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.34 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.75 (d, J = 1.4 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.83-4.36 (m, 4H), 3.86 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.00-1.90 (m, 2H). m/z 460.3 (M + H)+ (ES+) 459.49 1-(2-Fluoroethyl)-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 250 [00576] 1-Isopropyl-N-((5-(2-methoxypyridin-4- 1H NMR (DMSO-d6) 8.01 (dd, J = 5.3, 0.7 Hz, 1H), 7.84 (d, J = 0.6 Hz, 1H), 7.49 (d, J = 0.6 Hz, 1H), 7.18 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.79- 6.70 (m, 1H), 4.46 (hept, J = 6.7 Hz, 1H), 3.85 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 456.3 (M + H)+ (ES+); 454.2 (M H) (ES) 455.53 yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-4- sulfonamide, sodium salt 251 [00577] 1H NMR (DMSO-d6) 8.04-7.93 (m, 1H), 7.65- 7.49 (m, 2H), 7.26-7.21 (m, 2H), 7.19 (s, 1H), 7.04 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.84 (dd, J = 5.3, 1.5 Hz, 1H), 6.75-6.68 (m, 1H), 3.86 (s, 3H), 3.38 (s, 2H), 2.85 (t, J = 7.4 Hz, 2H), 2.68 (t, J = 7.4 Hz, 2H), 2.13 (s, 6H), 1.91 (p, J = 7.4 Hz, 2H). m/z 481.3 (M + H)+ (ES+); 479.2 (M H) (ES) 480.58 4-((Dimethylamino)methyl)-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4- yl)carbamoyl)benzenesulfonamide, sodium salt 252 [00578] 1H NMR (DMSO-d6) 8.05 (d, J = 5.4 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.33 (br s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 5.3, 1.5 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 6.30 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 2.87 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.03-1.86 (m, 2H), 1.50 (s, 9H). m/z 470.4 (M + H)+ (ES+); 468.2 (M H) (ES) 469.56 1-(tert-Butyl)-N-((5-(2-methoxypyridin-4- yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 253 [00579] 1H NMR (DMSO-d6) 7.91 (d, J = 5.2 Hz, 1H), 7.78 (s, 1H), 7.38 (s, 1H), 7.09 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 6.48-6.37 (m, 3H), 6.35 (s, 1H), 3.86-3.66 (m, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.78 (d, J = 4.7 Hz, 3H), 2.72-2.62 (m, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.08-0.94 (m, 4H). One exchangeable proton not observed. m/z 453.3 (M + H)+ (ES+) 452.53 1-Cyclopropyl-N-((5-(2- (methylamino)pyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 254 [00580] 1-Cyclopropyl-N-((5-(tetrahydro-2H- 1H NMR (DMSO-d6) 7.78 (s, 1H), 7.64 (s, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.49-6.38 (m, 1H), 3.92- 3.86 (m, 2H), 3.77-3.71 (m, 1H), 3.35-3.28 (m, 2H), 2.98-2.90 (m, 1H), 2.81 (t, J = 7.4 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 1.91 (p, J = 7.5 Hz, 2H), 1.56-1.47 (m, 4H), 1.05- 0.95 (m, 4H). Acidic NH not observed. m/z 431.8 (M + H)+ (ES+) 430.52 pyran-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3-sulfonamide 255 [00581] 1-Cyclopropyl-N-((5-(5-fluoro-2- 1H NMR (DMSO-d6) 8.09 (d, J = 1.5 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.44 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 5.0 Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H), 3.84 (s, 3H), 3.70 (tt, J = 7.4, 3.9 Hz, 1H), 2.89 (t, J = 7.4 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H), 1.06-0.99 (m, 2H), 0.99-0.92 (m, 2H). m/z 472.3 (M + H)+ (ES+) 471.50 methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 256 [00582] 1H NMR (DMSO-d6) 8.10 (d, J = 5.3, 1H), 7.38 (br s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.98 (dd, J = 5.3, 1.4 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 4.38 (hept, J = 6.4 Hz, 1H), 3.85 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.83 (t, J = 7.4 Hz, 2H), 1.99 (p, J = 7.4 Hz, 2H), 1.11 (d, J = 6.4 Hz, 6H). m/z 406.3 (M + H)+ (ES+); 404.1 (M H) (ES) 405.47 Isopropyl (5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4- yl)carbamoylsulfamate, sodium salt 257 [00583] 1H NMR (DMSO-d6) 8.07-8.01 (m, 1H), 7.79- 7.71 (m, 1H), 7.42 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.92-6.87 (m, 1H), 6.73 (s, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.38-6.31 (m, 1H), 4.82 (p, J = 8.5 Hz, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.05 (t, J = 8.7 Hz, 2H), 2.49- 2.40 (m, 2H), 2.39-2.30 (m, 2H), 1.82-1.70 (m, 2H). m/z 470.3 (M + H)+ (ES+); 468.2 (M H) (ES) 469.51 1-Cyclobutyl-N-((5-(2-methoxypyridin-4- yl)-2,3-dihydrobenzofuran-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 258 [00584] 1H NMR (DMSO-d6) 8.06 (t, J = 5.6 Hz, 1H), 7.71-7.63 (m, 1H), 7.47- 7.36 (m, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.95-6.88 (m, 1H), 6.74 (d, J = 1.5 Hz, 1H), 6.60 (dd, J = 8.2, 3.8 Hz, 1H), 6.36-6.29 (m, 1H), 4.49 (t, J = 8.8 Hz, 2H), 3.87 (s, 3H), 3.04 (t, J = 8.7 Hz, 2H), 2.93 (t, J = 7.0, 2.5 Hz, 4H), 2.64 (s, 2H), 1.80 (p, J = 6.8 Hz, 2H), 1.44 (s, 6H). m/z 527.4 (M + H)+ (ES+); 525.1 (M H) (ES) 526.61 1-(1-(Azetidin-1-yl)-2-rnethylpropan-2- yl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 259 [00585] 1H NMR (DMSO-d6) 8.04 (dd, J = 5.3, 0.7 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.42 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.73- 6.73 (m, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 4.48 (t, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.02 (t, J = 8.8 Hz, 2H), 1.50 (s, 9H). m/z 472.1 (M + H)+ (ES+) 471.53 1-(tert-Butyl)-N-((5-(2-methoxypyridin-4- yl)-2,3-dihydrobenzofuran-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 260 [00586] 1H NMR (DMSO-d6) 8.59 (dd, J = 5.1, 0.8 Hz, 1H), 7.92 (d, J = 1.9 Hz 1H), 7.65 (br s, 1H), 7.6 (dd, J = 5.1, 1.7 Hz, 1H), 7.55 (s, 1H), 7.12 (s, 2H), 4.78 (hept, J = 6.7 Hz, 1H), 2.90 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 1.97 (p, J = 7.5 Hz, 2H), 1.48 (d, J = 6.7 Hz, 6H). m/z 452.1 (M + H)+ (ES+); 450.1 (M H) (ES) 451.50 N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-2-isopropyl- 2H-1,2,3-triazole-4-sulfonamide, sodium salt 261 [00587] N-((5-(2-Cyclopropoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1- cyclopropyl-1H-pyrazole-3-sulfonamide, sodium salt 1H NMR (DMSO-d6) 8.07 (d, J = 5.2 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.37 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.95 (dd, J = 5.3, 1.4 Hz, 1H), 6.84 (d, J = 1.3 Hz, 1H), 6.29 (d, J = 2.3 Hz, 1H), 4.18 (tt, J = 6.3, 3.0 Hz, 1H), 3.72 (tt, J = 7.4, 3.9 Hz, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.09-1.01 (m, 2H), 0.95 (td, J = 7.4, 4.9 Hz, 2H), 0.79-0.72 (m, 2H), 0.69-0.64 (m, 2H). m/z 480.1 (M + H)+ (ES+) 479.55 262 [00588] 1-Cyclopropyl-N-((5-(2- (difluoromethoxy)pyridin-4-yl)-2,3- 1H NMR (DMSO-d6) 8.12 (d, J = 5.3 Hz, 1H), 7.73 (t, J = 73.1 Hz, 1H), 7.69-7.66 (m, 1H), 7.51 (s, 1H), 7.20 (dd, J = 5.4, 1.4 Hz, 1H), 7.09 (t, J = 5.7 Hz, 2H), 6.99 (d, J = 1.4 Hz, 1H), 6.26 (t, J = 2.3 Hz, 1H), 3.71 (tt, J = 7.5, 3.7 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 1.97 (p, J = 7.5 Hz, 2H), 1.06-1.00 (m, 2H), 0.97-0.92 (m, 2H). m/z 490.2 (M + H)+ (ES+); 488.0 (M H) (ES) 489.5 dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 263 [00589] 1-(Cyclopropylmethyl)-N-((5-(2- 1H NMR (DMSO-d6) 8.02 (d, J = 5.3 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.37 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.90 (dd, J = 5.3, 1.4 Hz, 1H), 6.75 (d, J = 1.4 Hz, 1H), 6.32 (d, J = 2.2 Hz, 1H), 3.95 (d, J = 7.2 Hz, 2H), 3.86 (s, 3H), 2.87 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.30-1.21 (m, 1H), 0.55- 0.47 (m, 2H), 0.40-0.32 (m, 2H). m/z 468.1 (M + H)+ (ES+); 466.2 (M H) (ES) 467.54 methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 264 [00590] 1H NMR (DMSO-d6) 8.58 (d, J = 5.1, 1H), 7.92 (d, J = 1.7, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.70 (s, 1H), 7.62 (dd, J = 5.1, 1.7, 1H), 7.13 (s, 2H), 6.26 (d, J = 2.3 Hz, 1H), 2.90 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 1.97 (p, J = 7.5 Hz, 2H), 1.50 (s, 9H). m/z 465.1 (M + H)+ (ES+); 463.1 (M H) (ES) 464.54 1-(tert-Butyl)-N-((5-(2-cyanopyridin-4- yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 265 [00591] 1-Cyclopropyl-N-((5-(5-fluoro-2- 1H NMR (DMSO-d6) 8.09 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.49 (s, 1H), 6.97 (dd, J = 8.2, 1.4 Hz, 1H), 6.66 (d, J = 5.1 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 6.23 (d, J = 2.3 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.83 (s, 3H), 3.73-3.65 (m,1H), 3.07 (t, J = 8.8 Hz, 2H), 1.04- 0.98 (m, 2H), 0.98-0.91 (m, 2H). m/z 474.1 (M + H)+ (ES+) 473.48 methoxypyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 266 [00592] 1H NMR (DMSO-d6) 8.06 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.42 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.92 (dd, J = 5.2, 1.5 Hz, 1H), 6.81 (s, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 2.3 Hz, 1H), 4.89-4.75 (m, 1H), 4.49 (t, J = 8.8 Hz, 2H), 4.26-4.09 (m, 1H), 3.04 (t, J = 8.8 Hz, 2H), 2.48- 2.40 (m, 2H), 2.38-2.28 (m, 2H), 1.83-1.69 (m, 2H), 0.78-0.71 (m, 2H), 0.71-0.63 (m, 2H). m/z 496.1 (M + H)+ (ES+) 495.55 1-Cyclobutyl-N-((5-(2- cyclopropoxypyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 267 [00593] 1-(Cyclopropylmethyl)-N-((5-(2- 1H NMR (DMSO-d6) 8.03 (d, J = 5.3 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.42 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.72 (d, J = 1.4 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 2.2 Hz, 1H), 4.49 (t, J = 8.8 Hz, 2H), 3.94 (d, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.04 (t, J = 8.8 Hz, 2H), 1.29-1.18 (m, 1H), 0.56- 0.46 (m, 2H), 0.41-0.32 (m, 2H). m/z 470.1 (M + H)+ (ES+) 469.51 methoxypyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 268 [00594] 1-Cyclopropyl-N-((5-(1-methyl-6-oxo-1,6- 1H NMR (DMSO-d6) 7.88 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 7.63 (d, J = 2.6 Hz, 1H), 7.31 (dd, J = 9.4, 2.7 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.58-6.51 (m, 1H), 6.33 (d, J = 9.3 Hz, 1H), 3.85-3.78 (m, 1H), 3.44 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.97 (p, J = 7.5 Hz, 2H), 1.12-0.96 (m, 4H). Acidic proton not observed m/z 454.1 (M + H)+ (ES+) 453.51 dihydropyridin-3-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 269 [00595] 1-Cyclobutyl-N-((5-(2-methylpyridin-4- yl)-2,3-dihydro-1H-inden-4- 1H NMR (DMSO-d6) 8.31 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.32 (s, 1H), 7.19 (s, 1H), 7.12 (dd, J = 5.3, 1.7 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 4.82 (p, J = 8.5 Hz, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 2.49-2.45 (m, 2H), 2.43 (s, 3H), 2.39-2.31 (m, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.82-1.71 (m, 2H). m/z 452.1 (M + H)+ (ES+); 450.0 (M H) (ES) 451.54 yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 270 [00596] 1-Cyclopropyl-N-((5-(2-methylpyridin-4- 1H NMR (DMSO-d6) 8.33 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 7.13 (d, J = 4.0 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.27 (d, J = 2.3 Hz, 1H), 3.73-3.65 (m, 1H), 2.89 (t, J = 7.4 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.44 (s, 3H), 1.96 (p, J = 7.5 Hz, 2H), 1.07-0.99 (m, 2H), 0.99-0.91 (m, 2H). m/z 438.2 (M + H)+ (ES+); 436.1 (M H) (ES) 437.51 yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 271 [00597] N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H NMR (DMSO-d6) 11.0 (br s, 1H), 8.65 (d, J = 5.1 Hz, 1H), 8.05 (br s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.82 (s, 1H), 7.62 (dd, J = 5.1, 1.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 6.47 (s, 1H), 4.02 (d, J = 7.2 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 2.01 (p, J = 7.5 Hz, 2H), 1.29-1.21 (m, 1H), 0.59-0.52 (m, 2H), 0.40-0.37 (m, 2H). m/z 463.1 (M + H)+ (ES+); 461.1 (M H) (ES) 462.52 1H-inden-4-yl)carbamoyl)-1- (cyclopropylmethyl)-1H-pyrazole-3- sulfonamide 272 [00598] 1-Cyclopropyl-N-((5-(1-methyl-2-oxo-1,2- 1H NMR (DMSO-d6) 7.69 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 7.0 Hz, 1H), 7.36 (s, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.00 (d, J = 7.7 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 6.29 (d, J = 1.9 Hz, 1H), 6.18 (dd, J = 7.0, 2.0 Hz, 1H), 3.72 (tt, J = 7.5, 3.8 Hz, 1H), 3.43 (s, 3H), 2.87 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.07-1.01 (m, 2H), 1.00-0.92 (m, 2H). m/z 454.2 (M + H)+ (ES+) 453.51 dihydropyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 273 [00599] 1H NMR (DMSO-d6) 11.59 (s, 1H), 8.63 (s, 1H), 8.55-8.45 (m, 2H), 7.88 (s, 1H), 7.61-7.45 (m, 2H), 6.57 (s, 1H), 3.85- 3.77 (m, 1H), 2.64 (dd, J = 9.1, 5.7 Hz, 2H), 2.30 (p, J = 7.4 Hz, 2H), 1.14-0.91 (m, 4H). 2H Obscured by DMSO peak, m/z 414.1 (M + H)+ (ES+) 413.45 1-Cyclopropyl-N-((2-(pyridin-4-yl)- 2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3- yl)carbamoyl)-1H-pyrazole-3-sulfonamide 274 [00600] 1H NMR (DMSO-d6) 8.09 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.38 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.97 (dd, J = 5.3, 1.4 Hz, 1H), 6.86 (s, 1H), 6.30 (d, J = 2.3 Hz, 1H), 4.20 (tt, J = 6.3, 3.1 Hz, 1H), 2.95 (t, J = 7.0 Hz, 4H), 2.87 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.65 (s, 2H), 1.93 (p, J = 7.5 Hz, 2H), 1.82 (p, J = 7.0 Hz, 2H), 1.45 (s, 6H), 0.80-0.73 (m, 2H), 0.72-0.65 (m, 2H). m/z 551.1 (M + H)+ (ES+) 550.67 1-(1-(Azetidin-1-yl)-2-methylpropan-2- yl)-N-((5-(2-cyclopropoxypyridin-4-yl)- 2,3-dihydro-1H-inden-4-yl)carbamoyl)- 1H-pyrazole-3-sulfonamide, sodium salt 275 [00601] 1-Cyclobutyl-N-((5-(2- 1H NMR (DMSO-d6) 8.11 (d, J = 5.3 Hz, 1H), 7.96-7.51 (m, 3H), 7.17 (dd, J = 5.3, 1.5 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 1.3 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 4.81 (p, J = 8.4 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.06 (t, J = 8.8 Hz, 2H), 2.48-2.39 (m, 2H), 2.38- 2.29 (m, 2H), 1.81-1.71 (m, 2H). m/z 506.0 (M + H)+ (ES+) 505.49 (difluoromethoxy)pyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 276 [00602] 1H NMR (DMSO-d6) 8.07 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.40 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 5.3, 1.4 Hz, 1H), 6.81 (d, J = 1.3 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 4.50 (t, J = 8.8 Hz, 2H), 4.22-4.12 (m, 1H), 3.78-3.65 (m, 1H), 3.06 (t, J = 8.8 Hz, 2H), 1.06-0.98 (m, 2H), 0.98-0.91 (m, 2H), 0.78- 0.71 (m, 2H), 0.71-0.64 (m, 2H). m/z 482.1 (M + H)+ (ES+) 481.52 N-((5-(2-Cyclopropoxypyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1- cyclopropyl-1H-pyrazole-3-sulfonamide, sodium salt 277 [00603] 1-Cyclopropyl-N-((5-(2- 1H NMR (DMSO-d6) 8.12 (d, J = 5.3 Hz, 1H), 7.94-7.50 (m, 3H), 7.18 (dd, J = 5.3, 1.5 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 1.3 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.28 (d, J = 2.3 Hz, 1H), 4.52 (t, J = 8.8 Hz, 2H), 3.79-3.64 (m, 1H), 3.08 (t, J = 8.7 Hz, 2H), 1.05- 0.98 (m, 2H), 0.97-0.91 (m, 2H). m/z 492.1 (M + H)+ (ES+) 491.47 (difluoromethoxy)pyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 278 [00604] 1-Cyclopropyl-N-((5-(2-(methoxy- 1H NMR (DMSO-d6) 8.04 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.39 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.89 (dd, J = 5.3, 1.4 Hz, 1H), 6.72 (d, J = 1.3 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.80-3.64 (m, 1H), 3.05 (t, J = 8.7 Hz, 2H), 1.06-0.97 (m, 2H), 1.00-0.90 (m, 2H). m/z 459.2 (M + H)+ (ES+) 458.51 d3)pyridin-4-yl)-2,3-dihydrobenzofuran- 4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 279 [00605] 1-Cyclopropyl-N-((5-(2-(methoxy- 1H NMR (DMSO-d6) 8.03 (d, J = 5.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.36 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.91 (dd, J = 5.3, 1.3 Hz, 1H), 6.75 (d, J = 1.3 Hz, 1H), 6.29 (d, J = 2.3 Hz, 1H), 3.72 (tt, J = 7.4, 3.9 Hz, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.07-0.92 (m, 4H). m/z 457.2 (M + H)+ (ES+) 456.53 d3)pyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 280 [00606] 1-Cyclobutyl-N-((5-(2-(methoxy- 1H NMR (DMSO-d6) 8.05 (d, J = 5.3 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.35 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 5.3, 1.4 Hz, 1H), 6.73 (d, J = 1.3 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 4.80 (p, J = 8.5 Hz, 1H), 4.49 (t, J = 8.8 Hz, 2H), 3.05 (t, J = 8.8 Hz, 2H), 2.47-2.39 (m, 2H), 2.38-2.30 (m, 2H), 1.82-1.71 (m, 2H). m/z 472.8 (M + H)+ (ES+); 471.0 (M H) (ES) 472.53 d3)pyridin-4-yl)-2,3-dihydrobenzofuran- 4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 281 [00607] 1H NMR (DMSO-d6) 8.09 (d, J = 1.7 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.45 (s, 1H), 6.99-6.89 (m, 1H), 6.68 (d, J = 5.0 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.22 (s, 1H), 4.78 (p, J = 8.4 Hz, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.06 (t, J = 8.8 Hz, 2H), 2.46-2.38 (m, 2H), 2.38-2.29 (m, 2H), 1.88-1.70 (m, 2H). m/z 488.1 (M + H)+ (ES+) 487.50 1-Cyclobutyl-N-((5-(5-fluoro-2- methoxypyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 282 [00608] 3-((Dimethylamino)methyl)-4-isopropyl- 1H NMR (DMSO-d6) 8.02 (d, J = 5.1 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.1, 2.1 HZ, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.23 (br s,1H), 7.06 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.90 (dd, J = 5.1, 1.3 Hz, 1H), 6.76 (t, J = 1.3 Hz, 1H), 3.87 (s, 3H), 3.38 (sept, J = 6.9 Hz, 1H), 3.37 (s, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.13 (s, 6H), 1.91 (p, J = 7.5 Hz, 2H), 1.18 (d, J = 6.8 Hz, 6H). m/z 523.1 (M + H)+ (ES+); 521.0 (M H) (ES) 522.66 N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl) benzenesulfonamide, sodium salt 283 [00609] N-((5-(2,3-Dihydrofuro[2,3-b]pyridin-4- yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1-isopropyl-1H-pyrazole-3- 1H NMR (DMSO-d6) 7.89 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 5.3 Hz, 1H), 7.77 (s, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.60 (dd, J = 5.4, 1.1 Hz, 1H), 6.53 (s, 1H), 4.58 (sept, J = 6.7 Hz, 1H), 4.46 (t, J = 8.5 Hz, 2H), 3.01 (t, J = 8.5 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.97 (p, J = 7.5 Hz, 2H), 1.43 (d, J = 6.7 Hz, 6H). Acidic NH not observed. m/z 468.1 (M + H)+ (ES+) 467.54 sulfonamide 284 [00610] 1-Methylpyrrolidin-3-yl (5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- 1H NMR (DMSO-d6) 9.92 (br s, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.51 (br s, 1H), 7.12 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.99 (dd, J = 5.3, 1.3 Hz, 1H), 6.80 (d, J = 1.3 Hz, 1H), 4.99-4.91 (m, 1H), 3.87 (s, 3H), 3.49 (d, J = 12.3 Hz, 1H), 3.20- 3.13 (m, 3H), 2.91 (t, J = 7.4 Hz, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.76 (s, 3H), 2.26-2.13 (m, 1H), 2.09- 1.95 (m, 3H). m/z 447.2 (M + H)+ (ES+); 445.1 (M H) (ES) 446.52 inden-4-yl)carbamoylsulfamate 285 [00611] 1H NMR (DMSO-d6) 10.86 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 5.2 Hz, 1H), 7.78 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.37-6.33 (m, 2H), 5.98 (s, 2H), 4.61 (sept, J = 6.7 Hz, 1H), 2.89 (t, J = 7.4 Hz, 2H), 2.58 (t, J = 7.5 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.44 (d, J = 6.7 Hz, 6H). m/z 441.2 (M + H)+ (ES+); 439.5 (M H) (ES) 440.52 N-((5-(2-Aminopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1-isopropyl- 1H-pyrazole-3-sulfonamide 286 [00612] 1H NMR (DMSO-d6) 8.03-7.97 (m, 1H), 7.69- 7.64 (m, 1H), 7.51-7.39 (m, 3H), 7.20 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 7.5 Hz, 2H), 7.11-7.03 (m, 3H), 6.98 (s, 1H), 6.40- 6.24 (m, 1H), 4.47 (sept, J = 6.6 Hz, 1H), 2.89 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.39 (d, J = 6.7 Hz, 6H). m/z 518.1 (M + H)+ (ES+); 516.4 (M H) (ES) 517.6 1-Isopropyl-N-((5-(2-phenoxypyridin-4- yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 287 [00613] 1H NMR (DMSO-d6) 7.99 (d, J = 5.3 Hz, 1H), 7.69 (s, 1H), 7.37 (s, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 5.2 Hz, 1H), 6.69 (s, 1H), 6.31 (s, 1H), 5.03-4.93 (m, 1H), 4.49 (sept, J = 6.8 Hz, 1H), 2.87 (t, J = 7.5 Hz, 2H), 2.75-2.61 (m, 4H), 2.19 (s, 3H), 2.14 (t, J = 10.8 Hz, 2H), 2.03-1.97 (m, 2H), 1.93 (p, J = 7.5 Hz, 2H), 1.73-1.64 (m, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 539.2 (M + H)+ (ES+); 537.3 (M H) (ES) 538.66 1-Isopropyl-N-((5-(2-((1-methylpiperidin- 4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 288 [00614] 1-Isopropyl-N-((5-(2-((tetrahydro-2H- pyran-3-yl)oxy)pyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 1H NMR (DMSO-d6) 8.00 (d, J = 5.3 Hz, 1H), 7.74 (s, 1H), 7.44 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H), 6.71 (d, J = 1.3 Hz, 1H), 6.35 (s, 1H), 5.05-4.99 (m, 1H), 4.51 (p, J = 6.4 Hz, 1H), 3.90 (dd, J = 11.2, 2.3 Hz, 1H), 3.69- 3.63 (m, 1H), 3.56-3.46 (m, 2H), 2.87 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.11-2.03 (m, 1H), 1.93 (p, J = 7.5 Hz, 2H), 1.84-1.71 (m, 2H), 1.61-1.52 (m, 1H), 1.40 m/z 526.1 (M + H)+ (ES+) 525.62 (d, J = 6.6 Hz, 6H). 289 [00615] 1-Isopropyl-N-((5-(2-((1-methoxypropan- 2-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 1H NMR (DMSO-d6) 7.98 (dd, J = 5.3, 0.7 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.40 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.86 (dd, J = 5.3, 1.5 Hz, 1H), 6.71- 6.67 (m, 1H), 6.33 (d, J = 2.3 Hz, 1H), 5.38-5.29 (m, 1H), 4.51 (sept, J = 6.7 Hz, 1H), 3.56 (dd, J = 10.3, 6.0 Hz, 1H), 3.46 (dd, J = 10.3, 4.3 Hz, 1H), 3.30 (s, 3H), 2.87 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H),1.93 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H), 1.27 (d, J = m/z 514.1 (M + H)+ (ES+) 513.61 6.3 Hz, 3H). 290 [00616] 1H NMR (DMSO-d6) 8.02 (dd, J = 5.3, 0.7 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.36 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.91 (dd, J = 5.3, 1.4 Hz, 1H), 6.78- 6.73 (m, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.88-4.76 (m, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.50-2.42 (m, 2H), 2.39-2.30 (m, 2H), 1.94 (p, J = 7.5 Hz, 2H), 1.81-1.71 (m, 2H). m/z 471.2 (M + H)+ (ES+) 470.56 1-Cyclobutyl-N-((5-(2-(methoxy- d3)pyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 291 [00617] 1-Isopropyl-N-((5-(2-((tetrahydrofuran-3- yl)oxy)pyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 1H NMR (DMSO-d6) 8.02 (d, J = 5.3 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.44 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.77- 6.70 (m, 1H), 6.34 (s, 1H), 5.54-5.48 (m, 1H), 4.51 (sept, J = 6.8 Hz, 1H), 3.94 (dd, J = 10.2,4.8 Hz, 1H), 3.90-3.83 (m, 1H), 3.82-3.73 (m, 2H), 2.88 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.29- 2.20 (m, 1H), 2.07-1.99 (m, 1H), 1.94 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 512.1 (M + H)+ (ES+) 511.59 292 [00618] 1-Isopropyl-N-((5-(2-((tetrahydro-2H- pyran-4-yl)oxy)pyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide, sodium salt 1H NMR (DMSO-d6) 7.99 (d, J = 5.0 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.42 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.74- 6.70 (m, 1H), 6.34 (d, J = 2.3 Hz, 1H), 5.20 (tt, J = 8.9, 4.1 Hz, 1H), 4.51 (sept, J = 6.7 Hz, 1H), 3.88 (dt, J = 11.7, 4.2 Hz, 2H), 3.56-3.46 (m, 2H), 2.87 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.07-2.00 (m, 2H), 1.93 (p, J = 7.5 Hz, 2H), 1.71- 1.59 (m, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 526.1 (M + H)+ (ES+) 525.62 293 [00619] 2-Cyclopropyl-N-((5-(2-methoxypyridin- 1H NMR (DMSO-d6) 8.06 (d, J = 5.1 Hz, 1H), 7.81 (s, 1H), 7.38 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.95 (dd, J = 5.3, 1.5 Hz, 1H), 6.76 (d, J = 1.7 Hz, 1H), 3.86 (s, 3H), 2.89 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 2.13-2.05 (m, 1H), 1.97 (p, J = 7.5 Hz, 2H), 1.07-1.01 (m, 2H), 0.97-0.91 (m, 2H). m/z 455.2 (M + H)+ (ES+) 454.5 4-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)oxazole-4-sulfonamide, sodium salt 294 [00620] N-((5-(2-Cyclobutoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide, sodium salt 1H NMR (DMSO-d6) 7.99 (d, J = 5.3 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.43 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.87 (dd, J = 5.3, 1.5 Hz, 1H), 6.70 (d, J = 1.3 Hz, 1H), 6.35 (s, 1H), 5.19-5.10 (m, 1H), 4.51 (sept, J = 6.6 Hz, 1H), 2.87 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.45-2.38 (m, 2H), 2.12- 2.03 (m, 2H), 1.93 (p, J = 7.5 Hz, 2H), 1.83-1.75 (m, 1H), 1.70-1.60 (m, 1H), 1.40 (d, J = 6.7 Hz, 6H). m/z 496.2 (M + H)+ (ES+) 495.59 295 [00621] N-((5-(2-Cyclopropylpyridin-4-yl)-2,3- 1H NMR (DMSO-d6) 8.24 (d, J = 5.1 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.37 (s, 1H), 7.21 (dd, J = 1.7, 0.8 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 7.02 (dd, J = 5.1, 1.7 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.50 (sept, J = 6.6 Hz, 1H), 2.88 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.06-1.88 (m, 3H), 1.40 (d, J = 6.7 Hz, 6H), 0.96-0.87 (m, 4H). m/z 466.0 (M + H)+ (ES+) 465.57 dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide, sodium salt 296 [00622] 1-Isopropyl-N-((5-(2- (methoxymethyl)pyridin-4-yl)-2,3- 1H NMR (DMSO-d6) 8.35 (dd, J = 5.1, 0.8 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.43 (s, 1H), 7.33 (dd, J = 1.7, 0.8 Hz, 1H), 7.21 (dd, J = 5.1, 1.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 4.55-4.46 (m, 3H), 3.30 (s, 3H), 2.89 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 470.2 (M + H)+ (ES+) 469.56 dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide, sodium salt 297 [00623] 1H NMR (DMSO-d6) 10.46 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.04 (s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.41 (s, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.05-6.94 (m, 2H), 6.33 (d, J = 2.4 Hz, 1H), 4.50 (sept, J = 6.7 Hz, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.10 (s, 3H), 1.94 (p, J = 7.5 Hz, 2H), 1.41 (d, J = 6.7 Hz, 6H). m/z 483.3 (M + H)+ (ES+) 482.56 N-(4-(4-(3-((1-Isopropyl-1H-pyrazol-3- yl)sulfonyl)ureido)-2,3-dihydro-1H- inden-5-yl)pyridin-2-yl)acetamide, sodium salt 298 [00624] N-((5-(2-(Hydroxymethyl)pyridin-4-yl)- 1H NMR (DMSO-d6) 8.40 (d, J = 5.0 Hz, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.39 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.17-7.12 (m, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.56 (s, 1H), 5.38 (t, J = 5.8 Hz, 1H), 4.62-4.53 (m, 3H), 2.92 (t, J = 7.5 Hz, 2H), 2.68-2.59 (m, 2H), 1.98 (p, J = 7.5 Hz, 2H), 1.43 (d, J = 6.7 Hz, 6H). Acidic NH not observed. m/z 456.3 (M + H)+ (ES+) 455.53 2,3-dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide 299 [00625] N-((5-(2-(2-Hydroxyethoxy)pyridin-4-yl)- 2,3-dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide 1H NMR (DMSO-d6) 8.08 (d, J = 5.4 Hz, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 5.3 Hz, 1H), 6.72 (s, 1H), 6.53 (s, 1H), 4.90-4.82 (m, 1H), 4.60- 4.52 (m, 1H), 4.30 (t, J = 5.2 Hz, 2H), 3.77-3.69 (m, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.68-2.60 (m, 2H), 1.96 (p, J = 7.4 Hz, 2H), 1.43 (d, J = 6.7 Hz, 6H). Acidic NH not observed. m/z 486.1 (M + H)+ (ES+) 485.56 300 [00626] 1-Isopropyl-N-((5-(2-(2- methoxyethoxy)pyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- 1H NMR (DMSO-d6) 8.00 (dd, J = 5.3, 0.7 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.40 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.4 Hz, 1H), 6.75 (d, J = 1.2 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.50 (sept, J = 6.6 Hz, 1H), 4.41- 4.37 (m, 2H), 3.71-3.65 (m, 2H), 3.31 (s, 3H), 2.87 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 1.93 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 500.2 (M + H)+ (ES+) 499.58 pyrazole-3-sulfonamide, sodium salt 301 [00627] 1-Isopropyl-N-((5-(2-((1- methylpyrrolidin-3-yl)oxy)pyridin-4-yl)- 2,3-dihydro-1H-inden-4-yl)carbamoyl)- 1H-pyrazole-3-sulfonamide, sodium salt 1H NMR (DMSO-d6) 8.01 (d, J = 5.3 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.44 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 5.41-5.35 (m, 1H), 4.51 (sept, J = 6.6 Hz, 1H), 2.91-2.84 (m, 3H), 2.77-2.67 (m, 4H), 2.43 (q, J = 7.6 Hz, 1H), 2.34-2.26 (m, 4H), 1.93 (p, J = 7.5 Hz, 2H), 1.89-1.81 (m, 1H), 1.40 (d, J = 6.7 Hz, 6H). m/z 525.2 (M + H)+ (ES+) 524.64 302 [00628] N-((5-(2-(2- (Dimethylamino)ethoxy)pyridin-4-yl)- 1H NMR (DMSO-d6) 8.01 (d, J = 5.3 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.43 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (s, 1H), 6.34 (d, J = 2.3 Hz, 1H), 4.51 (sept, J = 6.7 Hz, 1H), 4.36 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 7.4 Hz, 2H), 2.72-2.64 (m, 4H), 2.25 (s, 6H), 1.93 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). m/z 513.2 (M + H)+ (ES+) 512.62 2,3-dihydro-1H-inden-4-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3-sulfonamide, sodium salt 303 [00629] 1H NMR (DMSO-d6) 8.60-8.48 (m, 2H), 7.93 (s, 1H), 7.88 (br. s, 1H), 7.30-7.25 (m, 2H), 7.22 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.56 (s, 1H), 3.88-3.83 (m, 1H), 2.92 (t, J = 7.4 Hz, 2H), 2.76-2.60 (m, 2H), 2.00 (p, J = 7.5 Hz, 2H), 1.09-1.01 (m, 4H). One exchangeable proton not observed. m/z 424.5 (M + H)+ (ES+) 423.49 1-Cyclopropyl-N-((5-(pyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 304 [00630] 1H NMR (DMSO-d6) 8.54-8.49 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H), 7.89 (s, 1H), 7.38-7.23 (m, 2H), 7.22 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.59 (s, 1H), 4.93 (p, J = 8.4 Hz, 1H), 2.91 (t, J = 7.4 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.47 (m, 4H), 1.98 (p, J = 7.4 Hz, 2H), 1.88-1.73 (m, 2H). Exchangeable proton not observed. m/z 438.2 (M + H)+ (ES+) 437.51 1-Cyclobutyl-N-((5-(pyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 305 [00631] 1H NMR (DMSO-d6) 11.16 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H), 6.72 (s, 1H), 3.88 (s, 3H), 3.78 (br. s, 1H), 2.91 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.99 (p, J = 7.5 Hz, 2H), 1.11-0.93 (m, 4H). m/z 472.1 (M + H)+ (ES+); 470.0 (M H) (ES) 471.5 1-Cyclopropyl-4-fluoro-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 306 [00632] 1H NMR (DMSO-d6) 10.90 (br s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.92 (br s, 2H), 7.19 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 5.1 Hz, 1H), 6.73 (s, 1H), 6.59 (br s, 1H), 3.88 (s, 3H), 2.93- 2.85 (m, 4H), 2.67-2.61 (m, 2H), 1.96 (p, J = 7.4 Hz, 2H), 1.51 (s, 6H). 4H obscured by solvent. m/z 561.3 (M + H)+ (ES+) 560.62 1-(1-(3,3-Difluoroazetidin-1-yl)-2- methylpropan-2-yl)-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 307 [00633] 1H NMR (DMSO-d6) 8.13 (d, J = 5.3 Hz, 1H), 7.99-7.84 (m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 5.3 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.70 (br s, 1H), 6.60 (br s, 1H), 4.96 (dp, J = 57.9, 5.2 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 2.78 (s, 3H), 3.01- 2.88 (m, 4H), 1.88 (s, 2H), 1.48 (s, 6H). Acidic NH not observed, 2H partially obscured by water peak. m/z 545.2 (M + H)+ (ES+) 544.60 1-(1-(3-Fluoroazetidin-1-yl)-2- methylpropan-2-yl)-N-((5-(2- methoxypyridin-4-yl)-2,3- dihydrobenzofuran-4-yl)carbamoyl)-1H- pyrazole-3-sulfonamide 308 [00634] 1H NMR (DMSO-d6) 8.03 (d, J = 5.3 Hz, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 7.25 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 5.3 Hz, 1H), 6.73 (s, 1H), 3.86 (s, 3H), 3.00 (s, 3H), 2.91 (s, 3H), 2.87 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 1.93 (p, J = 7.5 Hz, 2H). m/z 495.2 (M + H)+ (ES+); 493.4 (M H) (ES) 494.56 4-(N-((5-(2Mmethoxypyridin-4-yl)-2,3- dihydro-1H-inden-4- yl)carbamoyl)sulfamoyl)-N,N- dimethylbenzamide, sodium salt 309 [00635] 1H NMR (DMSO-d6) 8.04 (d, J = 5.3 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.38 (s, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 6.70 (s, 1H), 6.60 (d, J = 8.2 Hz, 1H), 4.48 (t, J = 8.7 Hz, 2H), 3.86 (s, 3H), 3.02 (t, J = 8.7 Hz, 2H), 3.00 (s, 3H), 2.90 (s, 3H). m/z 497.1 (M + H)+ (ES+); 495.0 (M H) (ES) 496.54 4-(N-((5-(2-Methoxypyridyl-4-yl)-2,3- dihydrobenzofuran-4- yl)carbamoyl)sulfamoyl)-N,N- dimethylbenzamide, sodium salt 310 [00636] 1H NMR (DMSO-d6) 10.52 (br s, 1H), 8.04 (d, J = 5.3 Hz, 1H), 7.80- 7.72 (m, 3H), 7.48 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 5.2 Hz, 1H), 6.67 (s, 1H), 3.69 (br s, 2H), 2.88 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.31 (br s, 6H), 1.93 (p, J = 7.4 Hz, 2H). m/z 484.3 (M + H)+ (ES+) 483.6 4-((Dimethylamino)methyl)-N-((5-(2- (methoxy-d3)pyridin-4-yl)-2,3-dihydro- 1H-inden-4- yl)carbamoyl)benzenesulfonamide 311 [00637] 1H NMR (DMSO-d6) 8.04 (d, J = 5.3 Hz, 1H), 7.80-7.72 (m, 3H), 7.48 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.78- 6.73 (m, 1H), 6.71-6.63 (m, 2H), 4.50 (t, J = 8.7 Hz, 2H), 3.88 (s, 3H), 3.80 (s, 2H), 2.96 (t, J = 8.8 Hz, 2H), 2.38 (s, 6H). Acidic NH not observed. m/z, 483.3 (M + H)+ (ES+) 482.55 4-((Dimethylamino)methyl)-N-((5-(2- methoxypyridin-4-yl)-2,3- dihydrobenzofuran-4- yl)carbamoyl)benzenesulfonamide 312 [00638] 1H NMR (DMSO-d6) 8.13 (d, J = 5.3 Hz, 1H), 7.82 (s, 1H), 7.74 (br s, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 5.3 Hz, 1H), 6.47 (s, 1H), 6.54 (br s, 1H), 3.88 (s, 3H), 3.08- 2.94 (m, 6H), 2.89 (t, J = 7.4 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H), 2.50-2.41 (m, 2H), 2.33-2.22 (m, 2H), 2.01-1.78 (m, 6H). Acidic NH not observed. m/z 537.2 (M + H)+ (ES+); 535.1 (M H) (ES) 536.65 1-(1-(Azetidin-1-ylmethyl)cyclobutyl)-N- ((5-(2-methoxypyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1H-pyrazole-3- sulfonamide 313 [00639] 3-Cyclopropyl-4- ((dimethylamino)methyl)-N-((5-(2- 1H NMR (DMSO-d6) 10.53 (s, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.89 (s, 1H), 7.63-7.57 1H), (m, 7.49 (d, J = 8.0 Hz, 1H), 7.46- 7.42 (m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.80-6.74 (m, 1H), 6.68 (s, 1H), 3.87 (s, 3H), 3.77 (s, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.31 (s, 6H), 2.27-2.18 (m, 1H), 1.98-1.88 (m, 2H), 1.06- 0.98 (m, 2H), 0.63-0.59 (m, 2H). 2H under DMSO peak. m/z 521.2 (M + H)+ (ES+) 520.64 methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4- yl)carbamoyl)benzenesulfonamide 314 [00640] 1H NMR (DMSO-d6) 10.67 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 6.65 (d, J = 5.2 Hz, 1H), 6.61-6.47 (m, 2H), 3.93-3.83 (m, 4H), 2.87 (t, J = 7.5 Hz, 2H), 2.61-2.52 (m, 2H), 2.02-1.88 (m, H), 1.11- 0.98 (m, 4H). m/z 468.3 (M + H)+ (ES+) 467.54 1-Cyclopropyl-N-((5-(2-methoxypyridin- 4-yl)-6-methyl-2,3-dihydro-1H-inden-4- yl)carbamoyl)-1H-pyrazole-3-sulfonamide 315 [00641] .sup.1H NMR (Methanol-d.sub.4) 8.71 (dd, 1H), 7.97 (d, 1H), 7.73 (dd, 1H), 7.19 (dd, 1H), 7.02 (dd, 1H), 4.44 (q, 1H), 3.09-3.00 (m, 2H), 3.00-2.91 (m, 2H), 2.91-2.71 (m, 1H), 2.64 (s, 3H), 2.59 (s, 3H), 2.05 (dq, 1H), 1.98-1.82 (m, 1H), 1.35-1.16 (m, 6H). m/z 475.2 (M + H).sup.+ (ES.sup.+) 474.56 3-(N-Methyl-N-(1-methylpyrrolidin-3- yl)sulfamoyl)-1-(5-(2-cyanopyridin-4-yl)- 4-fluoro-6-isopropylphenyl)urea 316 [00642] .sup.1H NMR (Methanol-d.sub.4) 8.73 (d, 1H), 8.03 (d, 1H), 7.78 (d, 1H), 7.21 (dd, 1H), 7.07 (dd, 1H), 4.57 (m, 1H), 3.37-3.07 (m, 3H), 2.91 (m, 2H), 2.79 (s, 3H), 2.65 (s, 3H), 2.22-1.83 (m, 4H), 1.25 (dd, 6H). m/z 489.2 (M + H).sup.+ (ES.sup.+) 488.58 3-(N-Methyl-N-((1-methylpyrrolidin-2- yl)methyl)sulfamoyl)-1-(5-(2- cyanopyridin-4-yl)-4-fluoro-6- isopropylphenyl)urea 317 [00643] .sup.1H NMR (Methanol-d.sub.4) 8.68 (dd, 1H), 7.95 (dd, 1H), 7.73 (dd, 1H), 7.32- 7.14 (m, 3H), 4.51 (q, 1H), 3.26-3.13 (m, 1H), 3.1- 2.89 (m, 6H), 2.70 (d, 6H), 2.14 (m, 3H), 2.09- 1.89 (m, 1H). m/z 455.2 (M + H).sup.+ (ES.sup.+) 454.55 3-(N-Methyl-N-(1-methylpyrrolidin-3- yl)sulfamoyl)-1-(5-(2-cyanopyridin-4-yl)- 2,3-dihydro-1H-inden-4-yl)urea 318 [00644] .sup.1H NMR (Methanol-d.sub.4) 8.67 (dd, 1H), 7.95 (dd, 1H), 7.73 (dd, 1H), 7.21 (q, 2H), 3.62-3.40 (m, 2H), 3.16-2.88 (m, 9H), 2.81, (dt, 1H), 2.72 (s, 3H), 2.38-2.25 (m, 1H), 2.25- 2.04 (m, 2H), 1.57 (dd, 1H). m/z 467.2 (M + H).sup.+ (ES.sup.+) 466.56 N-((5-(2-Cyanopyridin-4-yl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-1- methylhexahydropyrrolo[3,4-b]pyrrole- 5(1H)-sulfonamide 319 [00645] .sup.1H NMR (Methanol-d.sub.4) 8.71 (dd, 1H), 7.97 (d, 1H), 7.74 (dd, 1H), 7.19 (dd, 1H), 7.02 (dd, 1H), 3.46 (dd, 2H), 3.04-2.86 (m, 6H), 2.88-2.73 (m, 1H), 2.68 (s, 3H), 2.32-2.21 (m, 1H), 1.67-1.41 (m, 1H), 1.37-1.13 (m, 6H). m/z 487.2 (M + H).sup.+ (ES.sup.+) 486.57 N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6- isopropylphenyl)carbamoyl)-1- methylhexahydropyrrolo[3,4-b]pyrrole- 5(1H)-sulfonamide 320 [00646] .sup.1H NMR (Methanol-d.sub.4) 8.12 (dd, 1H), 7.27-7.10 (m, 2H), 7.02 (dd, 1H), 6.85 (d, 1H), 3.93 (s, 3H), 3.55 (dd, 2H), 3.18-3.05 (m, 3H), 2.96 (dt, 6H), 2.80 (dt, 1H), 2.72 (s, 3H), 2.30 (dt, 1H), 2.11 (p, 2H), 1.62 (ddd, 1H). m/z 472.2 (M + H).sup.+ (ES.sup.+) 471.58 N-((5-(2-Methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)-1- methylhexahydropyrrolo[3,4-b]pyrrole- 5(1H)-sulfonamide, potassium salt 321 [00647] .sup.1H NMR (Methanol-d.sub.4) 8.68 (dd, 1H), 8.03 (dd, 1H), 7.78 (dd, 1H), 7.23 (d, 2H), 3.72 (dd, 1H), 3.51 (d, 1H), 3.19-3.09 (m, 1H), 3.09-2.91 (m, 6H), 2.79 (s, 3H), 2.71 (s, 3H), 2.13 (p, 2H), 1.99 (m, 3H), 1.65 (m, 1H). m/z 469.4 (M + H).sup.+ (ES.sup.+) 468.58 3-(N-Methyl-N-((1-methylpyrrolidin-2- yl)methyl)sulfamoyl)-1-(5-(2- cyanopyridin-4-yl)-2,3-dihydro-1H-inden- 4-yl)urea 322 [00648] 1H NMR (DMSO-d6) 8.09 (d, J =6.o Hz, 1H), 7.39 (s, 1H), 7.25 (d, J = 6.0 Hz, 1H), 7.02 (s, 1H), 6.58 (s, 1H), 3.86 (s, 3H), 2.63-2.58 (m, 2H), 2.58- 2.54 (m, 2H), 2.29-2.25 (m, 2H), 1.35 (s, 6H), NH and OH missing. m/z 462.0 (M + H).sup.+ (ES.sup.+) 461.49 4-(2-Hydroxypropan-2-yl)-N-((2-(2- methoxypyridin-4-yl)-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-3- yl)carbamoyl)furan-2-sulfonamide 323 [00649] 1H NMR (DMSO- d6 + D2O) 8.52 (d, J = 6.0 Hz, 2H), 7.60 (d, J = 6.0 Hz, 2H), 7.50 (s, 1H), 6.73 (s, 1H), 2.66-2.61 (m, 2H), 2.56-2.52 (m, 2H), 2.32- 2.25 (m, 2H), 1.36 (s, 6H), NH & OH missing. m/z 432.0 (M + H).sup.+ (ES.sup.+) 431.47 4-(2-Hydroxypropan-2-yl)-N-((2- (pyridin-4-yl)-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-3- yl)carbamoyl)furan-2-sulfonamide

EXAMPLESBIOLOGICAL STUDIES

NLRP3 and Pyroptosis

[1752] It is well established that the activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-1) from the cell.

THP-1 Cells: Culture and Preparation

[1753] THP-1 cells (ATCC #TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma #S8636) and penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma #P4333) in 10% Fetal Bovine Serum (FBS) (Sigma #F0804). The cells were routinely passaged and grown to confluency (10.sup.6 cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma #T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma #L4524) to give a 1 g/ml Final Assay Concentration (FAC). 40 l of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

THP-1 Cells Pyroptosis Assay

[1754] The following method step-by-step assay was followed for compound screening. [1755] 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 g/ml LPS in 40 l of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) [1756] 2. Add 5 compound (8 points half-log dilution, with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1757] 3. Incubate for 3 hrs at 37 C. and 5% CO.sub.2 [1758] 4. Add 5 nigericin (Sigma #N7143) (FAC 5 M) to all wells [1759] 5. Incubate for 1 hr at 37 C. and 5% CO.sub.2 [1760] 6. At the end of the incubation period, spin plates at 300g for 3 mins and remove supernatant [1761] 7. Then add 50 l of resazurin (Sigma #R7017) (FAC 100 M resazurin in RPMI medium without FBS) and incubate plates for a further 1-2 hrs at 37 C. and 5% CO.sub.2 [1762] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [1763] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

TABLE-US-00004 96-well Plate Map 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 Cornp 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 Camp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low F High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low G High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low H High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low High MCC950 (10 uM) LOW Drug free control Compound 8-point half-log dilution

[1764] The results of the pyroptosis assay performed are summarised in Table 3 below as THP IC.sub.50.

Human Whole Blood IL1 Release Assay

[1765] 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.

[1766] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [1767] 1. Plate out 80 l of whole blood containing 1 g/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [1768] 2. Add 10 l compound (8 points half-log dilution with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1769] 3. Incubate for 3 hrs at 37 C., 5% CO.sub.2 [1770] 4. Add 10 l nigericin (Sigma #N7143) (10 M FAC) to all wells [1771] 5. Incubate for 1 hr at 37 C., 5% CO.sub.2 [1772] 6. At the end of the incubation period, spin plates at 300g for 5 mins to pellet cells and remove 20 l of supernatant and add to 96-well v-bottom plates for IL-1 analysis (note: these plates containing the supernatants can be stored at 80 C. to be analysed at a later date) [1773] 7. IL-1 was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [1774] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[1775] The results of the human whole blood assay are summarised in Table 3 below as HWB IC.sub.50.

TABLE-US-00005 TABLE 3 NLRP3 inhibitory activity (0.5 M = ++++, 1 M = +++, 5 M = ++, 10 M = +, not determined = ND). Example No THP IC.sub.50 HWB IC.sub.50 1 ++++ ++++ 2 ++ ND 3 ++ ND 4 ++ ND 5 ++ ND 6 ++ ND 7 ++ ND 8 ++ ND 9 ++ ND 10 ++++ ++++ 11 ++++ ND 12 ++++ +++ 13 ++++ ND 14 ++ ND 15 ++ ND 16 ++ ND 17 ++ ND 18 +++ ND 19 +++ ND 20 ++ ND 21 ++ ND 22 +++ ND 23 ++++ +++ 24 ++++ +++ 25 ++++ ++++ 26 ++ ND 27 ++++ ++ 28 ++++ ++++ 29 ++ ND 30 ++ ++++ 31 ++ ND 32 ++++ ++++ 33 ++++ ++++ 34 +++ ++++ 35 ++++ +++ 36 ++++ ++++ 37 ++++ ++++ 38 ++++ ++++ 39 +++ +++ 40 ++++ +++ 41 ++++ +++ 42 ++ ND 43 ++ ND 44 ++++ ++++ 45 ++++ ++++ 46 +++ ++ 47 +++ ND 48 ++++ ++++ 49 ++++ ++++ 50 ++ ND 51 ++++ ++++ 52 ++++ ++++ 53 ++++ ++ 54 ++++ ++++ 55 ++++ +++ 56 ++++ ++++ 57 +++ +++ 58 ++++ ++++ 59 ++++ +++ 60 ++++ ++++ 61 ++++ ++++ 62 ++++ ++ 63 ++++ ++++ 64 ++++ ++++ 65 ++++ ++++ 66 ++++ ++++ 67 ++ ND 68 ++++ +++ 69 ++++ ++++ 70 ++++ ++++ 71 ++++ +++ 72 ++++ +++ 73 ++++ ++++ 74 + ND 75 ++++ ND 76 ++++ ++++ 77 ++++ +++ 78 + ND 79 ++++ +++ 80 ++++ +++ 81 ++++ +++ 82 + ND 83 ++ ND 84 +++ +++ 85 +++ ND 86 + ND 87 ++ ++ 88 +++ ND 89 ++++ +++ 90 ++++ +++ 91 ++++ +++ 92 +++ ND 93 + ND 94 ++ ND 95 ++++ +++ 96 +++ ND 97 ++ ND 98 ++ ND 99 + ND 100 ++ ++ 101 ++ +++ 102 ++++ ND 103 ++++ ND 104 ++++ ND 105 ++++ +++ 106 ++++ ++ 107 ++++ ND 108 ++++ ++ 109 ++++ ++ 110 + ND 111 ++ ND 112 +++ ND 113 ++ ND 114 ++++ ++ 115 ++++ ND 116 ++++ ++++ 117 ++++ +++ 118 ++++ +++ 119 ++++ ++ 120 ++++ ++ 121 ++++ +++ 122 ++++ ++++ 123 ++++ ++++ 124 ++++ ++++ 125 ++++ ++++ 126 ++++ ++++ 127 + ND 128 +++ ND 129 ++ ND 130 ++ ND 131 + ND 132 +++ ND 133 ++++ ND 134 +++ ND 135 +++ ND 136 ++++ ND 137 ++++ ND 138 +++ + 139 ++ ND 140 ++ ND 141 +++ ND 142 ++ ND 143 +++ ND 144 ++ ND 145 ++++ +++ 146 +++ ND 147 ++++ ND 148 ++++ ND 149 ++++ ++++ 150 ++++ ND 151 ++ ND 152 ++++ ND 153 ++++ ++ 154 ++ ND 155 ++++ ND 156 ++++ ND 157 ++ ND 158 + ND 159 + ND 160 + ND 161 + ND 162 + ND 163 ++++ ++++ 164 ++++ ++++ 165 ++ ND 166 ++ + 167 ++++ ++++ 168 ++++ ++ 169 ++++ ++++ 170 ++++ +++ 171 ++++ ++ 172 ++++ +++ 173 ++++ ++++ 174 ++++ +++ 175 ++++ ++++ 176 ++++ ++++ 177 ++++ +++ 178 ++++ ++ 179 ++ ++ 180 ++++ ++++ 181 ++++ ++++ 182 ++++ ++++ 183 ++++ ++++ 184 ++++ ++++ 185 ++++ ++++ 186 ++++ ++++ 187 ++++ ++++ 188 ++++ ++++ 189 ++++ ++++ 190 ++++ ++++ 191 ++++ +++ 192 ++++ ++++ 193 ++++ ++++ 194 +++ ND 195 ++++ ++++ 196 ++++ ++++ 197 ++++ ++++ 198 ++++ ++++ 199 ++++ ++++ 200 ++++ ++++ 201 ++++ ++++ 202 ++++ ++++ 203 ++++ ++++ 204 ++ ND 205 ++++ ++++ 206 ++++ ++ 207 +++ ++ 208 ++ ND 209 ++++ ++ 210 ++++ ++ 211 ++++ ++ 212 ++ ND 213 ++++ ++ 214 ++++ +++ 215 ++++ ++++ 216 ++++ ++ 217 + ND 218 ++++ +++ 219 ++++ ++++ 220 + ND 221 ++++ ++++ 222 ++++ ++++ 223 ++++ ++++ 224 ++++ ++++ 225 ++++ ++ 226 ++++ +++ 227 ++++ ++++ 228 ++++ ++++ 229 ++++ ++++ 230 ++++ ++++ 231 ++++ ++++ 232 ++++ +++ 233 ++++ +++ 234 ++++ +++ 235 ++++ ++++ 236 ++++ ++++ 237 ++++ +++ 238 ++ ND 239 ++++ ++++ 240 ++ ND 241 ++ ND 242 ++++ ++++ 243 ++++ ++++ 244 ++++ ++++ 245 ++++ ++++ 246 ++++ +++ 247 ++++ ++++ 248 ++++ ++++ 249 ++++ ++++ 250 ++++ ++++ 251 ++++ ++++ 252 ++++ ++++ 253 +++ ++ 254 ++ ND 255 ++++ ++++ 256 +++ ND 257 ++++ ++++ 258 ++++ ++++ 259 ++++ ++++ 260 ++++ ++ 261 ++++ ++ 262 ++++ +++ 263 ++++ ++++ 264 ++++ ++++ 265 ++++ ++++ 266 ++++ +++ 267 ++++ ++++ 268 ++ ND 269 ++++ ++++ 270 ++++ ++++ 271 ++++ ++++ 272 ++ ND 273 ++ ND 274 ++++ ++++ 275 ++++ ++++ 276 ++++ +++ 277 ++++ ++++ 278 ++++ ++++ 279 ++++ ++++ 280 ++++ ++++ 281 ++++ ++++ 282 ++++ ++++ 283 ++ ND 284 ++++ +++ 285 ++++ ++ 286 ++++ + 287 ++++ ++++ 288 ++++ ++ 289 ++++ ++ 290 ++++ ++++ 291 ++++ +++ 292 ++++ +++ 293 ++++ ++ 294 ++++ ++ 295 ++++ +++ 296 ++++ ++++ 297 +++ ND 298 ++++ +++ 299 ++++ ++++ 300 ++++ +++ 301 +++ ND 302 ++ ND 303 ++++ ++++ 304 ++++ ++++ 305 ++++ ++++ 306 ++++ ++++ 307 ++++ ++++ 308 ++++ +++ 309 ++ ND 310 ++++ ++++ 311 ++++ ++++ 312 ++++ ++++ 313 ++++ ++++ 314 ++++ +++ 315 ++ ND 316 ++ ND 317 ++++ ++++ 318 +++ ++++ 319 + ND 320 ++++ ++++ 321 +++ ++++ 322 ++ ND 323 ++ ++++

PK Protocol

[1776] 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.

[1777] For intravenous administration, compounds were formulated as a solution in water or DMSO:PBS [10:90] in 2 mL/kg dosing volume and administered via tail vein. For oral administration, compounds were formulated as a solution in DMSO:water [10:90] in 5 mL/kg dosing volume and administered orally.

[1778] Serial blood samples (about 120-300 L) were taken from each animal at each of 8 time-points post dose (0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h) or at each of 12 time-points post dose (0.03, 0.1, 0.17, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h) or pre-dose and at each of 9 time-points post dose (0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h). Samples were held on ice for no longer than 30 minutes before centrifugation (10,000 rpm (8,385 g) for 3 minutes; or 5,696 rpm (3,000 g) for 15 minutes) for plasma generation. Plasma was frozen on dry ice prior to bioanalysis. PK parameters were generated from LC-MS/MS data using Dotmatics or Phoenix WinNonlin 6.3 software.

TABLE-US-00006 TABLE 4 PK data (intravenous administration) Example Dose AUC T.sub.1/2 V.sub.dss Cl No (mg/kg) (ng .Math. hr/mL) (hr) (L/kg) (mL/min/kg) 1 1 340.9 3.3 4.49 49.1 10 1.98 806.3 3.8 7.14 40.9 25 1 411.5 0.4 0.41 41.9 28 1 385.5 1.2 1.07 43.3 30 1 182.5 2.3 2.72 91.3 33 1 274.4 6.3 3.95 60.7 34 1 661.2 12.1 3.03 25.2 36 1 356.0 0.5 0.8 47.6 37 1 247.8 0.3 1.32 67.2 38 1 375.4 1.2 1.14 51.5 44 1 259.0 0.5 0.75 64.9 45 1 259.1 0.5 0.98 65.6 51 1 600.1 3.7 3.68 27.8 54 1 200 1.6 2.5 85.4 55 1 1862.5 6.9 3.25 9.8 58 1 591.0 0.9 0.55 28.2 60 1 300.2 1.0 1.22 56.3 61 1.69 1145.0 1.2 0.6 24.6 64 1.7 2710.4 3.8 1.23 10.5 69 1 896 5.8 0.78 19 70 1 510.7 1.1 1.21 32.6 73 1 1518.0 1.0 0.31 11.0 103 1 346.3 2.2 1.77 48.1 104 1 841.0 1.2 1.04 19.8 122 1 1318.7 11.1 8.69 12.6 205 1 4872.7 2.6 0.57 3.4 221 1 65385 15 0.36 0.39 223 1 1741.8 0.9 0.31 9.6 224 1 6480.1 3.2 0.47 2.6 230 1 1949.8 1.3 0.24 8.5 251 1 1257.3 2.9 2.12 13.3

TABLE-US-00007 TABLE 5 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 69 3 113 504 0.5 5.0 112 19 221 3 7220 135743 0.75 12 0.48 83

[1779] As is evident from the results presented in Table 3, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and in particular in the human whole blood assay.

[1780] As is evident from the results presented in Tables 4 and 5, 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.

[1781] 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.