Sulfonylureas and sulfonylthioureas as NLRP3 inhibitors

Abstract

The present invention relates to compounds of formula (I): ##STR00001##
wherein Q is O or S, R.sup.1 is a 6-membered heteroaryl group containing at least one nitrogen atom in the 6-membered ring structure, wherein R.sup.1 may optionally be substituted, and R.sup.2 is a cyclic group substituted at the α-position, wherein R.sup.2 may optionally be further substituted. 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): ##STR00260## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is O or S; R.sup.1 is a 6-membered heteroaryl group containing at least two nitrogen atoms in the 6-membered ring structure, wherein the 6-membered heteroaryl group of R.sup.1 is substituted with at least one monovalent group X, wherein X is at each occurrence any group that can mesomerically donate a lone pair of electrons from a nitrogen, oxygen or sulphur atom onto at least one nitrogen atom in the 6-membered ring structure, and wherein the 6-membered heteroaryl group may optionally be further substituted; and R.sup.2 is a cyclic group substituted at the α-position, wherein R.sup.2 may optionally be further substituted, provided that the substitutent at the a-position is not an optionally substituted monovalent heterocyclic group or an optionally substituted monovalent aromatic group, wherein a ring atom of the heterocyclic or aromatic group is directly attached to the α-ring atom of the cyclic group.

2. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein at least one of the two nitrogen atoms is located at the 3, 4 or 5-position of the 6-membered ring structure.

3. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein X is at each occurrence a monovalent group X′, wherein: each X′ is attached at a position ortho- or para- to at least one nitrogen atom in the 6-membered ring structure; the 6-membered heteroaryl group of R1 may optionally be further substituted; X′ is at each occurrence independently selected from a —OR.sup.3, —SR.sup.3, —N(R.sup.3).sub.2,—O-L-OR.sup.3, —O-L-SR.sup.3, —O-L-N(R.sup.3).sub.2, —S-L-OR.sup.3, —S-L-SR.sup.3, —S-L-N(R.sup.3).sub.2, —NR.sup.3-L-OR.sup.3, —NR.sup.3-L-SR.sup.3 or —NR.sup.3-L-N(R.sup.3).sub.2 group; each R.sup.3 is independently selected from hydrogen or an alkyl, alkenyl, alkynyl or cyclic group, or any two R.sup.3 in the same group X′ may together with the atom or atoms to which they are attached form a heterocyclic group; each L is independently selected from an alkylene, alkenylene or alkynylene group; and any L or R.sup.3 may optionally be substituted.

4. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein at least one nitrogen atom is located at the 4-position of the 6-membered ring structure of R.sup.1.

5. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein (i) the 6-membered heteroaryl group of R.sup.1 is monocyclic; or (ii) the 6-membered heteroaryl group of R.sup.1 is substituted with one or more fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings such that the resultant group is bicyclic, tricyclic or polycyclic.

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

7. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein R.sup.2 is a cyclic group substituted at the α and α′ positions, wherein R.sup.2 may optionally be further substituted.

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

9. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, which is (a) a compound selected from the group consisting of: ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## or (b) a pharmaceutically acceptable salt, solvate or prodrug of the selected compound.

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

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

12. The method as claimed in claim 11, 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.

13. The method as claimed in claim 11, 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 A.sub.20 (HA.sub.20).

14. The method as claimed in claim 11, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

15. 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.

16. 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.

17. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein the 6-membered heteroaryl group of R.sup.1 is a pyrazinyl or a pyridazinyl group.

18. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 1, which is the compound, pharmaceutically acceptable salt or solvate.

19. The compound or pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 9, which is the compound, pharmaceutically acceptable salt or solvate.

Description

EXAMPLES-COMPOUND SYNTHESIS

(1) All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

(2) 2-MeTHF 2-methyltetrahydrofuran Ac.sub.2O acetic anhydride AcOH acetic acid aq aqueous Boc tert-butyloxycarbonyl br broad Cbz carboxybenzyl CDI 1,1-carbonyl-diimidazole conc concentrated d doublet DABCO 1,4-diazabicyclo[2.2.2]octane DCE 1,2-dichloroethane, also called ethylene dichloride DCM dichloromethane DIPEA N,N-diisopropylethylamine, also called Hünig's base DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine DME dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide (ES+) electrospray ionization, positive mode Et ethyl EtOAc ethyl acetate EtOH ethanol h hour(s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HPLC high performance liquid chromatography LC liquid chromatography m multiplet m-CPBA 3-chloroperoxybenzoic acid Me methyl MeCN acetonitrile MeOH methanol (M+H)+ protonated molecular ion MHz megahertz min minute(s) MS mass spectrometry Ms mesyl, also called methanesulfonyl MSCl mesyl chloride, also called methanesulfonyl chloride MTBE methyl tert-butyl ether, also called tert-butyl methyl ether m/z mass-to-charge ratio NaOtBu sodium tert-butoxide NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide Ni(dppp)Cl.sub.2 [1,3-bis(diphenylphosphino)propane]nickel(II) chloride NMP N-methylpyrrolidine NMR nuclear magnetic resonance (spectroscopy) Pd(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o) Pd(dppf)Cl.sub.2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PE petroleum ether Ph phenyl PMB p-methoxybenzyl prep-HPLC preparative high performance liquid chromatography prep-TLC preparative thin layer chromatography PTSA p-toluenesulfonic acid q quartet RP reversed phase RT room temperature s singlet Sept septuplet sat saturated SCX solid supported cation exchange (resin) t triplet T3P propylphosphonic anhydride TBME tert-butyl methyl ether, also called methyl tert-butyl ether TEA triethylamine TFA 2,2,2-trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography wt % weight percent or percent by weight Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

(3) Analytical Methods

(4) NMR spectra were recorded at 300 MHz (unless stated otherwise) with chemical shifts reported in parts per million. Spectra were collected using one of the three machines below: 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. An Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console. A Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control.

(5) Spectra were measured at 298K, unless indicated otherwise, and were referenced relative to the solvent resonance.

(6) HPLC and LC-MS were recorded on an Agilent 1290 series with UV detector and HP 6130 MSD mass detector. Mobile phase A: ammonium acetate (10 mM); water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM); water/MeOH/acetonitrile (100:540:360); column, Waters XBridge BEH C18 XP (2.1×50 mm, 2.5 μM)

(7) TABLE-US-00001 Pump flow: 0.6 mL/min UV detection: 215, 238 nm Injection volume: 0.2 μL Run time: 4.0 min Column temperature: 35° C. Mass detection: API-ES +ve and −ve

(8) Pump Program:

(9) TABLE-US-00002 Gradient Time (min) % A % B 0.0 80 20 0.5 80 20 2.0 0 100

(10) Preparative Reversed Phase HPLC General Methods

(11) Purification Method 1

(12) Automated reversed phase column chromatography was carried out using a Buchi Sepracore® X50 system driven by a C-605 pump module, C-620 Sepracore control package, C-640 UV photometer detection unit and C-660 fraction collector.

(13) Revelis C18 Reversed-Phase 12 g Cartridge

(14) TABLE-US-00003 Carbon loading 18% Surface area 568 m.sup.2/g Pore diameter 65 Angstrom pH (5% slurry) 5.1 Average particle size 40 μm

(15) Column was conditioned before use with MeOH (5 min) then brought to H.sub.2O (in 5 min) and kept 5 min at H.sub.2O. Flow rate=30 mL/min.

(16) Separation Runs:

(17) TABLE-US-00004 Time (min) A: water (%) B: MeOH (%) 0 100 0 5 100 0 30 30 70 30.1 0 100 35 0 100

(18) Detection wavelength: 215, 235, 254 and 280 nm. Before each new run, the cartridge was cleaned using the conditioning method.

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

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

SYNTHESIS OF INTERMEDIATES

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

(21) ##STR00133##

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

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

Intermediate A2: 2-Isocyanato-1,3-diisopropylbenzene

(24) ##STR00134##

(25) To a suspension of 2,6-diisopropylaniline hydrochloride (1 g, 4.7 mmol) in toluene (50 mL) was added 1 drop of pyridine and the resulting mixture was heated to near reflux whilst a solution of phosgene (7.3 mL, 20% wt in toluene, 13.8 mmol) was added drop-wise over a period of 10 minutes. The mixture was stirred for an additional 45 minutes at 105° C. and then allowed to partially cool before being concentrated in vacua to afford the title compound as a mobile yellow oil (1.5 g, >100% yield). The crude product was used directly in the next step without further purification.

(26) .sup.1H NMR (CDCl.sub.3): δ 7.2 (m, 3H), 3.12 (m, 2H) and 1.25 (d, 12H).

Intermediate A3: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile

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

(27) ##STR00135##

(28) 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 (boo mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (2×600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (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.

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

(30) LCMS: m/z 152.2 (M+H).sup.+(ES.sup.+).

Step B: 4-Fluoro-2-isopropylaniline

(31) ##STR00136##

(32) 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 vacua and purged with H2 several times. The reaction mixture was stirred at 25° C. for 12 hours under H2 (so psi). The reaction mixture was filtered and the filtrate was concentrated in vacua to give the title compound (20 g, crude) as a yellow oil.

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

(34) LCMS: m/z 154.2 (M+H).sup.+(ES.sup.+).

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

(35) ##STR00137##

(36) 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 (2×250 mL). The combined organic phases were washed with brine (2×400 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.

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

(38) LCMS: m/z 232.1 (M+H).sup.+(ES.sup.+).

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

(39) ##STR00138##

(40) 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 N.sub.2 atmosphere. The resulting mixture was stirred at 80° C. for 2 hours under N.sub.2 atmosphere. 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.

(41) .sup.1H NMR (CDCl.sub.3): δ 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).

(42) LCMS: m/z 256.2 (M+H).sup.+(ES.sup.+).

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

(43) ##STR00139##

(44) 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). Then triphosgene (465 mg, 1.57 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 then filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.2 g, crude) as a yellow solid, which was used directly in the next step.

Intermediate A4: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine

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

(45) ##STR00140##

(46) 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 N.sub.2 three times. Then Pd(dppf)C12 (3.78 g, 5.17 mmol, 0.1 eq) was added to the mixture under N.sub.2 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 (2×600 mL). The combined organic layers were washed with brine (2×800 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).

(47) .sup.1H NMR (CDCl.sub.3): δ 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), 1.29 (dd, 6H).

(48) LCMS: m/z 261.1 (M+H).sup.+(ES.sup.+).

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

(49) ##STR00141##

(50) 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 vacua to give the title compound (1.1 g, crude) as yellow oil, which was used directly in the next step.

Intermediate A5: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

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

(51) ##STR00142##

(52) To a mixture of 2,3-dihydro-1H-indene (60 g, 57.72 mmol, 62.50 mL, 1 eq) in concentrated H.sub.2SO.sub.4 (30 mL) was added a mixture of HNO.sub.3 (50 mL, 69 wt % in water) and concentrated H.sub.2SO.sub.4 (50 mL) dropwise at 0° C. over a period of 3.5 hours. The reaction mixture was stirred at 0° C. for 0.5 hour. Then the reaction mixture was poured into ice water (600 mL) and extracted with ethyl acetate (2×400 mL). The combined organic layers were washed with water (500 mL), saturated aqueous NaHCO.sub.3 solution (500 mL) and brine (2×500 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (55 g, 66%) as a colourless oil.

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

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

(54) ##STR00143##

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

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

(57) LCMS: m/z 134.2 (M+H).sup.+(ES.sup.+).

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

(58) ##STR00144##

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

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

(61) LCMS: m/z 176.2 (M+H).sup.+(ES.sup.+)

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

(62) ##STR00145##

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

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

(65) LCMS: m/z 254.1 (M+H).sup.+(ES.sup.+).

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

(66) ##STR00146##

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

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

(69) LCMS: m/z 212.0 (M+H).sup.+(ES.sup.+).

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

(70) ##STR00147##

(71) A solution of (2-methoxypyridin-4-yl)boronic acid (25.11 g, 164.15 mmol, 1.2 eq), 5-bromo-2,3-dihydro-1H-inden-4-amine (34 g, 136.80 mmol, 1 eq, HCl salt) and K.sub.2CO.sub.3 (60.50 g, 437.74 mmol, 3.2 eq) in dioxane (500 mL) and H.sub.2O (100 mL) was degassed with nitrogen for 15 minutes before Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (6 g, 7.35 mmol, 0.053 eq) was added. The reaction mixture was heated to 80° C. for 12 hours. The mixture was poured into water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic phases were washed with brine (2×700 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in 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 (27.4 g, 79% yield, 95% purity on LCMS) as a white solid.

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

(73) LCMS: m/z 241.2 (M+H).sup.+(ES.sup.+).

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

(74) ##STR00148##

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

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

Intermediate A6: 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

(77) ##STR00149##

(78) 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 (3×300 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 3:1) to give the title compound (11.4 g, 92%) as a yellow solid.

(79) .sup.1H NMR (CDCl.sub.3): δ 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

(80) ##STR00150##

(81) 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. Then the reaction mixture was stirred at 15° C. for 1 hour. The mixture was poured into the water (500 mL) and extracted with DCM (2×200 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacua to give the title compound (30 g, crude) as brown oil.

(82) .sup.1H NMR (CDCl.sub.3): δ 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

(83) ##STR00151##

(84) 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. Then the reaction mixture was stirred at 2.sub.5° C. for 12 hours. The mixture was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated aqueous NaHCO.sub.3 solution (2×100 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.

(85) .sup.1H NMR (CDCl.sub.3): δ 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

(86) ##STR00152##

(87) 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 N.sub.2 atmosphere. Then the reaction mixture was stirred at 25° C. for 12 hours under H.sub.2 (15 psi). 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, 5:1 to 10:1) to give the title compound (1.8 g, 43%) as a brown solid.

(88) .sup.1H NMR (CDCl.sub.3): δ 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

(89) ##STR00153##

(90) 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 (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 20:1) to give the title compound (8.51 g, 67%) as a brown solid.

(91) .sup.1H NMR (CDCl.sub.3): δ 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

(92) ##STR00154##

(93) 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 N.sub.2 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 (3×100 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.

(94) .sup.1H NMR (CDCl.sub.3): δ 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

(95) ##STR00155##

(96) 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, 487.82 μL, 2 eq) in THF (30 mL) was added bis(trichloromethyl) carbonate (208 mg, 700.94 μmol, 0.4 eq) at 0° C. The reaction mixture was stirred at 70° C. for 30 minutes. 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 vacua to reduce to 10 mL, which was used directly in the next step.

Intermediate P3: 6-Chloropyridazine-3-sulfonamide

Step A: 6-Chloropyridazine-3(2H)-thione

(97) ##STR00156##

(98) To a suspension of thiourea (3.8 g, 49.9 mmol) in acetone (150 mL) was added 3,6-dichloropyridazine (7.5 g, 5.3 mmol) at ambient temperature. The resulting reaction mixture was heated to reflux for 2 hours and upon cooling the mixture was filtered and the precipitate washed with acetone (2×20 mL). The solid was dissolved in aqueous sodium hydroxide solution (4 g in 80 mL water) and acidified with 37% hydrochloric acid to pH5. The resulting precipitate was filtered and washed with water (10 mL), then dried in vacuo to afford the title compound as a yellow solid (4.3 g, 58% yield). The crude product was used directly in the next step without further purification.

(99) .sup.1H NMR (DMSO-d.sub.6): δ 7.6 (d, 1H), 7.37 (d, 1H) and 7.35 (s, 1H).

Step B: 6-Chloropyridazine-3-sulfonamide

(100) ##STR00157##

(101) To a solution of 6-chloropyridazine-3(2H)-thione (250 mg, 1.7 mmol) in dichloromethane (10 mL) was added hydrochloric acid (10 mL 1 M). The mixture was cooled to −10° C. before a solution of sodium hypochlorite (3.5 mL, 10-15%) was added drop-wise. After 10 minutes stirring at −10° C., the dichloromethane layer was separated and poured into aqueous ammonium hydroxide (200 mL 25%). The aqueous layer was evaporated and the residue was triturated with methanol before the suspension was isolated by filtration and the mother liquors evaporated. The residue was purified over silica using ethyl acetate-methanol as the solvent. The product containing fractions were combined and evaporated. The product was triturated with TBME-heptane to afford the title compound (120 mg; 33%) as a pale brown solid.

(102) .sup.1H NMR (300 MHz, CD.sub.3OD): δ 8.2 (d, J=Hz, 1H), 8.0 (d, J=Hz, 1H).

Intermediate P4: 3,6-Dimethoxypyridazine-4-sulfonamide

Step A: 4-Iodo-3,6-dimethoxypyridazine

(103) ##STR00158##

(104) To a cold (−50° C.) solution of n-BuLi (2.5 M in hexanes, 12 mL, 30 mmol) in anhydrous THF (110 mL) under nitrogen was added 2,2,6,6-tetramethylpiperidine (5.1 mL, 30 mmol) drop-wise and the mixture was stirred towards −20° C. for 50 min, then recooled to −78° C. A solution of 3,6-dimethoxypyridazine (2 g, 14.3 mmol) in THF (30 mL) was added drop-wise and the resulting mixture was stirred at −78° C. for 60 min. Iodine (8 g, 31.4 mmol) was added and the reaction was stirred for a further 90 min and quenched at −50° C. with saturated aqueous sodium thiosulphate (30 mL). The mixture was allowed to warm to room temperature and partitioned between dichloromethane (200 mL) and water (50 mL). The organic layer was separated, washed with brine (20 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacua to give a crude yellow semi-solid (4.5 g). The material was subjected to column chromatography (silica, eluting with heptane/EtOAc gradient, 0 to 20%) to give 4-iodo-3,6-dimethoxypyridazine as a white solid (1.7 g, 45% yield).

(105) .sup.1H NMR (CDCl.sub.3): δ 7.48 (s, 1H), 4.04 (s, 3H) and 4.02 (s, 3H).

Step B: 4-(Benzylthio)-3,6-dimethoxypyridazine

(106) ##STR00159##

(107) To a solution of 4-iodo-3,6-dimethoxypyridazine (1 g, 3.76 mmol) in 1,4-dioxane (20 mL) was added diisopropylethylamine (1.24 mL, 7.52 mmol) and Xantphos (218 mg, 0.38 mmol) and the resulting mixture was degassed with nitrogen for 10 minutes. Subsequently, tris(dibenzylideneacetone)dipalladium (172 mg, 0.19 mmol) was added, followed by benzyl mercaptan (0.44 mL, 3.76 mmol). The solution was heated with stirring under microwave irradiation for 2 hours at to 0° C. The resulting mixture was allowed to cool to room temperature and diluted with water and ethyl acetate. The aqueous phase was extracted with further ethyl acetate. The combined organic phase was dried (Na.sub.2SO.sub.4), filtered and concentrated to afford a bright orange oil (3.23 g). The material was subjected to column chromatography (silica, eluting with heptane/ethyl acetate gradient, 0 to 40%) to afford the title compound as a white solid (0.7 g, 71% yield).

(108) .sup.1H NMR (CDCl.sub.3): δ 7.4 (s, 1H), 6.63 (s, 5H), 4.11 (s, 2H), 4.09 (s, 3H) and 4.0 (s, 3H).

Step C: 3,6-Dimethoxypyridazine-4-sulfonamide

(109) ##STR00160##

(110) Prepared as described for 6-chloropyridazine-3-sulfonamide (intermediate P3, step B) to afford the title compound as a pale brown solid (52 mg, 36%).

(111) .sup.1H NMR (CD.sub.3OD): δ 7.46 (s, 1H), 4.17 (s, 3H) and 4.07 (s, 3H).

Intermediate 6-(Dimethylamino)pyridazine-sulfonamide

(112) ##STR00161##

(113) To 6-chloropyridazine-3-sulfonamide (19 mg, 0.13 mmol) was added a solution of dimethylamine in methanol (2 mL, 2 M) and the mixture was heated for to minutes at 120° C. in a microwave. The solvents were evaporated and triethylamine (too mg, 1 mmol) and THF (1 mL) were added to the residue. After stirring for 1 hour at room temperature the mixture was filtered and the THF was evaporated to afford the title compound as a solid (20 mg, 77%).

(114) .sup.1H NMR (CD.sub.3OD): δ=7.82 (d, 1H), 7.18 (d, 1H) and 3.25 (s, 6H).

Intermediate P6: 5-(Dimethylamino)pyridazine-3-sulfonamide

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

(115) ##STR00162##

(116) To 3,5-dichloropyridazine (500 mg, 3.36 mmol) was added a solution of dimethylamine in tetrahydrofuran (10 mL 2 M). The mixture was stirred for 18 hours at room temperature before the solvents were evaporated and to the residue was added triethylamine (720 mg, 1 mmol) and tetrahydrofuran (10 mL). After stirring for 1 hour, the mixture was filtered and the solvent was evaporated to afford the title compound as a solid (510 mg, 96%).

(117) .sup.1H NMR (CDCl.sub.3): δ=8.64 (d, 1H), 6.53 (d 1H) and 3.09 (s, 6H).

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

(118) ##STR00163##

(119) To a solution of 6-chloro-N,N-dimethylpyridazin-4-amine (500 mg, 3.2 mmol) in 1,4-dioxane (10 mL) was added diisopropylethylamine (833 mg, 6.4 mmol) and Xantphos [4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, 184 mg, 0.3 mmol]. The resulting mixture was degassed with nitrogen for 10 minutes. Subsequently, tris(dibenzylidene acetone)dipalladium (145 mg, 0.16 mmol) was added, followed by benzyl mercaptan (433 mg, 3.5 mmol) and the solution was heated to reflux overnight under a nitrogen atmosphere and upon cooling the solution was concentrated in vacua. The residue was purified via chromatography over neutral aluminium oxide using dichloromethane as the eluent to afford the title compound (220 mg, 26%) as a pale brown solid.

(120) .sup.1H NMR (CDCl.sub.3): δ=8.50 (d, 1H), 7.42 (d, 2H), 7.26 (m, 3H), 6.32 (d, 1H), 4.56 (s, 2H) and 2.99 (s, 6H).

Step C: 5-(dimethylamino)pyridazine-3-sulfonamide

(121) ##STR00164##

(122) Prepared as described for 6-chloropyridazine-3-sulfonamide (intermediate P3, step B). This afforded the title compound as a pale brown solid (100 mg, 30%).

(123) .sup.1H NMR (CD.sub.3OD): δ 8.81 (d, 1H), 7.24 (d, 1H) and 3.22 (s, 6H).

Intermediate P7: 5-((2-(Dimethylamino)ethyl)amino)pyrazine-2-sulfonamide

(124) ##STR00165##

(125) To a solution of 5-chloropyrazine-2-sulfonamide (150 mg, 775 μmol) in tetrahydrofuran (20 mL) was added N,N-dimethylethane-1,2-diamine (341 mg, 3.9 mmol) and triethylamine (235.19 mg, 2.32 mmol). The mixture was stirred at 50° C. for 5 hours before being allowed to cool and concentrated in vacua. The crude material was purified by preparative HPLC (column: Gemini 150*25 5u; mobile phase: [water (0.04% ammonia)-acetonitrile]; 1-30%, 10 minutes) to give the pure title compound (103 mg, 54%) as a white solid.

(126) .sup.1H NMR (DMSO): δ 8.37 (d, 1H), 7.99 (d, 1H), 7.78 (br s, 1H), 7.19 (br s, 2H), 3.41 (q, 2H), 2.42 (t, 2H) and 2.17 (s, 6H).

(127) LCMS: m/z 246 (M+H)+(ES+); 513 (M*2+Na)+(ES+).

Intermediate P8: 5-(Dimethylamino)pyrazine-2-sulfonamide

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

(128) ##STR00166##

(129) To a mixture of 2,5-dichloropyrazine (2 g, 13.42 mmol) and phenylmethanethiol (1.63 g, 13.12 mmol, 1.54 mL) in N,N-dimethylformamide (20 mL) was added potassium carbonate (3.71 g, 26.85 mmol) in one portion at 20° C. The mixture was stirred at 20° C. for 2 hours and then diluted with water (80 mL) and extracted into ethyl acetate (30 mL×3). The organic layers were combined, washed with water (40 mL) and brine (40 mL), dried (anhydrous sodium sulfate), filtered and concentrated in vacuo to afford a crude product. This was purified by column chromatography (petroleum ether) to give the title compound (2.9 g, 12.25 mmol, 91% yield) as a yellow oil.

(130) .sup.1H NMR (CDCl.sub.3): δ 8.45-8.40 (m, 1H), 8.23 (d, 1H), 7.43-7.38 (m, 2H), 7.36-7.29 (m, 3H) and 4.42 (s, 2H).

Step B: 5-Chloropyrazine-2-sulfonamide

(131) ##STR00167##

(132) Chlorine gas was bubbled into the solution of 2-(benzylthio)-5-chloropyrazine (800 mg, 3.38 mmol) in carbon tetrachloride (20 mL) and water (5 mL) at 0° C. for 30 minutes and the resulting mixture was stirred at 20° C. for 1 hour. The phases were separated and into the organic phase was bubbled ammonia gas at 0° C. for 30 minutes. The mixture was stirred at 20° C. for another 1 hour and the mixture was concentrated in vacua and then purified by column chromatography (petroleum ether:ethyl acetate=3:1-2:1) to give the pure product (300 mg, 47% yield) as a white solid.

(133) .sup.1H NMR (DMSO): δ 9.01 (d, 1H), 8.97 (d, 1H) and 7.89 (s, 2H).

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

(134) ##STR00168##

(135) To a solution of 5-chloropyrazine-2-sulfonamide (200 mg, 1.03 mmol) in tetrahydrofuran (5 mL) was added N,N-dimethylamine (2 M, 1.03 mL). The mixture was stirred at 20° C. for 0.5 hours and then concentrated in vacua to afford a crude product. This was purified by preparative TLC (petroleum ether:ethyl acetate=0-100%) to give the title compound (16 mg, yield: 8%) as a white solid.

(136) .sup.1H NMR (DMSO): δ 8.45 (d, 1H), 8.18 (d, 1H), 7.26 (s, 2H) and 3.16 (s, 6H).

(137) LCMS: m/z 225 (M+Na)+(ES+); 427 (M*2+Na)+(ES+).

Intermediate P9: 6-(Dimethylamino)pyrazine-2-sulfonamide

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

(138) ##STR00169##

(139) To a solution of phenylmethanethiol (3.8 g, 30.4 mmol) and 2,6-dichloropyrazine (50.0 g, 33.5 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (4.2 g, 30.4 mmol). The reaction was stirred at 20° C. for 15 hours and the resulting mixture was diluted with water (200 mL) and then extracted into ethyl acetate (200 mL×3). The combined organic layers were washed with brine (100 mL×2), dried (anhydrous sodium sulfate), filtered and concentrated in vacua to afford the title compound (6.8 g, 94% yield) as a yellow oil. The crude product was used in next step without further purification.

(140) LCMS: m/z 237 (M+H).sup.+(ES.sup.+).

Step B: 6-Chloropyrazine-2-sulfonyl chloride

(141) ##STR00170##

(142) Chlorine gas was bubbled into a solution of 2-(benzylthio)-6-chloropyrazine (0.5 g, 2.11 mmol) in carbon tetrachloride (20 mL) and water (5 mL) at 0° C. for 30 minutes. The resulting mixture was concentrated in vacua and the residue was taken up into dichloromethane (30 mL) and washed with brine (10 mL×3). The organic layer was dried (anhydrous sodium sulfate), filtered and concentrated in vacuo to afford the title compound (0.3 g, 1.41 mmol, 67% yield) as yellow oil. The crude product was used in next step without further purification.

Step C: 6-Chloropyrazine-2-sulfonamide

(143) ##STR00171##

(144) Ammonia gas was bubbled into a solution of 6-chloropyrazine-2-sulfonyl chloride (0.3 g, 1.41 mmol) in tetrahydrofuran (20 mL) at 0° C. for 20 minutes and then the mixture was stirred at 0-20° C. for 2 hours. The reaction was then concentrated in vacua and the residue was diluted with ethyl acetate (30 mL), washed with brine (10 mL×2), dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 1:1) to give the title compound (0.26 g, 95% yield) as a yellow solid.

(145) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.09 (d, 2H) and 7.94 (s, 2H).

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

(146) ##STR00172##

(147) To a solution of 6-chloropyrazine-2-sulfonamide (170 mg, 0.88 mmol) in acetonitrile (2 mL) was added N-methylmethanamine (47.5 mg, 1.1 mmol). The resulting mixture was stirred at 20° C. for 2 hours and then concentrated in vacua. The residue was purified by preparative TLC (silica gel, petroleum ether:ethyl acetate=1:8) to afford the title compound (110 mg, 59% yield) as white solid.

(148) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.34 (s, 1H), 8.16, (s, 1H), 7.46 (s, 2H) and 3.14 (s, 6H).

(149) LCMS: m/z 203 (M+H).sup.+(ES.sup.+).

Intermediate P10: 6-Morpholinopyrazine-2-sulfonamide

(150) ##STR00173##

(151) To a solution of 6-chloropyrazine-2-sulfonamide (0.25 g, 1.29 mmol) in acetonitrile (5 mL) was added morpholine (225 mg, 2.58 mmol, 227 μL) under an atmosphere of dry nitrogen. The reaction was stirred at 40° C. for 6 hours and then poured into ice water (10 mL) causing a white solid to precipitate. After stirring for 0.5 hours the mixture was filtrated and the residue was washed with petroleum ether, followed by methyl tert-butyl methylether. The residual solid was dried in vacuo to afford the title compound (0.12 g, 38%) as light yellow solid.

(152) .sup.1H NMR (DMSO-d.sub.6) δ 8.51 (s, 1H), 8.23 (s, 1H), 7.48 (s, 2H), 3.72 (t, 4H) and 3.65 (t,H).

(153) LCMS: m/z 245.0 (M+H).sup.+(ES.sup.+).

Intermediate P11: 6-(Dimethylamino)pyrazine-2-sulfonamide

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

(154) ##STR00174##

(155) A solution of 2,6-dichloropyrazine (5 g, 33.56 mmol, 1.1 eq) and sodium phenylmethanethiolate (4.46 g, 3.51 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 (3×50 mL) and brine (3×50 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.

(156) .sup.1H NMR (CDCl.sub.3): δ 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).

(157) LCMS: m/z 237.0 (M+H).sup.+(ES.sup.+).

Step B: 6-Chloropyrazine-2-sulfonyl chloride

(158) ##STR00175##

(159) 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 to 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

(160) ##STR00176##

(161) A solution of 6-chloropyrazine-2-sulfonyl chloride (1.8 g, crude) in THF (so mL) was bubbled with NH.sub.3 at 0° C. for to minutes. The reaction mixture was filtered and the filtrate was concentrated in vacua. 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.

(162) .sup.1H NMR (DMSO-d.sub.6): δ 9.09 (d, 2H) and 7.96 (s, 2H).

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

(163) ##STR00177##

(164) 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 vacuo. 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.

(165) .sup.1H NMR (CD.sub.3OD): δ 8.26 (s, 1H), 8.22 (s, 1H) and 3.22 (s, 6H).

(166) LCMS: m/z 203.1 (M+H).sup.+(ES.sup.+).

Intermediate P12: 5-(Dimethylamino)pyrazine-2-sulfonamide

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

(167) ##STR00178##

(168) 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 (2×100 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.

(169) .sup.1H NMR (CDCl.sub.3): δ 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

(170) ##STR00179##

(171) 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

(172) ##STR00180##

(173) 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 vacua.

(174) The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 3:1 to 1:1) to give the title compound (1.6 g, 44%) as a yellow oil.

(175) .sup.1H NMR (CDCl.sub.3): δ 8.98 (dd, 1H) and 7.88 (s, 1H).

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

(176) ##STR00181##

(177) 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.

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

Intermediate P13: 3-(Difluoromethyl)pyrazine-2-sulfonamide

Step A: 3-Chloropyrazine-2-carbaldehyde

(179) ##STR00182##

(180) 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 (3×300 mL). The combined organic layers were washed with brine, 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 5:1) to give the title compound (2.4 g, 19%) as a yellow oil.

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

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

(182) ##STR00183##

(183) To a solution of 3-chloropyrazine-2-carbaldehyde (1.2 g, 8.42 mmol, 1 eq) in DCM (50 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 (3×80 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.

(184) .sup.1H NMR (CDCl.sub.3): δ 8.54 (d, 1H), 8.47 (d, 1H) and 6.85 (t, 1H).

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

(185) ##STR00184##

(186) 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 (2×50 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.

(187) .sup.1H NMR (CDCl.sub.3): δ 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

(188) ##STR00185##

(189) 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

(190) ##STR00186##

(191) 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 vacua. The residue was treated with water (50 mL) and the mixture was washed with EtOAc (3×80 mL). The aqueous layer was concentrated in vacuo. 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.

(192) .sup.1H NMR (DMSO-d.sub.6): δ 9.08 (d, 1H), 9.02 (s, 1H), 8.10 (br s, 2H) and 7.52 (t, 1H).

(193) LCMS: m/z 210.1 (M+H).sup.+(ES.sup.+).

Intermediate P14: 4,6-Dimethylpyrimidine-2-sulfonamide

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

(194) ##STR00187##

(195) 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.

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

(197) LCMS: m/z 279.1 (M+H).sup.+(ES.sup.+).

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

(198) ##STR00188##

(199) 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 (2×40 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

(200) ##STR00189##

(201) 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 vacuo. 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.

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

(203) LCMS: m/z 188.1 (M+H).sup.+(ES.sup.+).

Intermediate P15: 5-(Dimethylamino)pyridazine-3-sulfonamide

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

(204) ##STR00190##

(205) 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 vacuo. 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.

(206) .sup.1H NMR (CDCl.sub.3): δ 8.63 (d, 1H), 6.53 (d, 1H) and 3.09 (s, 6H).

(207) LCMS: m/z 158.1 (M+H).sup.+(ES.sup.+).

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

(208) ##STR00191##

(209) 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 (3×200 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, 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.

(210) .sup.1H NMR (CDCl.sub.3): δ 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

(211) ##STR00192##

(212) 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 (2×50 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

(213) ##STR00193##

(214) 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.

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

(216) LCMS: m/z 203.1 (M+H).sup.+(ES.sup.+).

Intermediate P16: 4-(Dimethylamino)-6-methylpyrimidine-2-sulfonamide

Step A: 2-(Benzylthio)-N,N,6-trimethylpyrimidin-4-amine

(217) ##STR00194##

(218) To a solution of 2-chloro-N,N,6-trimethylpyrimidin-4-amine (250 mg, 1.46 mmol) in dioxane (12 mL) was added diisopropylethylamine (383 mg, 2.90 mmol) and Xantphos (90 mg, 0.16 mmol). The solution was purged with N.sub.2 for 10 minutes. Then Pd(dba).sub.3 (70 mg, 0.08 mol) was added, followed by benzylmercaptane (300 mg, 2.65 mmol). The mixture was refluxed under nitrogen for 30 hours. The solvents were evaporated and the residue was purified over silica using dichloromethane/methanol/ammonia as the eluent to afford the title compound (300 mg, 77%) as an oil, still containing 30% starting material.

(219) .sup.1H NMR (CDCl.sub.3): δ7.4 (m, 2H), 7.25 (m, 3H), 5.97 (s, 1H), 4.39 (s, 2H), 3.07 (s, 6H), 2.3 (s, 3H).

Step B: 4-(Dimethylamino)-6-methylpyrimidine-2-sulfonamide

(220) ##STR00195##

(221) 2-(Benzylthio)-N,N6-trimethylpyrimidin-4-amine (200 mg, 0.77 mmol) was dissolved in dichloromethane (10 ml) and 1 N HCl (5 mL) was added. The mixture was cooled to −10° C. Then sodium hypochlorite (1.6 mL, 2.54 mmol) was added dropwise over 15 minutes, during which the temperature was allowed to reach 0° C. The mixture was poured into ammonia in methanol (50 mL, 7N). After 1 hour stirring at room temperature, the solvents were evaporated. The residue was triturated in THF (15 mL) containing Et.sub.3N (1 mL). The mixture was filtered and the solvents were evaporated. The residue was purified over silica using dichloromethane/methanol/ammonia as the eluent to afford the title compound as an oil (20 mg, 17%).

(222) .sup.1H NMR (CD.sub.3OD): δ 6.43 (s, 1H), 3.3 (s, 6H), 2.5 (s, 3H).

Intermediate P17: 2-Isopropylpyridine-4-sulfonamide

Step A: 2-Chloropyridine-4-sulfonyl chloride

(223) ##STR00196##

(224) 2-Chloropyridin-4-amine (1.29 g, 10.0 mmol) was added portionwise to a mixture of TFA (10 mL) and conc. HCl (5 mL) at 0° C. The resultant solution was treated with a solution of sodium nitrite (2.07 g, 29.1 mmol) in water (7.5 mL) and stirred at 0° C. for 1 hour. The reaction mixture was filtered into a pre-cooled (0° C.) flask and then added via cannula to a suspension of CuCl (0.1 g, 1.0 mmol) and CuCl.sub.2 (0.67 g, 4.83 mmol) in acetic acid containing dissolved SO.sub.2 (60 mL) (prepared by bubbling SO.sub.2 through acetic acid for 45 minutes at room temperature). The reaction mixture was stirred at 0° C. for 1 hour, diluted with DCM (50 mL) and the organic layer was washed with ice-water (2×50 mL), sat aq NaHCO.sub.3 (2×50 mL), brine (50 mL), dried (MgSO.sub.4) and concentrated in vacua to afford the title compound as a pale yellow oil. The crude was used in the next step without further purification.

(225) .sup.1H NMR (Chloroform-d) δ 8.77 (d, J=5.2 Hz, 1H), 7.91 (d, J=1.1 Hz, 1H), 7.81 (dd, J=5.2, 1.7 Hz, 1H).

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

(226) ##STR00197##

(227) A solution of bis(4-methoxybenzyl)amine (1.788 g, 6.95 mmol) and Et.sub.3N (1.15 mL, 8.25 mmol) in DCM (50 mL) at 0° C. was treated dropwise with a solution of 2-chloropyridine-4-sulfonyl chloride (1.46 g, 4.13 mmol) in DCM (6 mL). The resultant solution was stirred at 0° C. for 1 hour. Sat aq NH.sub.4Cl (50 mL) was added and the organic layer was collected. The aqueous was extracted with DCM (50 mL) and the combined organic extracts were washed with sat aq NH.sub.4Cl (2×50 mL), dried (MgSO.sub.4) and concentrated in vacua. The residue was triturated with TBME (1×30 mL) and the resultant solid was filtered, rinsing with TBME, and dried in vacuo to afford the title compound (1.04 g, 24% over 2 steps) as a tan solid.

(228) .sup.1H NMR (Chloroform-d) δ 8.52-8.48 (m, 1H), 7.48-7.44 (m, 2H), 7.07-7.02 (m, 4H), 6.84-6.77 (m, 4H), 4.31 (s, 4H), 3.80 (s, 6H).

Step C: 2-Isopropyl-N,N-bis(4-methoxybenzyl)pyridine-4-sulfonamide

(229) ##STR00198##

(230) A suspension of 2-chloro-N,N-bis(4-methoxybenzyl)pyridine-4-sulfonamide (0.30 g, 0.69 mmol) and Ni(dppp)C12 (96 mg, 0.177 mmol) in dry THF (7 mL) was stirred for 10 minutes and then treated dropwise with .sup.iPrMgCl (2 M in THF, 0.7 mL, 1.40 mmol). The resultant suspension was stirred at room temperature for 16 hours. HCl (1 M, 5 mL) and EtOAc (20 mL) were added and the organic layer was collected. The aqueous was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g column, 0-2.5% MeOH/DCM) to afford the title compound (0.268 g, 83%) as a yellow solid.

(231) .sup.1H NMR (Chloroform-d) δ 8.71-8.67 (m, 1H), 7.45-7.41 (m, 2H), 7.03-6.96 (m, 4H), 6.80-6.75 (m, 4H), 4.29 (s, 4H), 3.78 (s, 6H), 3.10 (sept, J=6.9 Hz, 1H), 1.30 (d, J=6.9 Hz, 6H).

(232) LCMS; m/z 441.0 (M+H).sup.+(ES.sup.+).

Step D: 2-Isopropylpyridine-4-sulfonamide

(233) ##STR00199##

(234) 2-Isopropyl-N,N-bis(4-methoxybenzyl)pyridine-4-sulfonamide (260 mg, 0.555 mmol) was treated with TFA (3 mL, 38.9 mmol) and the resultant yellow solution was stirred at room temperature for 6.sub.3 hours. TFA (3 mL, 38.9 mmol) was added and stirred for 5 hours. The reaction was concentrated in vacua and azeotroped with DCM (3×5 mL). The crude product was purified by chromatography on silica gel (4 g column, 0-10% MeOH/DCM) to afford the title compound (100 mg, 86%) as a sticky pale pink solid.

(235) .sup.1H NMR (DMSO-d.sub.6) δ 8.74 (d, J=5.1 Hz, 1H), 7.65 (m, 3H), 7.60-7.56 (m, .sup.1H), 3.14 (sept, J=6.8 Hz, 1H), 1.26 (d, J=6.9 Hz, 6H).

(236) LCMS; m/z 201.1 (M+H).sup.+(ES.sup.+); 199.1 (M−H).sup.−(ES.sup.−).

SYNTHESIS OF EXAMPLES

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

(237) ##STR00200##

(238) To a cooled (0° C.) solution of pyrazine-2-sulfonamide (55 mg, 0.35 mmol) in tetrahydrofuran (2 mL) was added potassium tert-butoxide (43 mg, 0.38 mmol). The ice bath was removed and the reaction mixture was stirred whilst being allowed to warm to room temperature over 40 minutes. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1; 76 mg, 0.38 mmol) in THF (1 mL) was added followed by further THF (2 mL; to aid stirring) and the mixture was stirred overnight at room temperature. The resulting formed precipitate was collected by filtration and washed with THF (1 mL). The material was triturated with ethyl acetate (2 mL) for 1 hour, filtered and dried in vacuo to afford the title compound (84 mg; 67%) as a white solid.

(239) .sup.1H NMR (DMSO-d.sub.6) δ 8.96 (d, 1H), 8.59 (m, 2H), 7.52 (s, 1H), 6.73 (s, 1H), 2.7 (t, 4H), 2.58 (t, 4H) and 1.85 (m, 4H).

(240) LCMS: m/z 359 (M+H).sup.+(ES.sup.+); 357 (M−H).sup.−(ES.sup.−).

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

(241) ##STR00201##

(242) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and pyridazine-3-sulfonamide except that the final reaction mixture was concentrated in vacua, water (2 mL) and TBME (2 mL) were added and the resulting suspension was filtered, but no solid was isolated. Therefore, the layers were separated and the product containing aqueous fraction was washed with TBME (2 mL) and ethyl acetate (2 mL) and subsequently submitted for purification by reversed phase column chromatography to afford the title compound (2.sub.7%) as a white solid.

(243) .sup.1H NMR (DMSO-d.sub.6) δ 9.16 (m, 1H), 7.99 (d, 1H), 7.71 (m, 1H), 7.53 (s, 1H), 6.73 (s, 1H), 2.7 (t, 4H), 2.58 (t, 4H) and 1.85 (m, 4H).

(244) LCMS: m/z 359 (M+H).sup.+(ES.sup.+); 357 (M−H).sup.−(ES.sup.−).

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

(245) ##STR00202##

(246) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and pyrimidine-2-sulfonamide. The resulting mixture was concentrated in vacuo and submitted for purification by reversed phase column chromatography to afford the title compound (21% yield) as a white solid.

(247) .sup.1H NMR (DMSO-d.sub.6) δ 8.8 (d, 2H), 7.54 (s, 1H), 7.48 (t, 1H), 6.73 (s, 1H), 2.7 (t, 4H), 2.58 (t, 4H) and 1.85 (m, 4H).

(248) LCMS: m/z 359 (M+H).sup.+(ES.sup.+); 357 (M−H).sup.−(ES.sup.−).

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

(249) ##STR00203##

(250) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 6-methylpyridazine-3-sulfonamide except that sodium tert-butoxide was used as the base. The final mixture was concentrated in vacua and submitted for purification by reversed phase column chromatography to afford the title compound (7% yield) as a white solid.

(251) .sup.1H NMR (CD.sub.3OD) δ 8.14 (d, 1H), 7.7 (d, 1H), 6.83 (s, 1H), 2.79 (t, J=7.4 Hz, 4H), 2.72 (s, 3H), 2.68 (t, 4H) and 1.97 (m, 4H).

(252) LCMS: m/z 373 (M+H).sup.+(ES.sup.+).

Example 5: N-((2,6-Diisopropylphenyl)carbamoyl)-6-methylpyridazine-3-sulfonamide, Potassium Salt

(253) ##STR00204##

(254) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 2-isocyanato-1,3-diisopropylbenzene (intermediate A2) and 6-methylpyridazine-3-sulfonamide. The mixture was concentrated in vacua and submitted for purification by reversed phase column chromatography which afforded the title compound (6.sub.9% yield) as a white solid.

(255) .sup.1H NMR (CD.sub.3OD) δ 8.17 (d, 1H), 7.68 (d, 1H), 7.02-7.17 (m, 3H), 3.08 (m, 2H), 2.71 (s, 3H) and 1.05 (d, 12H).

(256) LCMS: m/z 377 (M+H).sup.+(ES.sup.+); 375 (M−H).sup.−(ES.sup.−).

Example 6: N-((2,6-Diisopropylphenyl)carbamoyl)pyrazine-2-sulfonamide, Sodium Salt

(257) ##STR00205##

(258) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 2-isocyanato-1,3-diisopropylbenzene (intermediate A2) and pyrazine-2-sulfonamide except that sodium tert-butoxide was used as the base. The residue was purified by means of reversed phase chromatography and the product containing fractions were lyophilized to afford the title compound (44% yield) as a white solid.

(259) .sup.1H NMR (D.sub.2O): δ 9.0 (s, 1H), 8.7 (m, 2H), 7.3 (br s, 1H), 7.2 (m, 1H), 7.1 (d, 2H), 2.9 (m, 2H), 1.0 (d, 6H) and 0.9 (d, 6H).

(260) LCMS: m/z 363 (M+H).sup.+(ES.sup.+); 361 (M−H).sup.−(ES.sup.−).

Example 7: N-((2,6-Diisopropylphenyl)carbamoyl)pyridazine-3-sulfonamide, Sodium Salt

(261) ##STR00206##

(262) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 2-isocyanato-1,3-diisopropylbenzene (intermediate A2) and pyridazine-3-sulfonamide except that NaOtBu was used as the base. The residue was purified by means of reversed phase chromatography and the product containing fractions were lyophilized to afford the title compound (50% yield) as a white solid.

(263) .sup.1H NMR (D.sub.2O): δ 9.2 (d, J=4.7 Hz, 1H), 8.0 (d, J=7.6 Hz, 1H), 7.7 (m, J=5.3 Hz, and 70.6 Hz, 1H), 7.3 (br s, 1H), 7.1 (m, J=7.0 Hz, 1H), 7.0 (d, J=7.6 Hz, 2H), 3.1 (m, 2H) and 1.0 (m, 12H).

(264) LCMS: m/z 363 (M+H).sup.+(ES.sup.+); 361 (M−H).sup.−(ES.sup.−).

Example 8: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-methoxypyrazine-2-sulfonamide, Potassium Salt

(265) ##STR00207##

(266) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 3-methoxypyrazine-2-sulfonamide, except that the reaction mixture was concentrated in vacua and water (2 mL) was added. The suspension was filtered over cotton wool and subsequently submitted for purification by reversed phase column chromatography to afford the title compound (27%) as a white solid.

(267) .sup.1H NMR (D.sub.2O) δ 8.22 (d, 1H), 8.07 (d, 1H), 6.92 (s, 1H), 3.97 (s, 3H), 2.7 (t, 4H), 2.55 (t, 4H) and 1.87 (m, 4H).

(268) LCMS: m/z 389 (M+H).sup.+(ES.sup.+); 387 (M−H).sup.−(ES.sup.−).

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

(269) ##STR00208##

(270) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1; 1.5 equiv. compared to sulfonamide), 2-aminopyrimidine-5-sulfonamide and potassium tert-butoxide (2 mole equiv.) to afford the title compound (4%) as a white solid.

(271) .sup.1H NMR (CD.sub.3OD) δ 8.68 (s, 2H), 6.83 (s, 1H), 2.8 (t, 4H), 2.7 (t, 4H) and 1.97 (m, 4H).

(272) LCMS: m/z 374 (M+H).sup.+(ES.sup.+); 372 (M−H).sup.−(ES.sup.−).

Example 10: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) pyrimidine-5-sulfonamide, Potassium Salt

(273) ##STR00209##

(274) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methoxypyrazine-2-sulfonamide (example 8) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and pyrimidine-5-sulfonamide to afford the title compound (8%) as a white solid.

(275) .sup.1H NMR (CD.sub.3OD) δ 9.19 (s, 1H), 9.18 (d, 2H), 6.83 (s, 1H), 2.8 (t, 4H), 2.7 (t, 4H) and 1.97 (m, 4H).

(276) LCMS: m/z 359 (M+H).sup.+(ES.sup.+); 357 (M−H).sup.−(ES.sup.−).

Example 11: 6-Chloro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) pyridazine-3-sulfonamide, Potassium Salt

(277) ##STR00210##

(278) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 8) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 6-chloropyridazine-3-sulfonamide (intermediate P3) to afford the title compound (48%) as a white solid.

(279) .sup.1H NMR (D.sub.2O): δ 8.15 (d, J=8.8 Hz, 1H), 7.94 (d, 1H), 6.98 (s, 1H), 2.75 (t, 4H), 2.57 (t, 4H), 1.91 (m, 4H).

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

Example 12: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3,6-di methoxypyridazine-4-sulfonamide, potassium salt

(281) ##STR00211##

(282) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 8) from (intermediate A1) and 3,6-dimethoxypyridazine-4-sulfonamide (intermediate P4) to afford the title compound (94%) as a white solid.

(283) .sup.1H NMR (D.sub.2O): δ 7.47 (s, 1H), 6.98 (s, 1H), 4.02 (S, 3H), 3.95 (s, 3H), 2.75 (t, 4H), 2.59 (t, 4H) and 1.92 (m, 4H).

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

Example 13: 6-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridazine-3-sulfonamide, potassium salt

(285) ##STR00212##

(286) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 6-(dimethylamino)pyridazine-3-sulfonamide (intermediate P5) to afford the title compound (48%) as a white solid.

(287) .sup.1H NMR (D.sub.2O): δ 7.73 (d, 1H), 7.10 (d, 1H), 6.97 (s, 1H), 3.05 (s, 6H), 2.75 (t, 4H), 2.57 (t, 4H) and 1.91 (m, 4H).

(288) LCMS: m/z 402 (M+H).sup.+(ES.sup.+).

Example 14: 3-(Difluoromethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyrazine-2-sulfonamide, potassium salt

(289) ##STR00213##

(290) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 3-(difluoromethyl)-2-pyrazinesulfonamide to afford the title compound (34%) as a white solid.

(291) .sup.1H NMR (CD.sub.3OD) δ 8.82 (d, 1H), 8.77 (d, 1H), 7.84 (t, 1H), 6.83 (s, 1H), 2.8 (t, 4H), 2.7 (t, 4H) and 1.97 (m, 4H).

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

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

(293) ##STR00214##

(294) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 2-methoxypyridine-3-sulfonamide to afford the title compound (24%) as a white solid.

(295) .sup.1H NMR (CD.sub.3OD) δ 8.22 (d, 2H), 7.01 (m, 1H), 6.83 (s, 1H), 4.03 (s, 3H), 2.8 (t, 4H), 2.7 (t, 4H) and 1.97 (m, 4H).

(296) LCMS: m/z 388 (M+H).sup.+(ES.sup.+); 386 (M−H).sup.−(ES.sup.−).

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

(297) ##STR00215##

(298) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-pyrazine-2-sulfonamide (example 1) from 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 5-(trifluoromethyl) pyridazine-3-sulfonamide to afford the title compound (54%) as a white solid.

(299) .sup.1H NMR (CD.sub.3OD) δ 9.59 (s, 1H), 8.53 (s, 1H), 6.83 (s, 1H), 2.8 (t, 4H), 2.7 (t, 4H) and 1.97 (m, 4H).

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

Example 17: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, Potassium Salt

(301) ##STR00216##

(302) To a cooled (0° C.) solution of 4-methylpyrimidine-2-sulfonamide (68 mg, 0.39 mmol) in THF (2.5 mL) was added potassium tert-butoxide (44 mg, 0.39 mmol). The ice bath was removed and the reaction mixture was stirred whilst being allowed to warm to room temperature over 40 minutes. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1; 78 mg, 0.39 mmol) in THF (1 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacua and DMSO (1 mL) was added. The suspension was filtered over cotton wool and subsequently purified by reversed phase column chromatography (see General Methods, “Purification Method 1” above) to afford the title compound (39 mg; 27%) as a white solid.

(303) .sup.1H NMR (CD.sub.3OD) δ 8.67 (d, 1H), 7.4 (d, 1H), 6.84 (s, 1H), 2.78 (m, 8H), 2.59 (s, 3H) and 1.98 (m, 4H).

(304) LCMS: m/z 373 (M+H).sup.+(ES.sup.+).

Example 18: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-4,6-dimethyl pyrimidine-2-sulfonamide, Potassium Salt

(305) ##STR00217##

(306) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 4,6-dimethylpyrimidine-2-sulfonamide to afford the title compound (38%) as a white solid.

(307) .sup.1H NMR (CD.sub.3OD) δ 7.28 (s, 1H), 6.84 (s, 1H), 2.78 (m, 8H), 2.53 (s, 6H) and 1.98 (m, 4H).

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

Example 19: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxypyrimidine-4-sulfonamide, Potassium Salt

(309) ##STR00218##

(310) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 6-methoxypyrimidine-4-sulfonamide to afford the title compound (12%) as a white solid.

(311) .sup.1H NMR (CD.sub.3OD) δ 8.76 (s, 1H), 7.36 (s, 1H), 6.85 (s, 1H), 4.03 (s, 3H), 2.76 (m, 8H), and 1.98 (m, 4H).

(312) LCMS: m/z 389 (M+H).sup.+(ES.sup.+); 387 (M−H).sup.−(ES.sup.−).

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

(313) ##STR00219##

(314) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17), except that 2 eq of KO.sup.tBu were used, furthermore using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 6-sulfamoylpyridazine-3-carboxamide to afford the title compound (11%) as a white solid.

(315) .sup.1H NMR (CD.sub.3OD) δ 8.38 (d, 2H), 6.83 (s, 1H), 2.82 (t, 4H), 2.72 (t, 4H) and 1.98 (m, 4H).

(316) LCMS: m/z 402 (M+H).sup.+(ES.sup.+).

Example 21: 5-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridazine-3-sulfonamide, Potassium Salt

(317) ##STR00220##

(318) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 5-(dimethylamino)-pyridazine-3-sulfonamide (intermediate P6) to afford the title compound (31%) as a white solid.

(319) .sup.1H NMR (CD.sub.3OD) δ 8.7 (s, 1H), 7.34 (s, 1H), 6.84 (s, 1H), 3.13 (s, 6H), 2.82 (t, 4H), 2.72 (t, 4H) and 1.98 (m, 4H).

(320) LCMS: m/z 402 (M+H).sup.+(ES.sup.+); 400 (M−H).sup.−(ES.sup.−).

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

(321) ##STR00221##

(322) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 6-methoxypyridazine-3-sulfonamide to afford the title compound (56%) as a white solid.

(323) .sup.1H NMR (CD.sub.3OD) δ 8.11 (d, 1H), 7.22 (d, 1H), 6.84 (s, 1H), 4.17 (s, 3H), 2.82 (t, 4H), 2.72 (t, 4H) and 1.98 (m, 4H).

(324) LCMS: m/z 389 (M+H).sup.+(ES.sup.+); 387 (M−H).sup.−(ES.sup.−).

Example 23: N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide, Potassium Salt

(325) ##STR00222##

(326) Diphenylcarbonate (107 mg, 0.5 mmol) was dissolved in acetonitrile (5 mL) and to this was added 4-dimethylaminopyridine (123 mg, 1 mmol) and 6-oxo-1,6-dihydropyridine-3-sulfonamide (90 mg, 0.5 mmol). The resultant mixture was heated to reflux for 4 hours and then 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (85 mg, 0.5 mmol) was added and the mixture refluxed overnight. The mixture was cooled to room temperature and potassium tert-butoxide (56 mg, 0.5 mmol) and water (1 mL) were added, the mixture was filtered and the residue was purified by means of reversed phase chromatography and the product containing fractions were lyophilized to afford the title compound (28%) as a white solid.

(327) .sup.1H NMR (D.sub.2O) δ 7.99 (s, 1H), 7.82 (d, 1H), 6.94 (s, 1H), 6.53 (d, 1H), 2.72 (m, 4H), 2.55 (m, 4H) and 1.87 (m, 4H).

(328) LCMS: m/z 374 (M+H).sup.+(ES.sup.+); 372 (M−H).sup.−(ES.sup.−).

Example 24: 3-Cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyrazine-2-sulfonamide, Potassium Salt

(329) ##STR00223##

(330) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 3-cyanopyrazine-2-sulfonamide to afford the title compound (2%) as a white solid.

(331) LCMS: m/z 384 (M+H).sup.+(ES.sup.+).

Example 25: 5-((2-(Dimethylamino)ethyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyrazine-2-sulfonamide, potassium Salt

(332) ##STR00224##

(333) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) except that 2 eq of KO.sup.tBu were used, furthermore using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 5-((2-(dimethylamino)ethyl)amino)pyrazine-2-sulfonamide (intermediate P7) to afford the title compound (24%) as a white solid.

(334) .sup.1H NMR (CD.sub.3OD) δ 8.46 (s, 1H), 7.89 (s, 1H), 6.84 (s, 1H), 3.55 (m, 2H), 2.82 (t, 4H), 2.72 (t, 4H), 2.57 (m, 2H), 2.29 (s, 6H) and 1.98 (m, 4H).

(335) LCMS: m/z 445 (M+H).sup.+(ES.sup.+); 443 (M−H).sup.−(ES.sup.−).

Example 26: 5-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyrazine-2-sulfonamide, Potassium Salt

(336) ##STR00225##

(337) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 5-(dimethylamino)-pyrazine-2-sulfonamide (intermediate P8) to afford the title compound (34%) as a white solid.

(338) .sup.1H NMR (CD.sub.3OD) δ 8.61 (s, 1H), 8.0 (s, 1H), 6.84 (s, 1H), 3.17 (s, 6H), 2.82 (t, 4H), 2.72 (t, 4H) and 1.98 (m, 4H).

(339) LCMS: m/z 402 (M+H).sup.+(ES.sup.+); 400 (M−H).sup.−(ES.sup.−).

Example 27: 6-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyrazine-2-sulfonamide, Potassium Salt

(340) ##STR00226##

(341) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 6-(dimethylamino)-pyrazine-2-sulfonamide (intermediate P9) to afford the title compound (53%) as a white solid.

(342) .sup.1H NMR (CD.sub.3OD) δ 8.28 (s, 1H), 8.08 (s, 1H), 6.84 (s, 1H), 3.15 (s, 6H), 2.82 (t, 4H), 2.72 (t, 4H) and 1.98 (m, 4H).

(343) LCMS: m/z 402 (M+H).sup.+(ES.sup.+); 400 (M−H).sup.−(ES.sup.−).

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

(344) ##STR00227##

(345) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 6-morpholinopyrazine-2-sulfonamide (intermediate P10) to afford the title compound (52%) as a white solid.

(346) .sup.1H NMR (CD.sub.3OD) δ 8.36 (s, 1H), 8.23 (s, 1H), 6.84 (s, 1H), 3.74 (m, 4H), 3.63 (m, 4H), 2.82 (t, 4H), 2.72 (t, 4H) and 1.98 (m, 4H).

(347) LCMS: m/z 444 (M+H).sup.+(ES.sup.+); 442 (M−H).sup.−(ES.sup.−).

Example 29: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-methylpyrazine-2-sulfonamide, Potassium Salt

(348) ##STR00228##

(349) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 3-methylpyrazine-2-sulfonamide to afford the title compound (49%) as a white solid.

(350) .sup.1H NMR (CD.sub.3OD) δ 8.53 (d, 1H), 8.42 (d, 1H), 6.84 (s, 1H), 2.95 (s, 3H), 2.76 (t, 4H), 2.68 (t, 4H) and 1.98 (m, 4H).

(351) LCMS: m/z 373 (M+H).sup.+(ES.sup.+); 371 (M−H).sup.−(ES.sup.−).

Example 30: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)quinoxaline-2-sulfonamide, Potassium Salt

(352) ##STR00229##

(353) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and quinoxaline-2-sulfonamide to afford the title compound (28%) as a white solid.

(354) .sup.1H NMR (CD.sub.3OD) δ 9.42 (s, 1H), 8.16 (m, 2H), 7.92 (m, 2H), 6.84 (s, 1H), 2.76 (t, 4H), 2.68 (t, 4H) and 1.9 (m, 4H).

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

Example 31: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-sulfonamide, Potassium Salt

(356) ##STR00230##

(357) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-sulfonamide to afford the title compound (9%) as a white solid.

(358) .sup.1H NMR (CD.sub.3OD) δ 9.03 (s, 1H), 8.68 (d, 1H), 6.82 (s, 1H), 4.04 (s, 3H), 2.78 (m, 8H), 2.57 (s, 3H) and 1.98 (m, 4H).

(359) LCMS: m/z 426 (M+H).sup.+(ES.sup.+); 424 (M−H).sup.−(ES.sup.−).

Example 32: 4-Ethoxy-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-3-sulfonamide, Potassium Salt

(360) ##STR00231##

(361) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 4-ethoxypyridine-3-sulfonamide to afford the title compound (26%) as a white solid.

(362) .sup.1H NMR (CD.sub.3OD) δ 8.87 (s, 1H), 8.41 (d, 1H), 7.12 (d, 1H), 6.84 (s, 1H), 4.26 (q, 2H), 2.78 (m, 8H), 1.98 (m, 4H) and 1.48 (t, 3H).

(363) LCMS: m/z 402 (M+H).sup.+(ES.sup.+); 400 (M−H).sup.−(ES.sup.−).

Example 33: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) pyridine-4-sulfonamide, potassium salt

(364) ##STR00232##

(365) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and pyridine-4-sulfonamide to afford the title compound (50%) as a white solid.

(366) .sup.1H NMR (CD.sub.3OD) δ 8.64 (d, 2H), 7.88 (d, 2H), 6.84 (s, 1H), 2.78 (m, 8H), and 1.98 (m, 4H).

(367) LCMS: m/z 358 (M+H).sup.+(ES.sup.+); 356 (M−H).sup.−(ES.sup.−).

Example 34: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-6-(dimethylamino)pyrazine-2-sulfonamide

(368) ##STR00233##

(369) To a solution of 6-(dimethylamino)pyrazine-2-sulfonamide (intermediate P11) (65 mg, 321.41 μmol, 1 eq) in THF (2 mL) was added with t-BuONa (30 mg, 321.41 μmol, 1 eq). The mixture was stirred at 25° C. for 30 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A3) (90 mg, 321.41 μmol, 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 μm; mobile phase: [A: water (0.05% ammonia 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.

(370) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(371) LCMS: m/z 484.2 (M+H).sup.+(ES.sup.+).

Example 35: 6-(Dimethylamino)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)pyrazine-2-sulfonamide

(372) ##STR00234##

(373) To a solution of 6-(dimethylamino) pyrazine-2-sulfonamide (intermediate P11) (65 mg, 321.41 μmol, 1 eq) in THF (2 mL) was added with t-BuONa (30 mg, 321.41 μmol, 1 eq). The mixture was stirred at 25° C. for 30 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A4) (92 mg, 321.41 μmol, 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 μm; 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.

(374) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(375) LCMS: m/z 489.2 (M+H).sup.+(ES.sup.+).

Example 36: 6-(Dimethylamino)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

(376) ##STR00235##

(377) To a solution of 6-(dimethylamino) pyrazine-2-sulfonamide (intermediate P11) (65 mg, 321.41 μmol, 1 eq) in THF (2 mL) was added with t-BuONa (30 mg, 321.41 μmol, 1 eq). The mixture was stirred at 25° C. for 30 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A5) (85 mg, 321.41 μmol, 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 μm; 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.

(378) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(379) LCMS: m/z 469.2 (M+H).sup.+(ES.sup.+).

Example 37: 6-(Dimethylamino)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

(380) ##STR00236##

(381) A mixture of 6-(dimethylamino)pyrazine-2-sulfonamide (intermediate P11) (60 mg, 296.69 μmol, 1 eq) and t-BuONa (29 mg, 296.69 μmol, 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 A6) (75 mg, 296.69 μmol, 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 μm; mobile phase: [A: water (0.05% ammonia 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.

(382) .sup.1H NMR (DMSO-d.sub.6): δ 11.13 (br s, 1H), 8.50 (d, 2H), 8.30 (s, 1H), 8.15 (s, 1H), 7.83 (br s, 1H), 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).

(383) LCMS: m/z 457.2 (M+H).sup.+(ES.sup.+).

Example 38: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-5-(dimethylamino)pyrazine-2-sulfonamide

(384) ##STR00237##

(385) To a solution of 5-(dimethylamino)pyrazine-2-sulfonamide (intermediate P12) (60 mg, 296.69 μmol, 1 eq) in THF (4 mL) was added t-BuONa (29 mg, 296.69 μmol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A3) (83 mg, 296.69 μmol, 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 μm; mobile phase: [A: water (0.05% ammonia 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.

(386) .sup.1H NMR (DMSO-d.sub.6): δ 8.58 (d, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.9.sup.2 (s, 1H), 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).

(387) LCMS: m/z 484.2 (M+H).sup.+(ES.sup.+).

Example 39: 5-(Dimethylamino)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)pyrazine-2-sulfonamide

(388) ##STR00238##

(389) To a solution of 5-(dimethylamino)pyrazine-2-sulfonamide (intermediate P12) (71 mg, 349.28 μmol, 1 eq) in THF (5 mL) was added t-BuONa (34 mg, 349.28 μmol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A4) (100 mg, 349.28 μmol, 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 μm; mobile phase: [A: water (0.05% ammonia 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.

(390) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(391) LCMS: m/z 489.3 (M+H).sup.+(ES.sup.+).

Example 40: 5-(Dimethylamino)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

(392) ##STR00239##

(393) To a solution of 5-(dimethylamino)pyrazine-2-sulfonamide (intermediate P12) (70 mg, 346.13 μmol, 1 eq) in THF (5 mL) was added t-BuONa (33 mg, 346.13 μmol, 1 eq) and 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A5) (92 mg, 346.13 μmol, 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 μm; mobile phase: [A: water (0.05% ammonia 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.

(394) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(395) LCMS: m/z 469.3 (M+H).sup.+(ES.sup.+).

Example 41: 5-(Dimethylamino)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

(396) ##STR00240##

(397) To a mixture of 5-(dimethylamino)pyrazine-2-sulfonamide (intermediate P12) (80 mg, 393.30 μmol, 1 eq) in THF (5 mL) was added t-BuONa (41 mg, 432.63 μmol, 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 A6) (100 mg, 393.3 μmol, 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 μm; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (72.57 mg, 40%) as an off-white solid.

(398) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(399) LCMS: m/z 457.2 (M+H).sup.+(ES.sup.+).

Example 42: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-3-(difluoromethyl)pyrazine-2-sulfonamide

(400) ##STR00241##

(401) To a solution of 3-(difluoromethyl)pyrazine-2-sulfonamide (intermediate P13) (74 mg, 355.51 μmol, 1 eq) in THF (4 mL) was added t-BuONa (34 mg, 355.51 μmol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A3) (0.1 g, 355.51 μmol, 1 eq). The mixture was stirred at 25° C. for 10 minutes and then concentrated in vacua. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 μm; 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.

(402) .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): δ 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).

(403) LCMS: m/z 491.2 (M+H).sup.+(ES.sup.+).

Example 43: 3-(Difluoromethyl)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)pyrazine-2-sulfonamide

(404) ##STR00242##

(405) To a solution of 3-(difluoromethyl)pyrazine-2-sulfonamide (intermediate P13) (73 mg, 34928 μmol, 1 eq) in THF (4 mL) was added t-BuONa (34 mg, 349.28 μmol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A4) (100 mg, 349.28 μmol, 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 μm; 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.

(406) .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): δ 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).

(407) LCMS: m/z 496.2 (M+H).sup.+(ES.sup.+).

Example 44: 3-(Difluoromethyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

(408) ##STR00243##

(409) To a solution of 3-(difluoromethyl)pyrazine-2-sulfonamide (intermediate P13) (75 mg, 358.55 μmol, 1 eq) in THF (5 mL) was added t-BuONa (34 mg, 358.55 μmol, 1 eq) and 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A5) (95 mg, 358.55 μmol, 1 eq). The mixture was stirred at 10° C. for 1 hour and then concentrated in vacua. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 μm; mobile phase: [A: water(10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 15%-45%, 12 min) to give the title compound (24.17 mg, 14% yield, 100% purity on LCMS) as a white solid.

(410) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(411) LCMS: m/z 476.2 (M+H).sup.+(ES.sup.+).

Example 45: 3-(Difluoromethyl)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrazine-2-sulfonamide

(412) ##STR00244##

(413) To a solution of 3-(difluoromethyl)pyrazine-2-sulfonamide (intermediate P13) (82.27 mg, 393.30 μmol, 1 eq) in THF (5 mL) was added t-BuONa (42 mg, 432.63 μmol, 1.1 eq) and a solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A6) (100 mg, 393.30 μmol, 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 vacua. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 μm; 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.

(414) .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): δ 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).

(415) LCMS: m/z 464.1 (M+H).sup.+(ES.sup.+).

Example 46: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-4,6-dimethylpyrimidine-2-sulfonamide

(416) ##STR00245##

(417) To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P14) (65 mg, 347.19 μmol, 1 eq) in THF (5 mL) was added t-BuONa (33 mg, 347.19 μmol, 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 A3) (98 mg, 347.19 μmol, 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 μm; 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.

(418) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(419) LCMS: m/z 469.2 (M+H).sup.+(ES.sup.+).

Example 47: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-4,6-dimethylpyrimidine-2-sulfonamide

(420) ##STR00246##

(421) To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P14) (65 mg, 349.28 μmol, 1 eq) in THF (5 mL) was added t-BuONa (34 mg, 349.28 μmol, 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 A4) (100 mg, 349.28 μmol, 1 eq) was added. The reaction 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: Waters Xbridge C18, 150 mm*50 mm*10 μm; mobile phase: [A: water (0.05% ammonia 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.

(422) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(423) LCMS: m/z 474.2 (M+H).sup.+(ES.sup.+).

Example 48: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4,6-dimethylpyrimidine-2-sulfonamide

(424) ##STR00247##

(425) To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P14) (70 mg, 375.52 μmol, 1 eq) in THF (5 mL) was added t-BuONa (36 mg, 375.52 μmol, 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 A5) (100 mg, 375.52 μmol, 1 eq) was added. The reaction 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: Waters Xbridge C18, 150 mm*50 mm*10 μm; mobile phase: [A: water (0.05% ammonia 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.

(426) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(427) LCMS: m/z 454.2 (M+H).sup.+(ES.sup.+).

Example 49: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4,6-dimethylpyrimidine-2-sulfonamide

(428) ##STR00248##

(429) To a mixture of 4,6-dimethylpyrimidine-2-sulfonamide (intermediate P14) (50 mg, 267.07 μmol, 1 eq) in THF (3 mL) was added t-BuONa (26 mg, 267.07 μmol, 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-indan-5-yl) pyridine (intermediate A6) (68 mg, 267.07 μmol, 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 μm; mobile phase: [A: water (0.05% ammonia 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.

(430) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(431) LCMS: m/z 442.1 (M+H).sup.+(ES.sup.+).

Example 50: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-5-(dimethylamino) pyridazine-3-sulfonamide

(432) ##STR00249##

(433) To a mixture of 5-(dimethylamino) pyridazine-3-sulfonamide (intermediate P15) (70 mg, 346.13 μmol, 1 eq) in THF (2 mL) was added t-BuONa (33 mg, 346.13 μmol, 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 A3) (97 mg, 346.13 μmol, 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 μm; mobile phase: [A: water (0.05% ammonia 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.

(434) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(435) LCMS: m/z 484.2 (M+H).sup.+(ES.sup.+).

Example 51: 5-(Dimethylamino)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl) pyridazine-3-sulfonamide

(436) ##STR00250##

(437) To a mixture of 5-(dimethylamino)pyridazine-3-sulfonamide (intermediate P15) (40 mg, 197.79 μmol, 1 eq) in THF (5 mL) was added t-BuONa (19 mg, 197.79 μmol, 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 A4) (57 mg, 197.79 μmol, 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 μm; 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.

(438) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(439) LCMS: m/z 489.2 (M+H).sup.+(ES.sup.+).

Example 52: 5-(Dimethylamino)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl) pyridazine-3-sulfonamide

(440) ##STR00251##

(441) To a mixture of 5-(dimethylamino)pyridazine-3-sulfonamide (intermediate P15) (35 mg, 1.sub.73.07 μmol, 1 eq) in THF (2 mL) was added t-BuONa (17 mg, 173.07 μmol, 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 A5) (46 mg, 173.07 μmol, 1 eq) was added. The reaction mixture was heated to 25° C. and stirred for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 μm; mobile phase: [A: water (0.05% ammonia 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.

(442) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(443) LCMS: m/z 469.2 (M+H).sup.+(ES.sup.+).

Example 53: 5-(Dimethylamino)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl) pyridazine-3-sulfonamide

(444) ##STR00252##

(445) To a mixture of 5-(dimethylamino)pyridazine-3-sulfonamide (intermediate P15) (50 mg, 247.24 μmol, 1 eq) in THF (3 mL) was added t-BuONa (24 mg, 247.24 μmol, 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 A6) (63 mg, 247.24 μmol, 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 μm; mobile phase: [A: water (0.05% ammonia 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.

(446) .sup.1H NMR (DMSO-d.sub.6): δ 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).

(447) LCMS: m/z 457.0 (M+H).sup.+(ES.sup.+).

Example 54: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-(4-methylpiperazin-1-yl)pyrazine-2-sulfonamide, Potassium Salt

(448) ##STR00253##

(449) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 6-(4-methylpiperazin-1-yl)pyrazine-2-sulfonamide to afford the title compound (30%) as a white solid.

(450) .sup.1H NMR (CD.sub.3OD) δ: 8.34 (s, 1H), 8.24 (s, 1H), 6.85 (s, 1H), 3.72 (m, 4H), 2.82 (t, 4H), 2.72 (t, 4H), 2.52 (m, 4H), 2.33 (s, 3H) and 1.98 (m, 4H).

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

Example 55: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-methoxypyrimidine-5-sulfonamide, Potassium Salt

(452) ##STR00254##

(453) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl pyrimidine-2-sulfonamide, potassium salt (example 17) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) and 2-methoxypyrimidine-5-sulfonamide to afford the title compound (25%) as a white solid.

(454) .sup.1H NMR (CD.sub.3OD) δ: 8.95 (s, 2H), 6.84 (s, 1H), 4.04 (s, 3H), 2.78 (m, 8H), and 1.98 (m, 4H).

(455) LCMS: m/z 389 (M+H).sup.+(ES.sup.+); 387 (M−H).sup.−(ES.sup.−).

Example 56: 4-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-6-methylpyrimidine-2-sulfonamide, potassium salt

(456) ##STR00255##

(457) To a solution of 4-(dimethylamino)-6-methylpyrimidine-2-sulfonamide (intermediate P16) (20 mg, 0.092 mmol) in THF (5 mL) was added potassium tert-butoxide (16 mg, 0.14 mmol). The mixture was stirred at room temperature for 45 minutes. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) (23 mg, 0.092 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and DMSO (1 mL) was added. The mixture (filtered over cotton wool when solids were present) was submitted for purification by reversed phase column chromatography (see General Methods, “Purification Method 1” above) to afford the title compound (2 mg, 5%) as a white solid.

(458) .sup.1H NMR (Methanol-d.sub.4): δ7.77 (s, 1H), 6.85 (s, 1H), 3.02 (s, 6H), 2.78 (m, 8H), 2.43 (d, 3H), 1.98 (m, 4H).

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

Example 57: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-isopropylpyridine-4-sulfonamide, Sodium Salt

(460) ##STR00256##

(461) A solution of 2-isopropylpyridine-4-sulfonamide (intermediate P17) (51 mg, 0.242 mmol) in THF (2 mL) under nitrogen was treated with NaOtBu (2 M in THF, 0.13 mL, 0.260 mmol). The resultant solution was stirred at room temperature for 1 hour and then treated with a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A1) (51 mg, 0.254 mmol) in THF (2 mL) and stirred for 17 hours. The reaction mixture was concentrated in vacua and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-isopropylpyridine-4-sulfonamide (39 mg, 40%) as a flocculent white solid. The sodium salt was generated by dissolving N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-isopropylpyridine-4-sulfonamide (32 mg, 0.079 mmol) in aq. NaOH (0.1M, 0.790 mL, 0.079 mmol). The mixture was freeze dried to afford the title compound (33 mg, 99%) as a white solid.

(462) .sup.1H NMR (DMSO-d.sub.6) δ 8.50 (dd, J=5.0, 0.8 Hz, 1H), 7.53 (s, 1H), 7.50 (br s, 1H), 7.45 (dd, J=5.0, 1.6 Hz, 1H), 6.76 (s, 1H), 3.03 (sept, J=6.9 Hz, 1H), 2.74 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.5 Hz, 4H), 1.88 (p, J=7.5 Hz, 4H), 1.23 (d, J=6.9 Hz, 6H).

(463) LCMS; m/z 400.3 (M+H).sup.+(ES.sup.+); 398.1 (M−H).sup.−(ES.sup.−).

(464) The compounds of examples 58-60 were synthesised by methods analogous to those outlined above.

(465) TABLE-US-00005 Ex Structure and Name 1H NMR spectrum Mass spec MW 58 lH NMR (DMSO- d6) δ 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, 2H), 7.10 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.81 (d, J = m/z 482.2 (M + H).sup.+ (ES.sup.+). 481.6 6-((Dimethylamino)methyl)-N-((5- 5.3 Hz, 2H), 6.69 (2-methoxypyridin-4-yl)-2,3- (s, 2H), 4.21 (s, dihydro-1H-inden-4- 2H), 3.86 (s, 3H), yl)carbamoyl)pyridine-3- 2.88 (t, J = 7.4 sulfonamide Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.62 (s, 6H), 1.94 (p, J = 7.5 Hz, 2H). 59 lH NMR (DMSO- d6) δ 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 = m/z 482.1 (M + H).sup.+ (ES.sup.+); 480.1 (M − H).sup.− (ES.sup.−). 481.6 2-((Dimethylamino)methyl)-N-((5- 5.3, 1.5 Hz, 1H), (2-methoxypyridin-4-yl)-2,3- 6.73 (d, J = 1.2 dihydro-1H-inden-4- Hz, 1H), 3.85 (s, yl)carbamoyl)pyridine-4- 3H), 3.52 (s, 2H), sulfonamide, sodium salt 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). 60 1H NMR (DMSO- d6) δ 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, m/z 467.3 (M + H).sup.+ (ES.sup.+); 465.2 (M − H).sup.− (ES.sup.−). 466.6 2-Isopropyl-N-((5-(2- 3H), 3.03 (sept, J = methoxypyridin-4-yl)-2,3-dihydro- 6.9 Hz, 1H), 1H-inden-4-yl)carbamoyl)pyridine- 2.87 (t, J = 7.4 Hz, 4-sulfonamide, sodium salt 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).

(466) Other compounds listed in the Summary of the Invention may be synthesised by methods analogous to those outlined above.

Examples—Biological Studies

(467) NLRP3 and Pyroptosis

(468) It is well established that the activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of the clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-1β) from the cell.

(469) THP-1 Cells: Culture and Preparation

(470) THP-1 cells (ATCC # TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma # S8636) and penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma # P4333) in 10% Fetal Bovine Serum (FBS) (Sigma # F0804). The cells were routinely passaged and grown to confluency (˜10.sup.6 cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma # T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma # L4524) to give a 1 μg/ml Final Assay Concentration (FAC). 40 μl of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

(471) THP-1 Cells Pyroptosis Assay

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

(473) TABLE-US-00006 1 2 3 4 5 6 7 8 9 10 11 12 A High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low B High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low C High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low D High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low E High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low F High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low G High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low H High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low High MCC950 (10 μM) Compound 8-point half-log dilution Low Drug free control

(474) The results of the pyroptosis assays performed are summarised in Table 1 below as THP IC.sub.50.

(475) TABLE-US-00007 TABLE 1 NLRP3 inhibitory activity (≤10 μM = ‘+’, ≤2000 nM = ‘++’, ≤1600 nM = ‘+++’, ≤1200 nM = ‘++++’, ≤800 nM = ‘+++++’). Example THP IC.sub.50 1 ++++ 2 ++ 3 +++ 4 + 5 + 6 + 7 + 8 +++++ 9 ++ 10 + 11 + 12 ++++ 13 +++ 14 ++ 15 ++++ 16 + 17 ++++ 18 +++++ 19 +++++ 20 + 21 +++++ 22 +++ 23 + 24 + 25 +++++ 26 +++++ 27 +++++ 28 +++++ 29 + 30 + 31 + 32 + 33 +++ 34 +++++ 35 +++++ 36 +++++ 37 +++++ 38 +++++ 39 +++++ 40 +++++ 41 +++++ 42 + 43 + 44 ++++ 45 + 46 +++++ 47 +++++ 48 +++++ 49 +++++ 50 +++++ 51 +++++ 52 +++++ 53 +++++ 54 ++ 55 + 56 +++++ 57 +++++ 58 +++++ 59 +++++ 60 +++++

(476) As is evident from the above, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity. It is evident in particular that where R.sup.1 is a 6-membered heteroaryl group containing at least two nitrogen atoms in the 6-membered ring structure, the compounds show high levels of NLRP3 inhibitory activity.

(477) Moreover, further analysis of the data above reveals a number of surprising trends. For example, it has unexpectedly been found that where the 6-membered heteroaryl group of R.sup.1 is substituted with at least one monovalent group that can mesomerically donate a lone pair of electrons from a nitrogen, oxygen or sulphur atom onto at least one nitrogen atom in the 6-membered ring structure, enhanced NLRP3 inhibitory activity results. This is demonstrated for instance by studying the pyrazine series, where

(478) Examples 8, 25, 26, 27, 28, 34, 35, 36, 37, 38, 39, 40 and 41, all of which are able to mesomerically donate a lone pair of electrons from a monovalent substituent onto a nitrogen atom in the pyrazine ring, all have greater activity than Examples 1, 14, 24, 29, 30, 4.sup.2, 43, 44 and 45, none of which have such lone pair-donating capacity. Similarly, in the pyridazine series, Examples 13, 21, 22, 50, 51, 52 and 53 (with lone pair-donating ability) all have greater activity than Examples 2, 4, 11, 16 and 20 (without lone pair-donating ability). Likewise, in the pyrimidine series, Example 9 has a greater activity than Example to. This effect occurs even when considering compounds of equivalent steric profile.

(479) A further unexpected trend may be observed where R.sup.1 is a 6-membered heteroaryl group containing at least two nitrogen atoms in the 6-membered ring structure, including a first nitrogen atom at the 2-position and a second nitrogen atom at the 6-position. Comparing Examples 3, 17 and 18, it is evident that the level of activity increases with increasing substitution at the 3- and/or 5-position of the 6-membered ring structure. For instance, Example 3 with no substitution has an IC.sub.50 value in excess of 1200 nM, a value which is reduced with the mono-alkylation of Example 17, and reduced still further with 3,5-dialkylation to give the highly active compound of Example 18. Likewise, Examples 46, 47, 48, 49 and 56, all with 3,5-di-substitution are all highly active.

(480) Human Whole Blood IL1β Release Assay

(481) 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.

(482) Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. 1. Plate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) 2. Add 10 μl compound (8 points half-log dilution with 10 μM top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 4. Add 10 μl Nigericin (Sigma # N7143) (10 μM FAC) to all wells 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 6. At the end of the incubation period, spin plates at 300×g for 5 mins to pellet cells and remove 20 μl of supernatant and add to 96-well v-bottom plates for IL-1β analysis (note: these plates containing the supernatants can be stored at −80° C. to be analysed at a later date) 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220E-5000) 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

(483) The results of the human whole blood assays are summarised in Table 2 below as HWB IC.sub.50.

(484) TABLE-US-00008 TABLE 2 NLRP3 inhibitory activity in HWB (≤10 μM = ‘+’, ≤7.5 μM = ‘++’, ≤5.0 μM = ‘+++’, ≤2.5 μM = ‘++++’). Example HWB IC.sub.50 7 ++++ 8 +++ 9 ++++ 10 ++ 17 +++ 18 ++++ 27 ++ 37 ++++ 38 ++++ 40 ++++ 41 +++ 46 ++++ 48 ++++ 49 ++++ 50 ++++ 51 ++++ 52 ++++ 53 ++++ 58 ++++ 59 ++++ 60 ++++

(485) Even in human whole blood, it has surprisingly been found that the compounds of the invention are highly effective inhibitors of NLRP3. Moreover, despite the complexities involved in the interaction with whole blood, the trends uncovered in the THP assays are repeated in the HWB assays. For instance, comparing Example 9 to Example to again reveals that the ability to mesomerically donate a lone pair of electrons from a monovalent substituent onto a nitrogen atom in the 6-membered heteroaryl ring enhances NLRP3 inhibitory activity. It can also be seen that the 3,5-dialkylated pyrimidine derivative of Example 18 possesses superior activity to the mono-alkylated derivative of Example 17.

(486) PK protocol

(487) Pharmacokinetic parameters were determined in male Sprague Dawley rats (Charles River, UK, 250-300 g; or Vital River Laboratory Animal Technology Co Ltd, Beijing, China, 7-9 weeks old). Animals were individually housed during the study and maintained under a 12 h light/dark cycle. Animals had free access to food and water.

(488) 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.

(489) Serial blood samples (about 120-300 μL) were taken from each animal at each of 8 time-points post dose (0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h). 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.

(490) TABLE-US-00009 TABLE 3 PK data (intravenous administration) Example Dose AUC T.sub.1/2 V.sub.dss Cl No (mg/kg) (ng .Math. hr/mL) (hr) (L/kg) (mL/min .Math. kg) 35 1 346.3 2.2 1.77 48.1 36 1 841.0 1.2 1.04 19.8

(491) As is evident from the results presented in Table 3, the compounds of the invention show advantageous pharmacokinetic properties, for example half-life T.sub.1/2, area under the curve AUC, clearance Cl and/or bioavailability, compared to the prior art compounds.

(492) 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.