Compounds

Abstract

The present invention relates to compounds of formula (I): wherein Q is selected from O or S; R.sup.1 is a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton; and R.sup.2 is a cyclic group substituted at the a-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 NLRP.sub.3. ##STR00001##

Claims

1. A compound of formula (I): ##STR00216## or a pharmaceutically acceptable salt or solvate thereof, wherein: Q is selected from O or S; R.sup.1 is a 4- to 10-membered cyclic group, wherein the cyclic group may optionally be substituted with one, two or three substituents independently selected from —NO.sub.2, —OH, —OR.sup.β, —SH, —SR.sup.β, —SOR.sup.β, —SO.sub.2H, —SO.sub.2NH.sub.2, —SO.sub.2NHR.sup.β, —SO.sub.2N(R.sup.β).sub.2, —R.sup.α—SH, —R.sup.α—SR.sup.β, —R.sup.α—SOR.sup.β, —R.sup.α—SO.sub.2H, —R.sup.α—SO.sub.2R.sup.β, —R.sup.α—SO.sub.2NH.sub.2, —R.sup.α—SO.sub.2NHR.sup.β, —R.sup.α—SO.sub.2N(R.sup.β).sub.2, —NH.sub.2, —NHR.sup.β, —N(R.sup.β).sub.2, —R.sup.α—NH.sub.2, —R.sup.α—NHR.sup.β, —CHO, —COR.sup.β, —COOH, —COOR.sup.β, —OCOR.sup.β, —R.sup.α—CHO, —R.sup.α—COR.sup.β, —R.sup.α—COOH, —R.sup.α—COOR.sup.β, —R.sup.α—OCOR.sup.β, C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl; wherein the C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl may optionally be substituted with one or more C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl, —O(C.sub.1-C.sub.4 alkyl), —O(C.sub.1-C.sub.4 haloalkyl), —O(C.sub.3-C.sub.7 cycloalkyl), halo, —OH, —NH.sub.2, —CN, —C≡CH, oxo (═O), or 4- to 6-membered heterocyclic group; each —R.sup.α— is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its backbone, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group may optionally be replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo and/or —R.sup.β groups; each —R.sup.β is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group, and wherein any —R.sup.β may optionally be substituted with one or more C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl, —O(C.sub.1-C.sub.4 alkyl), —O(C.sub.1-C.sub.4 haloalkyl), —O(C.sub.3-C.sub.7 cycloalkyl), halo, —OH, —NH.sub.2, —CN, —C≡CH, oxo (═O), or 4- to 6-membered heterocyclic group; and R.sup.2 is a cyclic group substituted at the α-position, wherein R.sup.2 may optionally be further substituted.

2. The compound or the pharmaceutically acceptable salt or solvate thereof as claimed in claim 1, wherein R.sup.1 is a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl group, all of which may optionally be substituted as defined in claim 1.

3. The compound or the pharmaceutically acceptable salt or solvate thereof as claimed in claim 1, wherein R.sup.2 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the α-position, and wherein R.sup.2 may optionally be further substituted.

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

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

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

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

9. A compound selected from the group consisting of: ##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221## or a pharmaceutically acceptable salt or solvate thereof.

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

11. A method of treating, delaying onset of or reducing risk of a disease, disorder or condition in a subject, the method comprising a step of administering an effective amount of the compound or the pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 to the subject, thereby treating, delaying onset of or reducing risk of the disease, disorder or condition, optionally 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 A20 (HA20).

14. The method as claimed in claim 11, wherein the compound or the pharmaceutically acceptable salt or solvate thereof 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 the pharmaceutically acceptable salt or solvate 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 the pharmaceutically acceptable salt or solvate thereof as claimed in claim 1, and analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 in the cell or non-human animal by the compound.

Description

EXAMPLES—COMPOUND SYNTHESIS

(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 DMA dimethylacetamide DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine DME dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide eq or equiv equivalent (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 NaO.sup.tBu sodium tert-butoxide NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide NMP N-methylpyrrolidine NMR nuclear magnetic resonance (spectroscopy) Pd(dba).sub.3 tris(dibenzylideneacetone) dipalladium(0) Pd(dppf)Cl.sub.2 [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) PE petroleum ether Ph phenyl PMB p-methoxybenzyl, also called 4-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

Experimental Methods

(3) Analytical Methods

(4) NMR spectra were run on Bruker 400 MHz spectrometers using ICON-NMR, under TopSpin program control. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance.

(5) LC-MS Methods: Using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC and Agilent 6110 MSD. Mobile Phase: A: 0.025% NH.sub.3.H.sub.2O in water (v/v); B: acetonitrile. Column: Kinetex EVO C18 2.1X30 mm, 5 μm.

(6) Reversed Phase HPLC Purification Method

(7) Automated reversed phase column chromatography was carried out using a Gilson GX-281 system driven by a Gilson-322 pump module, Gilson-156 UV photometer detection unit and Gilson-281 fraction collector. Detection wavelength: 220 and 254 nm.

(8) Alternatively, automated reversed phase column chromatography was carried out using a Gilson GX-215 system driven by a LC-20AP pump module, SPD-20A UV photometer detection unit and Gilson-215 fraction collector. Detection wavelength: 220 and 254 nm.

Synthesis of Intermediates

Intermediate L1: 1-iso-Propyl-1H-pyrazole-3-sulfinamide

(9) ##STR00044##

Step A: 1-iso-Propyl-1H-pyrazole-3-sulfonyl chloride

(10) ##STR00045##

(11) A solution of 1-isopropyl-1H-pyrazol-3-amine (11 g, 70.30 mmol, 1 eq) in MeCN (400 mL) at 0° C. was treated with a solution of concentrated HCl (80 mL) in H.sub.2O (35 mL) followed with aqueous solution of NaNO.sub.2 (5.82 g, 84.36 mmol, 1.2 eq) in H.sub.2O (25 mL) slowly. The resulting solution was stirred at 0° C. for 40 minutes. AcOH (30 mL), CuCl.sub.2 (4.73 g, 35.15 mmol, 0.5 eq) and CuCl (348.00 mg, 3.52 mmol, 84.06 μL, 0.05 eq) were sequentially added to the above mixture and purged with SO.sub.2 gas for 20 minutes at 0° C. The resulting reaction mixture was stirred at 0° C. to 10° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was diluted with water (200 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=30:1 to 5:1) to afford the title compound (5.1 g, 24.44 mmol, 35% yield, 100% purity) as a yellow oil.

(12) .sup.1H NMR (CDCl.sub.3): δ 7.57 (d, 1H), 6.88 (d, 1H), 4.67-4.64 (m, 1H) and 1.59 (d, 6H).

(13) LCMS: m/z 209 (M+H).sup.+ (ES.sup.+).

Step B: Sodium 1-iso-propyl-1H-pyrazole-3-sulfinate

(14) ##STR00046##

(15) A solution of Na.sub.2SO.sub.3 (4-35 g, 34.50 mmol, 2 eq) in H.sub.2O (12 mL) was stirred at 20° C. for 10 minutes and Na.sub.2CO.sub.3 (3.66 g, 34-50 mmol, 2 eq) was added with stirring. The resulting mixture was stirred at 50° C. for 10 minutes, 1-iso-propyl-1H-pyrazole-3-sulfonyl chloride (3.6 g, 17.25 mmol, 1 eq) was added drop-wise and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in EtOH (24 ml). The suspension was stirred at 20° C. for 10 minutes. The suspension was filtered and the filtrate was evaporated to afford a white solid. The white solid was triturated with EtOAc (20 ml) for 10 minutes and then filtered to afford the title compound (2.4 g, 11.62 mmol, 68% yield, 95% purity) as a white solid.

(16) .sup.1H NMR (DMSO-d.sub.6): δ 7.58 (d, 1H), 6.17 (d, 1H), 4.46-4.43 (m, 1H) and 1.37 (d, 6H).

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

Step C: 1-iso-Propyl-1H-pyrazole-3-sulfinamide

(18) ##STR00047##

(19) Oxalyl chloride (3.11 g, 24.46 mmol, 2.14 mL, 2 eq) was added drop-wise to a solution of sodium 1-iso-propyl-1H-pyrazole-3-sulfinate (2.4 g, 12.23 mmol, 1 eq) in THF (15 mL) at 0° C. After stirring for 1 hour at 20° C., the reaction mixture was added into a solution of aqueous ammonia (15 mL, 25%) at 0° C. and then the mixture was stirred at 20° C. for 1 hour. The reaction mixture was evaporated in vacuo and DCM (20 mL) was added to the residue. The mixture was stirred for 20 minutes at 20° C., and then filtered. The filtrate was concentrated under reduced pressure to afford the title compound (1.2 g, 6.23 mmol, 51% yield, ca. 90% purity) as yellow oil.

(20) .sup.1H NMR (DMSO-d.sub.6): δ 7.87 (d, 1H), 6.54 (d, 1H), 6.24 (s, 2H), 4.57-4.50 (m, 1H) and 1.43 (d, 6H).

(21) LCMS: m/z 196 (M+Na).sup.+ (ES.sup.+).

Intermediate L2: 1-((R)-2-Hydroxypropyl)-1H-pyrazole-3-sulfinamide

(22) ##STR00048##

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

(23) ##STR00049##

(24) To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (38 g, 249.68 mmol, 1 eq) in THF (450 mL) was added n-BuLi (2.5 M, 104.87 mL, 1.05 eq) at −78° C. Then the mixture was stirred for 1.5 hours. The mixture was purged with SO.sub.2 for 0.1 hour. Then the mixture was warmed to 25° C. and concentrated in vacuo. The residue was recrystallised from MTBE (1 L) to give the title compound (53 g, 96% yield) as a white solid.

(25) .sup.1H NMR (DMSO-d.sub.6): δ 7.25 (d, 1H), 6.09 (d, 1H), 5.99 (dd, 1H), 3.97-3.87 (m, 1H), 3.53-3.47 (m, 1H), 2.22-2.18 (m, 1H), 2.01-1.92 (m, 1H), 1.78-1.72 (m, 1H) and 1.53-1.43 (m, 3H).

Step B: N,N-Bis(4-methoxybenzyl)-1H-pyrazole-5-sulfinamide

(26) ##STR00050##

(27) To a solution of lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (53 g, 238.53 mmol, 1 eq) in THF (600 mL) was added oxalyl chloride (60.55 g, 477.07 mmol, 41.76 mL, 2 eq) at 0° C. Then the mixture was warmed to 25° C., stirred for 1 hour and then concentrated in vacuo. The residue was dissolved in DCM (600 mL). To the resulting mixture was added TEA (72.41 g, 715.60 mmol, 99.60 mL, 3 eq) followed by bis(4-methoxybenzyl)amine (61.38 g, 238.53 mmol, 1 eq) at 25° C. The mixture was stirred for 1 hour and then concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=1:1 to 1:3) to give the title compound (54 g, 59% yield, 97% purity on LCMS) as a light yellow oil.

(28) .sup.1H NMR (CDCl.sub.3): δ 7.77 (d, 1H), 7.06 (d, 4H), 6.77-6.72 (m, 4H), 6.51 (d, 1H), 4.03 (s, 4H) and 3.72 (s, 6H).

(29) LCMS: m/z 372.2 (M+H).sup.+ (ES.sup.+).

Step C: 1-((R)-2-Hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfinamide

(30) ##STR00051##

(31) To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-5-sulfinamide (10 g, 26.92 mmol, 1 eq) in DMF (200 mL) was added (R)-2-methyloxirane (3.13 g, 53.84 mmol, 3.77 mL, 2 eq) follow by K.sub.2CO.sub.3 (13.39 g, 96.92 mmol, 3.6 eq). The mixture was heated to 50° C. and stirred for 12 hours. Then the reaction mixture was cooled to 25° C. and diluted with H.sub.2O (1 L) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=1:1 to 0:1) to give the title compound (7.2 g, 62% yield, 100% purity on LCMS) as a light yellow oil.

(32) .sup.1H NMR (CDCl.sub.3): δ 7.51 (t, 1H), 7.16 (dd, 4H), 6.83 (d, 4H), 6.72 (t, 1H), 4.29-4.20 (m, 2H), 4.17-4.06 (m, 5H), 3.80 (s, 6H) and 1.25-1.19 (m, 3H).

(33) LCMS: m/z 430.2 (M+H).sup.+ (ES.sup.+).

Step D: Methyl 1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinate

(34) ##STR00052##

(35) To a solution of 1-((R)-2-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfinamide (6 g, 13.97 mmol, 1 eq) in MeOH (100 mL) was added TFA (1.59 g, 13.97 mmol, 1.03 mL, 1 eq). The mixture was stirred at 25° C. for 2 hours and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.05% NH.sub.3.H.sub.2O in water/MeCN) to give the title compound (2.8 g, 97% yield, 99% purity on LCMS) as a colourless oil.

(36) .sup.1H NMR (CDCl.sub.3): δ 7.57 (d, 1H), 6.74 (s, 1H), 4.29-4.24 (m, 2H), 4.12-4.07 (m, 1H), 3.74-3.72 (m, 1H), 3.66 (s, 3H) and 1.25 (d, 3H).

(37) LCMS: m/z 227.1 (M+Na).sup.+ (ES.sup.+).

Step E: Sodium (R)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfinate

(38) ##STR00053##

(39) To a solution of methyl 1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinate (3.1 g, 15.18 mmol, 1 eq) in MeOH (40 mL) was added an aqueous NaOH solution (1 M, 62.00 mL, 4.08 eq) and then the mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo to give the title compound (3.2 g, crude), which was used directly for the next step.

(40) LCMS: m/z 191.1 (M−Na+2H).sup.+ (ES.sup.+).

Step F: 1-((R)-2-Hydroxypropyl)-1H-pyrazole-3-sulfinic chloride

(41) ##STR00054##

(42) To a solution of sodium (R)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfinate (3.2 g, 15.08 mmol, 1 eq) in THF (50 mL) was added (COCl).sub.2 (7.66 g, 60.32 mmol, 5.28 mL, 4 eq) at 0° C., then the mixture was warmed to 25° C. and stirred for 1 hour. The reaction mixture was used directly for the next step.

Step G: 1-((R)-2-Hydroxypropyl)-1H-pyrazole-3-sulfinamide

(43) ##STR00055##

(44) A solution of THF (40 mL) was purged with NH.sub.3 at −78° C. for 0.1 hour. Then a solution of 1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinic chloride (3.5 g, crude) in THF (so mL) was added to the above mixture at 0° C. The resulting mixture was stirred at 0° C. for 0.1 hour and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.05% NH.sub.3.H.sub.2O in water/MeCN) to give the title compound (0.7 g, 17% yield, 75% purity on LCMS) as a colourless oil.

(45) .sup.1H NMR (CDCl.sub.3): δ 7.55 (dd, 1H), 6.66-6.63 (m, 1H), 4.71 (d, 2H), 4.27-4.21 (m, 2H), 4.09-4.03 (m, 1H) and 1.24 (d, 3H).

(46) LCMS: m/z 212.1 (M+Na).sup.+ (ES.sup.+).

Intermediate L3: tert-Butyl ethyl(3-sulfinamoylpropyl)carbamate

(47) ##STR00056##

Step A: 3-(Ethylamino)propan-1-ol

(48) ##STR00057##

(49) A mixture of 3-bromopropan-1-ol (77 g, 553.99 mmol, 50.00 mL, 1 eq) and ethanamine (74.93 g, 1.66 mol, 108.75 mL, 3 eq) in H.sub.2O (200 mL) was stirred at 25° C. for 20 hours. Then the reaction mixture was concentrated in vacuo to reduce to 200 mL. To the above mixture was added K.sub.2CO.sub.3 (76.57, 553.99 mmol, 1 eq). The reaction mixture was stirred at 25° C. for 0.5 hour and then concentrated in vacuo. The residue was treated with MeOH (500 mL). The filtrate was concentrated in vacuo to give the title compound (60 g, crude) as a yellow oil.

(50) .sup.1H NMR (CDCl.sub.3): δ 3.82 (t, 2H), 2.89 (t, 2H), 2.66 (q, 2H), 1.73-1.68 (m, 2H) and 1.10 (t, 3H).

Step B: tert-Butyl ethyl(3-hydroxypropyl)carbamate

(51) ##STR00058##

(52) To a mixture of 3-(ethylamino)propan-1-ol (60 g, 581.61 mmol, 1 eq) and TEA (117.71 g, 1.16 mol, 161.91 mL, 2 eq) in DCM (300 mL) were added dropwise Boc.sub.2O (139.63 g, 639.77 mmol, 146.98 mL, 1.1 eq) and DMAP (710 mg, 5.82 mmol, 0.01 eq) at 0° C. Then the reaction mixture was warmed to 25° C. and stirred for 12 hours. The mixture was quenched with water (200 mL) and extracted with DCM (2×200 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 column chromatography (SiO.sub.2, PE:EtOAc=50:1 to 2:1) to give the title compound (22 g, 15% yield, 82.0% purity on LCMS) as a yellow oil.

(53) .sup.1H NMR (CDCl.sub.3): δ 3.93 (br s, 1H), 3.58-3.54 (m, 2H), 3.40-3.36 (m, 2H), 3.28-3.24 (m, 2H), 1.70-1.62 (m, 2H), 1.47 (s, 9H) and 1.12 (t, 3H).

(54) LCMS: m/z 204.1 (M+H).sup.+ (ES.sup.+).

Step C: 3-((tert-Butoxycarbonyl)(ethyl)amino)propyl methanesulfonate

(55) ##STR00059##

(56) To a mixture of tert-butyl ethyl(3-hydroxypropyl)carbamate (22 g, 108.23 mmol, 1 eq) and TEA (21.9 g, 216.45 mmol, 30.13 mL, 2 eq) in DCM (150 mL) was added dropwise MsCl (15.45 g, 134.87 mmol, 10.44 mL, 1.25 eq) at 0° C. Then the reaction mixture was warmed to 25° C. and stirred for 1.5 hours. The mixture was quenched with water (200 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 vacuo to give the title compound (35 g, crude) as a brown oil, which was used directly in the next step without further purification.

(57) .sup.1H NMR (CDCl.sub.3): δ 4.26 (t, 2H), 3.31 (t, 2H), 3.29-3.23 (m, 2H), 3.03 (s, 3H), 2.00-1.95 (m, 2H), 1.46 (s, 9H) and 1.12 (t, 3H).

Step D: S-(3-((tert-Butoxycarbonyl)(ethyl)amino)propyl) ethanethioate

(58) ##STR00060##

(59) To a mixture of 3-((tert-butoxycarbonyl)(ethyl)amino)propyl methanesulfonate (35 g, 124.39 mmol, 1 eq) in MeCN (200 mL) was added potassium ethanethioate (17.02 g, 149.03 mmol, 1.2 eq) in one portion at 25° C. under nitrogen. Then the reaction mixture was stirred for 12 hours. The mixture was diluted with EtOAc (300 mL) and quenched with water (200 mL), then extracted with EtOAc (2×200 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 column chromatography (SiO.sub.2, PE:EtOAc=1:0 to 10:1) to give the title compound (30.5 g, 94% yield) as a yellow oil.

(60) .sup.1H NMR (CDCl.sub.3): δ 3.29-3.20 (m, 4H), 2.86 (t, 2H), 2.34 (s, 3H), 1.81 (q, 2H), 1.46 (s, 9H) and 1.10 (t, 3H).

Step E: tert-Butyl ethyl(3-mercaptopropyl)carbamate and di-tert-butyl (disulfanediylbis(propane-3,1-diyl))bis(ethylcarbamate)

(61) ##STR00061##

(62) To a mixture of S-(3-((tert-butoxycarbonyl)(ethyl)amino)propyl) ethanethioate (30.5 g, 116.69 mmol, 1 eq) in MeOH (150 mL) was added an aqueous NaOH solution (1 M, 175.03 mL, 1.5 eq) in one portion. Then the mixture was heated to 70° C. and stirred for 2 hours. The mixture was quenched with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a mixture of the title compounds tert-butyl ethyl(3-mercaptopropyl)carbamate (minor) and di-tert-butyl (disulfanediylbis(propane-3,1-diyl))bis(ethylcarbamate) (major) (26.6 g, 52% yield) as a green oil.

(63) .sup.1H NMR (CDCl.sub.3): δ 3.31-3.22 (m, 8H), 2.67-2.50 (m, 4H), 1.90-1.81 (m, 4H), 1.46 (s, 18H) and 1.26 (t, 6H).

(64) LCMS: m/z 459.4 (M+Na).sup.+ (ES.sup.+).

Step F: Methyl 3-((tert-butoxycarbonyl)(ethyl)amino)propane-1-sulfinate

(65) ##STR00062##

(66) To a mixture of tert-butyl ethyl(3-mercaptopropyl)carbamate and di-tert-butyl (disulfanediylbis(propane-3,1-diyl))bis(ethylcarbamate) (20 g, 45.80 mmol, 1 eq) in MeOH (200 mL) was added NBS (24.46 g, 137.40 mmol, 3 eq) in one portion. Then the reaction mixture was stirred at 25° C. for 1 hour. The mixture was quenched with water (200 mL) and extracted with EtOAc (3×200 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 column chromatography (SiO.sub.2. PE:EtOAc=20:1 to 5:1) to give the title compound (12.6 g, 97% yield, 94.0% purity on LCMS) as a yellow oil.

(67) .sup.1H NMR (CDCl.sub.3): δ 3.78 (s, 3H), 3.34-3.30 (m, 2H), 3.25-3.20 (m, 2H), 2.76-2.70 (m, 2H), 1.95-1.91 (m, 2H), 1.47 (s, 9H) and 1.11 (t, 3H).

(68) LCMS: m/z 166.0 (M-Boc).sup.+ (ES.sup.+).

Step G: Sodium 3-((tert-butoxycarbonyl)(ethyl)amino)propane-1-sulfinate

(69) ##STR00063##

(70) To a mixture of methyl 3-((tert-butoxycarbonyl)(ethyl)amino)propane-1-sulfinate (12.6 g, 47.48 mmol, 1 eq) in MeOH (150 mL) was added an aqueous NaOH solution (1 M, 72.65 mL, 1.53 eq) in one portion. Then the reaction mixture was stirred at 25° C. for 0.5 hour. The mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.05% NH.sub.3.H.sub.2O in water/MeCN) to give the title compound (10.5 g, 81% yield) as a white solid.

(71) .sup.1H NMR (DMSO-d.sub.6): δ 3.14-3.10 (m, 4H), 1.79-1.75 (m, 2H), 1.61-1.59 (m, 2H), 1.38 (s, 9H) and 1.10-1.00 (m, 3H).

Step H: tert-Butyl ethyl(3-sulfinamoylpropyl)carbamate

(72) ##STR00064##

(73) To a mixture of sodium 3-((tert-butoxycarbonyl)(ethyl)amino)propane-1-sulfinate (6.5 g, 23.78 mmol, 1 eq) in THF (200 mL) at 0° C. was added dropwise (COCl).sub.2 (7.70 g, 60.64 mmol, 5.31 mL, 2.55 eq). Then the reaction mixture was warmed to 25° C. and stirred for 2 hours. The reaction mixture was poured into a saturated solution of NH.sub.3 in THF (100 mL) at −78° C. The resulting mixture was stirred at 25° C. for another 1 hour. Then the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=50:1 to 1:1 and EtOAc:MeOH=50:1) to give the title compound (5.2 g, 87% yield) as a yellow oil.

(74) .sup.1H NMR (CDCl.sub.3): δ 4.10-3.99 (m, 2H), 3.45-3.22 (m, 4H), 2.81-2.70 (m, 2H), 1.96-1.92 (m, 2H), 1.47 (s, 9H) and 1.11 (t, 3H).

Intermediate L4: tert-Butyl 3-sulfinamoylazetidine-1-carboxylate

(75) ##STR00065##

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

(76) ##STR00066##

(77) To a solution of tert-butyl 3-(acetylthio)azetidine-1-carboxylate (18 g, 77.82 mmol, 1 eq) in MeOH (70 mL), THF (70 mL) and H.sub.2O (35 mL) was added LiOH.H.sub.2O (3.27 g, 77.82 mmol, 1 eq). The mixture was stirred at 70° C. for 2 hours. Then the reaction mixture was poured into water and extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (14 g, 73.97 mmol, 95% yield) as a light yellow oil, which was used in the next step without further purification.

(78) .sup.1H NMR (CDCl.sub.3): δ 4.35-431 (m, 2H), 3.80-3.76 (m, 2H), 3.70-3.64 (m, 1H) and 1.43 (s, 9H).

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

(79) ##STR00067##

(80) To a solution of tert-butyl 3-mercaptoazetidine-1-carboxylate (6 g, 31.70 mmol, 1 eq) in MeOH (120 mL) was added NBS (11.28 g, 63.40 mmol, 2 eq). The reaction mixture was stirred at 25° C. for 10 minutes. The reaction mixture was quenched with a saturated aqueous Na.sub.2SO.sub.3 solution (200 mL) and then extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (5 g, 21.25 mmol, 67% yield) as a light yellow oil.

(81) .sup.1H NMR (CDCl.sub.3): δ 4.32-4.28 (m, 1H), 4.12-4.07 (m, 3H), 3.81 (s, 3H), 3.64-3.61 (m, 1H) and 1.44 (s, 9H).

(82) LCMS: m/z 258.1 (M+Na).sup.+ (ES.sup.+).

Step C: 1-(tert-Butoxycarbonyl)azetidine-3-sulfinic acid

(83) ##STR00068##

(84) To a solution of tert-butyl 3-(methoxysulfinyl)azetidine-1-carboxylate (1 g, 4.25 mmol, 1 eq) in MeOH (10 mL) was added an aqueous NaOH solution (1 M, 6.50 mL, 1.53 eq). The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was adjusted with 1 N HCl to pH=7 and then the mixture was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (1 g, crude) as a yellow oil.

(85) .sup.1H NMR (DMSO-d.sub.6): δ 3.84-3.81 (m, 2H), 3.68-3.65 (m, 2H), 2.73-2.68 (m, 1H) and 1.37 (s, 9H).

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

(86) ##STR00069##

(87) To a solution of 1-(tert-butoxycarbonyl)azetidine-3-sulfinic acid (1 g, 4.52 mmol, 1 eq) in DCM (20 mL) was added oxalyl dichloride (1.15 g, 9.04 mmol, 791.19 μL, 2 eq). The mixture was stirred at 20° C. for 2 hours. Then the mixture was added at −78° C. into NH.sub.3/THF, which had been prepared by bubbling NH.sub.3 into THF (20 mL) at −78° C. for 10 minutes. The reaction mixture was stirred at 25° C. for another 50 minutes. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=1:1 to 0:1) to give the title compound (490 mg, 49% yield) as a colourless oil.

(88) .sup.1H NMR (DMSO-d.sub.6): δ 5.85 (br s, 2H), 4.08-3.99 (m, 3H), 3.78-3.74 (m, 1H), 3.62-3.58 (m, 1H) and 1.38 (s, 9H).

Intermediate L5: 1-(2-Hydroxyethyl)-1H-pyrazole-3-sulfinamide

(89) ##STR00070##

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

(90) ##STR00071##

(91) To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-5-sulfinamide (15 g, 40.38 mmol, 1 eq) and K.sub.2CO.sub.3 (16.74 g, 121.15 mmol, 3 eq) in DMF (150 mL) was added 2-bromoethanol (10.09 g, 80.76 mmol, 5.73 mL, 2 eq). Then the mixture was heated to 70° C. and stirred for 2 hours. The reaction mixture was quenched with H.sub.2O (500 mL) at 25° C. and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=1:0 to 0:1) to give the title compound (11 g, 66% yield) as a colourless oil.

(92) .sup.1H NMR (CDCl.sub.3): δ 7.54 (d, 1H), 7.19-7.16 (m, 4H), 6.89-6.84 (m, 4H), 6.71 (d, 1H), 4.34-4.31 (m, 2H), 4.16-4.12 (m, 4H), 4.05 (t, 2H) and 3.80 (s, 6H).

(93) LCMS: m/z 416.1 (M+H).sup.+ (ES.sup.+).

Step B: Methyl 1-(2-hydroxyethyl)-1H-pyrazole-3-sulfinate

(94) ##STR00072##

(95) To a solution of 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfinamide (8.8 g, 21.18 mmol, 1 eq) in MeOH (100 mL) was added TFA (2.41 g, 21.18 mmol, 1.57 mL, 1 eq). The mixture was stirred at 25° C. for 2 hours and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.05% NH.sub.3.H.sub.2O in water/MeCN) to give the title compound (3.5 g, 87% yield) as a colourless oil.

(96) .sup.1H NMR (CDCl.sub.3): δ 7.59 (d, 1H), 6.73 (d, 1H), 4.41-4.30 (m, 2H), 4.08-4.01 (m, 2H) and 3.66 (s, 3H).

(97) LCMS: m/z 213.1 (M+Na).sup.+ (ES.sup.+).

Step C: 1-(2-Hydroxyethyl)-1H-pyrazole-3-sulfinic acid

(98) ##STR00073##

(99) To a solution of methyl 1-(2-hydroxyethyl)-1H-pyrazole-3-sulfinate (3.8 g, 19.98 mmol, 1 eq) in MeOH (100 mL) was added an aqueous NaOH solution (1 M, 39.95 mL, 2 eq) and the mixture was stirred at 25° C. for 1 hour. Then the mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (neutral condition; MeCN/H.sub.2O) to give the title compound (3.5 g, 99% yield, 100% purity on LCMS) as a white solid.

(100) .sup.1H NMR (DMSO-d.sub.6): δ 7.51 (d, 1H), 7.20 (br s, 1H), 6.15 (d, 1H), 4.90 (br s, 1H), 4.08 (t, 2H) and 3.75-3.68 (m, 2H).

(101) LCMS: m/z 199.0 (M+Na).sup.+ (ES.sup.+).

Step D: 1-(2-Hydroxyethyl)-1H-pyrazole-3-sulfinic chloride

(102) ##STR00074##

(103) To a solution of 1-(2-hydroxyethyl)-1H-pyrazole-3-sulfinic acid (0.65 g, 3.69 mmol, 1 eq) in THF (40 mL) was added SOCl.sub.2 (878 mg, 7.38 mmol, 535.24 μL, 2 eq). Then the mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound (0.72 g, crude) as light yellow oil, which was used for the next step.

Step E: 1-(2-Hydroxyethyl)-1H-pyrazole-3-sulfinamide

(104) ##STR00075##

(105) A solution of THF (40 mL) was purged with NH.sub.3 (15 psi) at −78° C. and stirred for 0.1 hour. Then 1-(2-hydroxyethyl)-1H-pyrazole-3-sulfinic chloride (0.71 g, 3.65 mmol, 1 eq) was added and the resulting mixture was stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (neutral condition; MeCN/H.sub.2O) to give the title compound (0.23 g, 31% yield, 88% purity on LCMS) as a white solid.

(106) .sup.1H NMR (DMSO-d.sub.6): δ 7.80 (d, 1H), 6.53 (d, 1H), 6.26 (br s, 2H), 4.94 (t, 1H), 4.17 (t, 2H) and 3.75-3.71 (m, 2H).

(107) LCMS: m/z 198.1 (M+Na).sup.+ (ES.sup.+).

Intermediate L6: 4-Chloro-isopropyl-1H-pyrazole-3-sulfinamide

(108) ##STR00076##

Step A: 4-Chloro-1-isopropyl-1H-pyrazol-3-amine

(109) ##STR00077##

(110) To a solution of 1-isopropyl-1H-pyrazol-3-amine (34.8 g, 278.02 mmol, 1 eq) in THF (400 mL) was added NCS (40.84 g, 305.82 mmol, 1.1 eq) at 20° C. The mixture was stirred at 20° C. for 5 hours and then concentrated in vacuo. The residue was diluted with water (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=5:1 to 2:1) to give the title compound (33 g, 74% yield) as a brown oil.

(111) .sup.1H NMR (CDCl.sub.3): δ 7.17 (s, 1H), 4.21-4.16 (m, 1H), 3.67 (br s, 2H) and 1.39 (dd, 6H).

(112) LCMS: m/z 160.1 (M+H).sup.+ (ES.sup.+).

Step B: 4-Chloro-1-isopropyl-1H-pyrazole-3-sulfonyl chloride

(113) ##STR00078##

(114) To a solution of 4-chloro-1-isopropyl-1H-pyrazol-3-amine (28 g, 175.42 mmol, 1 eq) in MeCN (600 mL) at 0° C. was added an aqueous HCl solution (60 mL, 6 M), followed by an aqueous solution of NaNO.sub.2 (14.52 g, 210.50 mmol, 1.2 eq) in H.sub.2O (60 mL) slowly. The resulting mixture was stirred at 0° C. for 40 minutes. Then AcOH (6 mL), CuCl.sub.2 (11.79 g, 87.71 mmol, 0.5 eq) and CuCl (868 mg, 8.77 mmol, 209.74 μL, 0.05 eq) were added. Then SO.sub.2 gas (15 psi) was bubbled into the resulting mixture at 0° C. for 5 minutes. Then the reaction mixture was concentrated in vacuo. The residue was diluted with water (400 mL) and extracted with EtOAc (3×400 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=10:1 to 3:1) to give the title compound (8.18 g, 19% yield) as a yellow oil.

(115) .sup.1H NMR (CDCl.sub.3): δ 7.60 (s, 1H), 4.64-4.56 (m, 1H) and 1.57 (d, 6H).

Step C: Sodium 4-chloro-1-isopropyl-1H-pyrazole-3-sulfinate

(116) ##STR00079##

(117) A solution of Na.sub.2SO.sub.3 (8.48 g, 67.29 mmol, 2 eq) in H.sub.2O (25 mL) was stirred at 20° C. for 10 minutes. Na.sub.2CO.sub.3 (7.13 g, 67.29 mmol, 2 eq) was added and the resulting mixture stirred at 50° C. for 10 minutes. 4-Chloro-1-isopropyl-H-pyrazole-3-sulfonyl chloride (8.18 g, 33.65 mmol, 1 eq) was added dropwise and the resulting mixture was stirred at 50° C. for 2 hours. Then the reaction mixture was concentrated in vacuo. The residue was treated with EtOH (40 mL) and the mixture was stirred at 20° C. for 10 minutes. Then the suspension was filtered and the filtrate was concentrated in vacuo to afford a white solid. The white solid was treated with EtOAc (40 mL) for 10 minutes. Then the mixture was filtered. The filter cake was collected to give the title compound (4.6 g, 59% yield) as a yellow solid.

(118) .sup.1H NMR (DMSO-d.sub.6): δ 7.81 (s, 1H), 4.46-4.39 (m, 1H) and 1.36 (d, 6H).

(119) LCMS: m/z 191.0 (M−ONa).sup.+ (ES.sup.+).

Step D: 4-Chloro-1-isopropyl-1H-pyrazole-3-sulfinamide

(120) ##STR00080##

(121) To a solution of sodium 4-chloro-1-isopropyl-1H-pyrazole-3-sulfinate (2.5 g, 10.84 mmol, 1 eq) in THF (40 mL) was added (COCl).sub.2 (2.75 g, 21.68 mmol, 1.90 mL, 2 eq) at 0° C. After stirring at 20° C. for 1 hour, the reaction mixture was added into an aqueous NH.sub.3.H.sub.2O solution (40 mL) at 0° C. The mixture was stirred at 20° C. for 1 hour and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (0.47 g, 21% yield, 100% purity on LCMS) as a white solid.

(122) .sup.1H NMR (DMSO-d.sub.6): δ 8.17 (s, 1H), 6.37 (s, 2H), 4.54-4.47 (m, 1H) and 1.40 (d, 6H).

(123) LCMS: m/z 230.0 (M+Na).sup.+ (ES.sup.+).

Intermediate L7: 5-(1-Hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfinamide

(124) ##STR00081##

Step A: tert-Butyl (1-methyl-1H-pyrazol-3-yl)carbamate

(125) ##STR00082##

(126) To a solution of 1-methyl-1H-pyrazol-3-amine (40 g, 411.87 mmol, 1 eq) in THF (400 mL) was added a solution of NaOH (18.12 g, 453.06 mmol, 1.1 eq) in H.sub.2O (400 mL) and Boc.sub.2O (107.87 g, 494.24 mmol, 113.54 mL, 1.2 eq). The reaction mixture was stirred at 25° C. for 12 hours. Then the reaction mixture was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with MTBE (200 mL) to give the title compound (36 g, 44% yield, 100% purity on LCMS) as a white solid.

(127) .sup.1H NMR (CDCl.sub.3): δ 8.59 (br s, 1H), 7.19 (d, 1H), 6.45 (s, 1H), 3.81 (s, 3H) and 1.50 (s, 9H).

(128) LCMS: m/z 220.1 (M+Na).sup.+ (ES.sup.+).

Step B: tert-Butyl (5-(1-hydroxyethyl)-1-methyl-1H-pyrazol-3-yl)carbamate

(129) ##STR00083##

(130) A solution of tert-butyl (1-methyl-1H-pyrazol-3-yl)carbamate (18 g, 91.26 mmol, 1 eq) in THF (400 mL) was cooled to −75° C. Then n-BuLi (2.5 M, 80.31 mL, 2.2 eq) was added dropwise into the mixture at −75° C. The reaction mixture was stirred at −75° C. for 1 hour. Then CH.sub.3CHO (8.04 g, 182.52 mmol, 2 eq) was added. The resulting mixture was warmed to 25° C. and stirred at 25° C. for 1 hour. The reaction mixture was quenched with H.sub.2O (500 mL) at 25° C. and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=10:1 to 0:1) to give the title compound (11 g, 22% yield, 90% purity on HNMR) as a white solid.

(131) .sup.1H NMR (CDCl.sub.3): δ 8.07 (s, 1H), 6.41 (s, 1H), 4.83-4.81 (m, 1H), 3.78 (s, 3H), 1.56 (d, 3H) and 1.47 (s, 9H).

(132) LCMS: 264.1 m/z (M+Na).sup.+ (ES.sup.+).

Step C: 1-(3-Amino-1-methyl-1H-pyrazol-5-yl)ethanol

(133) ##STR00084##

(134) To a solution of tert-butyl (5-(1-hydroxyethyl)-1-methyl-1H-pyrazol-3-yl)carbamate (27 g, 111.90 mmol, 1 eq) in DCM (50 mL) was added HCl/EtOAc (4 M, 720.00 mL, 25.74 eq). The reaction mixture was stirred at 25° C. for 12 hours and then concentrated in vacuo to give the title compound (25 g, crude, HCl salt), which was used in the next step directly without further purification.

(135) LCMS: 142.2 m/z (M+H).sup.+ (ES.sup.+).

Step D: 5-(1-Hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfonyl chloride

(136) ##STR00085##

(137) A solution of 1-(3-amino-1-methyl-1H-pyrazol-5-yl)ethanol (25 g, 177.09 mmol, 1 eq) in MeCN (500 mL) at 0° C. was treated with concentrated HCl (so mL) and H.sub.2O (so mL. Then an aqueous solution of NaNO.sub.2 (14.66 g, 212.51 mmol, 1.2 eq) in H.sub.2O (50 mL) was added slowly. The resulting mixture was stirred at 0° C. for 40 minutes. AcOH (50 mL), CuCl (877 mg, 8.85 mmol, 211.74 μL, 0.05 eq) and CuCl.sub.2 (11.91 g, 88.55 mmol, 0.5 eq) were added into the reaction mixture. Then SO.sub.2 gas (15 psi) was bubbled into the mixture for 20 minutes at 0° C. The reaction mixture was stirred at 25° C. for 1 hour. Then the reaction mixture was diluted with H.sub.2O (300 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=30:1 to 1:1) to give the title compound (7 g, crude) as a yellow oil.

(138) .sup.1H NMR (CDCl.sub.3): δ 6.77 (s, 1H), 5.04-493 (m, 1H), 4.06 (s, 3H), and 1.65 (d, 3H).

Step E: Sodium 5-(1-hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfinate

(139) ##STR00086##

(140) A solution of Na.sub.2SO.sub.3 (7.85 g, 62.32 mmol, 2 eq), Na.sub.2CO.sub.3 (6.60 g, 62.32 mmol, 2 eq) in H.sub.2O (70 mL) was stirred at 20° C. for 10 minutes. Then the mixture was warmed to 50° C. for another 10 minutes. To the solution was added 5-(1-hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfonyl chloride (7 g, 31.16 mmol, 1 eq). The reaction mixture was stirred at 50° C. for 1 hour and then concentrated in vacuo. The residue was treated with MeOH (2×50 mL) and filtered. The filtrate was concentrated in vacuo. The residue was triturated with EtOAc (2×30 mL) to give the title compound (5.4 g, 79% yield, 97% purity on LCMS) as a white solid.

(141) .sup.1H NMR (DMSO-d.sub.6): δ 6.10 (s, 1H), 4.77-4.72 (m, 1H), 3.76 (s, 3H), and 1.38 (d, 3H).

(142) LCMS: m/z 213.1 (M+H).sup.+ (ES.sup.+).

Step F: 5-(1-Hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfinamide

(143) ##STR00087##

(144) To a solution of sodium 5-(1-hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfinate (3 g, 14-14 mmol, 1 eq) in THF (10 mL) was added oxalyl chloride (3.59 g, 28.27 mmol, 2.48 mL, 2 eq). The reaction mixture was stirred at 25° C. for 2 hours. Then the reaction mixture was added dropwise into a solution of NH.sub.3 in THF, which had been prepared by bubbling NH.sub.3 gas (15 psi) into THF (10 mL) at −70° C. for 10 minutes. The resulting mixture was stirred at 25° C. for 1 hour and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% NH.sub.3.H.sub.2O)-MeCN) to give the title compound (2.5 g, 39% yield, 83% purity on LCMS) as a yellow oil.

(145) .sup.1H NMR (DMSO-d.sub.6): δ 6.48 (s, 1H), 6.23 (br s, 2H), 4.86-4.76 (m, 1H), 3.85 (s, 3H), and 1.43-1.37 (m, 3H).

(146) LCMS: m/z 212.1 (M+Na).sup.+ (ES.sup.+).

Intermediate L8: 5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazole-3-sulfinamide

(147) ##STR00088##

Step A: tert-Butyl (1-methyl-1H-pyrazol-3-yl)carbamate

(148) ##STR00089##

(149) To a solution of 1-methyl-1H-pyrazol-3-amine (50 g, 514.84 mmol, 1 eq) in THF (500 mL) was added a solution of NaOH (22.65 g, 566.32 mmol, 1.1 eq) in H.sub.2O (500 mL) at 20° C. Then Boc.sub.2O (112.36 g, 514.84 mmol, 118.28 mL, 1 eq) was added at 0° C. The reaction mixture was stirred at 20° C. for 24 hours and then concentrated in vacuo to remove THF. The aqueous solution was extracted with EtOAc (3×300 mL). The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=10:1 to 2:1) to give the title compound (67 g, 66% yield) as a white solid.

(150) .sup.1H NMR (CDCl.sub.3): δ 8.42 (br s, 1H), 7.20 (d, 1H), 6.45 (s, 1H), 3.81 (s, 3H) and 1.51 (s, 9H).

Step B: tert-Butyl(5-formyl-1-methyl-1H-pyrazol-3-yl)carbamate

(151) ##STR00090##

(152) n-BuLi (2.5 M, 133.85 mL, 2 eq) was added dropwise to a stirred solution of tert-butyl (1-methyl-1H-pyrazol-3-yl)carbamate (33 g, 167-31 mmol, 1 eq) in THF (1 L) at −75° C. under N.sub.2. The reaction mixture was stirred at −75° C. for 1 hour. Then a solution of DMF (18.34 g, 250.97 mmol, 19.31 mL, 1.5 eq) in THF (100 mL) was added dropwise whilst maintaining the temperature below −65° C. The resulting mixture was stirred at −65° C. for 1 hour. The reaction mixture was quenched with water (500 mL) and concentrated in vacuo to remove THF. The aqueous layer was extracted with EtOAc (3×400 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=1:0 to 15:1) to give the title compound (32 g, crude) as a white solid.

(153) .sup.1H NMR (CDCl.sub.3): δ 9.44 (s, 1H), 6.94 (s, 1H), 6.77 (s, 1H), 3.74 (s, 3H) and 1.19 (s, 9H).

Step C: tert-Butyl (5-(hydroxymethyl)-1-methyl-1H-pyrazol-3-yl)carbamate

(154) ##STR00091##

(155) To a solution of tert-butyl (5-formyl-1-methyl-1H-pyrazol-3-yl)carbamate (32 g, 71.03 mmol, 1 eq) in MeOH (200 mL) was added NaBH.sub.4 (2.69 g, 71.03 mmol, 1 eq) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched with water (100 mL) and concentrated in vacuo to remove MeOH. The aqueous layer was diluted with water (100 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=15:1 to 1:1) to give the title compound (15 g, 79% yield, 85% purity on LCMS) as a white solid.

(156) .sup.1H NMR (CDCl.sub.3): δ 7.99 (s, 1H), 6.38 (s, 1H), 4.58 (s, 2H), 3.78 (s, 3H) and 1.50 (s, 9H).

(157) LCMS: m/z 250.2 (M+Na).sup.+ (ES.sup.+).

Step D: (3-Amino-1-methyl-1H-pyrazol-5-yl)methanol

(158) ##STR00092##

(159) To a solution of tert-butyl (5-(hydroxymethyl)-1-methyl-1H-pyrazol-3-yl)carbamate (32 g, 140.81 mmol, 1 eq) in DCM (300 mL) was added HCl/dioxane (4 M, 250 mL, 7.10 eq) at 0° C. The reaction mixture was stirred at 20° C. for 18 hours and then concentrated in vacuo to give the title compound (23 g, 99.8% yield, HCl salt) as a white solid, which was used in next step without further purification.

(160) .sup.1H NMR (CD.sub.3OD-d.sub.4): δ 6.06 (s, 1H), 4.60 (s, 2H) and 3.81 (s, 3H).

(161) LCMS: m/z 128.2 (M+H).sup.+ (ES.sup.+).

Step E: 5-(Hydroxymethyl)-1-methyl-1H-pyrazole-3-sulfonyl chloride

(162) ##STR00093##

(163) A solution of (3-amino-1-methyl-1H-pyrazol-5-yl)methanol (22.90 g, 140 mmol, 1 eq, HCl) in MeCN (500 mL) at 0° C. was treated with hydrochloric acid (100 mL, 6 M). Then a solution of NaNO.sub.2 (11.59 g, 168.00 mmol, 1.2 eq) in H.sub.2O (50 mL) was added slowly. The resulting mixture was stirred at 0° C. for 40 minutes. AcOH (50 mL), CuCl.sub.2 (9.41 g, 70.00 mmol, 0.5 eq) and CuCl (693 mg, 7.00 mmol, 167.39 μL, 0.05 eq) were added. Then SO.sub.2 gas (15 psi) was bubbled into the mixture at 0° C. for 5 minutes. The reaction mixture was concentrated in vacuo to remove most of MeCN. The aqueous layer was diluted with water (300 mL) and extracted with EtOAc (3×400 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=10:1 to 1:1) to give the title compound (14 g, 28% yield, 60% purity on HNMR) as a yellow oil. 20 .sup.1H NMR (CDCl.sub.3): δ 6.78 (s, 1H), 4.73 (s, 2H) and 4.03 (s, 3H).

Step F: Sodium 5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-sulfinate

(164) ##STR00094##

(165) A solution of Na.sub.2SO.sub.3 (10.05 g, 79.76 mmol, 2 eq) and Na.sub.2CO.sub.3 (8.45 g, 79.76 mmol, 2 eq) in H.sub.2O (60 mL) was stirred at 50° C. for 10 minutes. Then 5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-sulfonyl chloride (14 g, 39.88 mmol, 1 eq) was added dropwise. The resulting mixture was stirred at 50° C. for another 2 hours and then concentrated in vacuo. The residue was treated with MeOH (100 mL) and the mixture was stirred for 30 minutes. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was triturated with EtOAc (80 mL) to give the title compound (7.8 g, 99% yield) as a white solid.

(166) .sup.1H NMR (DMSO-d.sub.6): δ 6.10 (s, 1H), 4.42 (s, 2H) and 3.73 (s, 3H).

Step G: 5-(Hydroxymethyl)-1-methyl-1H-pyrazole-3-sulfinamide

(167) ##STR00095##

(168) To a solution of sodium 5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-sulfinate (3 g, 15.14 mmol, 1 eq) in THF (50 mL) was added oxalyl chloride (3.84 g, 30.28 mmol, 2.65 mL, 2 eq) at 0° C. After stirring for 1 hour at 20° C., the reaction mixture was added into an aqueous NH.sub.3.H.sub.2O solution (50 mL, 25%) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% NH.sub.3.H.sub.2O)-MeCN) to give the title compound (900 mg, 33% yield, 96% purity on LCMS) as colourless gum.

(169) .sup.1H NMR (DMSO-d.sub.6): δ 6.47 (s, 1H), 6.21 (s, 2H), 5.38 (t, 1H), 4.50 (d, 2H) and 3.81 (s, 3H).

(170) LCMS: m/z 198.1 (M+Na).sup.+ (ES.sup.+).

Step H: 5-(Chloromethyl)-1-methyl-1H-pyrazole-3-sulfinamide

(171) ##STR00096##

(172) To a solution of 5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-sulfinamide (800 mg, 4.57 mmol, 1 eq) and Et.sub.3N (924 mg, 9.13 mmol, 1.27 mL, 2 eq) in DMF (6 mL) was added methanesulfonyl chloride (523 mg, 4.57 mmol, 353.40 μL, 1 eq) at 0° C. The reaction mixture was stirred at 20° C. for 3 hours. The reaction mixture was diluted with MeOH (2 mL) and filtered. The filtrate was purified by reversed phase flash chromatography (water (0.05% NH.sub.3.H.sub.2O)-MeCN) to give the title compound (350 mg, 37% yield, 94% purity on LCMS) as a white solid.

(173) .sup.1H NMR (DMSO-d.sub.6): δ 6.65 (s, 1H), 6.33 (s, 2H), 4.96 (s, 2H) and 3.88 (s, 3H).

(174) LCMS: m/z 216.0 (M+Na).sup.+ (ES.sup.+).

Step I: 5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazole-3-sulfinamide

(175) ##STR00097##

(176) To a solution of 5-(chloromethyl)-1-methyl-1H-pyrazole-3-sulfinamide (350 mg, 1.81 mmol, 1 eq) in THF (5 mL) was added azetidine (413 mg, 7.23 mmol, 487.89 μL, 4 eq). The mixture was stirred at 50° C. for 2 hours and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% NH.sub.3.H.sub.2O)-MeCN) to give the title compound (280 mg, 59% yield, 81% purity on LCMS) as colourless gum.

(177) .sup.1H NMR (DMSO-d.sub.6): δ 6.42 (s, 1H), 6.21 (s, 2H), 3.79 (s, 3H), 3.56 (s, 2H), 3.16-3.11 (m, 4H) and 2.01-1.97 (m, 2H).

(178) LCMS: m/z 215.2 (M+H).sup.+ (ES.sup.+).

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

(179) ##STR00098##

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

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

Intermediate R2: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

(182) ##STR00099##

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

(183) ##STR00100##

(184) To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol, 62.50 mL, 1 eq) in H.sub.2SO.sub.4 (30 mL) was added a mixture of HNO.sub.3 (50 mL, 60% purity) and 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 EtOAc (2×400 mL). The combined organic layers were washed with water (500 mL), saturated aqueous NaHCO.sub.3 solution (500 mL) and brine (2×500 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=1:0 to 100:1) to give the title compound (55 g, 66% yield) as a colourless oil.

(185) .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

(186) ##STR00101##

(187) To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g, 337.07 mmol, 1 eq) in MeOH (500 mL) was added Pd/C (5 g, 10% purity) under N.sub.2. The suspension was degassed in vacuo and purged with H.sub.2 several times. The reaction mixture was stirred at 20° C. for 12 hours under H.sub.2 (50 psi), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=1:0 to 100:4) to give the title compound (19.82 g, 43% yield, 96.4% purity on LCMS) as a brown oil.

(188) .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).

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

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

(190) ##STR00102##

(191) 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, 26.90 mL, 1.3 eq) in DCM (300 mL) was added dropwise Ac.sub.2O (17.45 g, 170.96 mmol, 16.01 mL, 1.15 eq) over 0.1 hour at 0° C. Then the reaction mixture was warmed to 16° C. and stirred for 1.4 hours. The mixture was poured into water (500 mL) and extracted with DCM (2×300 mL). The combined organic phases were washed with brine (2×500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (25.74 g, 96% yield, 96.7% purity on LCMS) as a white solid.

(192) .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).

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

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

(194) ##STR00103##

(195) A mixture of N-(2,3-dihydro-1H-inden-4-yl)acetamide (34.6 g, 197.46 mmol, 1 eq), PTSA (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. Then NBS (38.66 g, 217.20 mmol, 1.1 eq) was added into the reaction mixture. The reaction mixture was stirred at 20° C. for 2 hours and then poured into water (500 mL) and extracted with EtOAc (2×500 mL). The combined organic phases were washed with brine (2×500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=10:1 to 2:1) to give the title compound (13.9 g, 27% yield, 98.1% purity on LCMS) as a white solid.

(196) .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).

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

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

(198) ##STR00104##

(199) 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%) was stirred at 80° C. for 36 hours. Then the reaction mixture was cooled to 0° C. in an ice bath and some solid was precipitated. The suspension was filtered. The filter cake was washed with ice water (50 mL) and dried in vacuo to give the title compound (34.1 g, 72% yield, 94.1% purity on LCMS, HCl salt) as a grey solid.

(200) .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).

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

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

(202) ##STR00105##

(203) 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 under N.sub.2. The mixture was poured into water (500 mL) and extracted with EtOAc (2×500 mL). The combined organic phases were washed with brine (2×700 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (SiO.sub.2, EtOAc:PE=0:1 to 1:10) to give the title compound (27.4 g, 79% yield, 95% purity on LCMS) as a white solid.

(204) .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).

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

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

(206) ##STR00106##

(207) To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50-35 mmol, 7.01 mL, 1.1 eq) in THF (275 mL) was added in portions bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) at 0° C. Then the reaction mixture was stirred at 16° C. for 0.5 hour. The reaction mixture was filtered and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacuo to give the title compound (9.04 g, 74% yield) as a light yellow solid.

(208) .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 R3: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile

(209) ##STR00107##

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

(210) ##STR00108##

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

(212) .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).

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

Step B: 4-Fluoro-2-isopropylaniline

(214) ##STR00109##

(215) 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% purity) under N.sub.2 atmosphere. The reaction mixture was degassed in vacuo and purged with H.sub.2 several times. Then the reaction mixture was stirred at 25° C. for 12 hours under H.sub.2 (50 psi), filtered and the filtrate was concentrated in vacuo to give the title compound (20 g, crude) as a yellow oil.

(216) .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).

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

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

(218) ##STR00110##

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

(220) .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).

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

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

(222) ##STR00111##

(223) 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 under N.sub.2 atmosphere. The resulting mixture was stirred at 80° C. for 2 hours under nitrogen and then concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=20:1 to 5:1) and then triturated with PE (10 mL) to give the title compound (2.65 g, 65% yield, 97% purity on LCMS) as a yellow solid.

(224) .sup.1HNMR (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).

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

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

(226) ##STR00112##

(227) 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, 1.09 mL, 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. Then the mixture was diluted with EtOAc (200 mL) and filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.2 g, crude) as a yellow solid, which was used directly in the next step.

Intermediate R4: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine

(228) ##STR00113##

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

(229) ##STR00114##

(230) 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)Cl.sub.2 (3.78 g, 5.17 mmol, 0.1 eq) was added under N.sub.2. The resulting mixture was heated at 80° C. for 2 hours. Then 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 column chromatography (SiO.sub.2, PE:EtOAc=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).

(231) 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) and 1.29 (dd, 6H).

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

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

(233) ##STR00115##

(234) 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, 1.07 mL, 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. Then the mixture was diluted with EtOAc (200 mL) and filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.1 g, crude) as yellow oil, which was used directly in the next step.

Intermediate R5: 5-Fluoro-2-isocyanato-1,3-diisopropylbenzene

(235) ##STR00116##

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

(236) ##STR00117##

(237) To a solution of 2,6-dibromo-4-fluoroaniline (32.96 g, 122.58 mmol, 1 eq) in dioxane (400 mL) and H.sub.2O (40 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (55 g, 327.30 mmol, 2.67 eq), Pd(dppf)Cl.sub.2 (4.48 g, 6.13 mmol, 0.05 eq) and Cs.sub.2CO.sub.3 (79.88 g, 245.17 mmol, 2 eq) under N.sub.2. The reaction mixture was stirred at 100° C. for 3 hours. Then the reaction mixture was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3×1 L). The combined organic layers were washed with brine (3×200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, eluting with PE) to give the title compound (25 g, crude) as a blue oil.

(238) .sup.1H NMR (CDCl.sub.3): δ 6.66 (d, 2H), 5.34-5.32 (m, 2H), 5.10-5.08 (m, 2H), 3.85 (br s, 2H) and 2.08 (s, 6H).

(239) LCMS: m/z 192.2 (M+H).sup.+ (ES.sup.+).

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

(240) ##STR00118##

(241) To a solution of 4-fluoro-2,6-di(prop-1-en-2-yl)aniline (25 g, 130.72 mmol, 1 eq) in MeOH (400 mL) was added Pd/C (3 g, 10% purity) under N.sub.2. The suspension was degassed in vacuo and purged with H.sub.2 several times. The reaction mixture was stirred at 25° C. for 12 hours under H.sub.2 (50 psi). Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, eluting with PE) to give the title compound (13 g, 50% yield, 98% purity on LCMS) as a yellow oil.

(242) .sup.1H NMR (CDCl.sub.3): δ 6.78 (d, 2H), 4.42 (br s, 2H), 3.04-2.93 (m, 2H) and 1.26 (d, 12H).

(243) LCMS: m/z 196.1 (M+H).sup.+ (ES.sup.+).

Step C: 5-Fluoro-2-isocyanato-1,3-diisopropylbenzene

(244) ##STR00119##

(245) To a solution of 4-fluoro-2,6-diisopropylaniline (540 mg, 2.77 mmol, 1 eq) and TEA (560 mg, 5.53 mmol, 769.80 μL, 2 eq) in THF (15 mL) was added triphosgene (279 mg, 940.21 μmol, 0.34 eq) at 0° C. The reaction mixture was stirred at 70° C. for 1 hour. Then the suspension was filtered and the filtrate was concentrated in vacuo to give the title compound (540 mg, 88% yield) as a brown oil, which was used directly in next step.

Intermediate R6: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

(246) ##STR00120##

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

(247) ##STR00121##

(248) To a mixture of 7-fluoro-2,3-dihydro-1H-inden-1-one (9.5 g, 63.27 mmol, 1 eq) in H.sub.2SO.sub.4 (100 mL) was added dropwise a solution of HNO.sub.3 (7.51 g, 82.25 mmol, 5.37 mL, 69% purity, 1.3 eq) in 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 column chromatography (SiO.sub.2, PE:EtOAc=10:1 to 3:1) to give the title compound (11.4 g, 92% yield) as a yellow solid.

(249) .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

(250) ##STR00122##

(251) 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 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 vacuo to give the title compound (30 g, crude) as brown oil.

(252) .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

(253) ##STR00123##

(254) 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, 10.94 mL, 3 eq) in one portion. Then the reaction mixture was stirred at 25° 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 vacuo to give the title compound (5 g, crude) as brown oil.

(255) .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

(256) ##STR00124##

(257) 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% purity) at 25° C. under N.sub.2. 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 vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=50:1 to 10:1) to give the title compound (1.8 g, 43% yield) as a brown solid.

(258) .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

(259) ##STR00125##

(260) 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 column chromatography (SiO.sub.2, PE:EtOAc=1:0 to 20:1) to give the title compound (8.51 g, 67% yield) as a brown solid.

(261) .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

(262) ##STR00126##

(263) 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. 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 vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=10:1 to 2:1) to give the title compound (1.7 g, 45% yield, 91.0% purity on HPLC) as a brown solid.

(264) .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

(265) ##STR00127##

(266) 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. Then the reaction mixture was filtered through a pad of silica gel and the filter cake was washed with THF (20 mL). The filtrate was concentrated in vacuo to a reduced volume of 10 mL, which was used directly in the next step.

PREPARATION OF EXAMPLES

Examples 1 and 2: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonimidamide and 4-chloro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonimidamide

(267) ##STR00128##

Step A: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfinamide

(268) ##STR00129##

(269) To a solution of 1-iso-propyl-1H-pyrazole-3-sulfinamide (intermediate L1) (950 mg, 5.48 mmol, 1 equiv.) in THF (20 mL) was added sodium methoxide (296.26 mg, 5.48 mmol, 1 eq) at 20° C. After stirring for 30 minutes, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate R1) (1.09 g, 5.48 mmol, 1 eq) was added and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO.sub.2, DCM:MeOH=50:1 to 20:1) to afford the title compound (1.1 g, 2.51 mmol, 46% yield, ca. 85% purity) as a white solid.

(270) .sup.1H NMR (DMSO-d.sub.6): δ 9.63 (s, 1H), 8.24 (s, 1H), 8.05 (d, 1H), 6.96 (s, 1H), 6.76 (d, 1H), 4.66-4.59 (m, 1H), 2.84-2.73 (m, 4H), 2.71-2.69 (m, 4H), 2.02-1.97 (m, 4H) and 1.45 (d, 6H).

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

Step B: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonimidamide and 4-chloro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonimidamide

(272) ##STR00130##

(273) N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfinamide (100 mg, 268.47 μmol, 1 eq) was suspended in THF (1 mL) under nitrogen and treated with 1-chlorobenzotriazole (37.11 mg, 241.62 μmol, 0.9 eq) in a single portion. The mixture became a homogeneous yellow solution after 10 minutes and was stirred for another 20 minutes at 20° C. This solution was added drop-wise over 10 minutes at −70° C. to a solution of ammonia in THF (5 mL), which had been prepared by bubbling NH.sub.3 gas into THF (5 mL) at −70° C. for 5 minutes. After being stirred for 15 minutes, the mixture was warmed to 20° C. and allowed to stir for 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by prep-TLC (SiO.sub.2, DCM:MeOH=10:1) to give a yellow solid, which was further purified by prep-HPLC (neutral conditions—column: Phenomenex Gemini C18 250 mm*50 mm*10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 32%-62%, 10 min) to afford N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonimidamide (example 1) (1.3 mg, 3.35 μmol, 1% yield) as a white solid and 4-chloro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonimidamid (example 2) (3.5 mg, 8.29 μmol, 3% yield), also as a white solid.

Example 1: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonimidamide

(274) .sup.1H NMR (DMSO-d.sub.6): δ 8.27 (br s, 1H), 7.91 (d, 1H), 7.42 (br s, 2H), 6.85 (s, 1H), 6.60 (d, 1H), 4.60-4.55 (m, 1H), 2.84-2.73 (m, 4H), 2.71-2.69 (m, 4H), 1.93-1.90 (m, 4H) and 1.45 (d, 6H).

(275) LCMS: m/z 388 (M+H).sup.+ (ES.sup.+).

Example 2: 4-Chloro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-iso-propyl-1H-pyrazole-3-sulfonimidamide

(276) .sup.1H NMR (DMSO-d.sub.6): δ 8.36 (br s, 1H), 7.91 (d, 1H), 7.38 (br s, 2H), 6.60 (d, 1H), 4.59-4.55 (m, 1H), 2.83-2.75 (m, 8H), 2.00-1.94 (m, 4H) and 1.43 (d, 6H).

(277) LCMS: m/z 422 (M+H).sup.+ (ES.sup.+).

Example 3: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfonimidamide

(278) ##STR00131##

Step A: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide

(279) ##STR00132##

(280) To a solution of 1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide (intermediate L2) (0.6 g, 3.17 mmol, 1 eq) in THF (20 mL) was added NaOMe (171 mg, 3.17 mmol, 1 eq) and the mixture was stirred at 25° C. for 0.5 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate R1) (631 mg, 3.17 mmol, 1 eq) was added and the resulting mixture was heated to 70° C. for 2 hours. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm×*25 mm*10 μm; mobile phase: [A: water (0.04% NH.sub.3.H.sub.2O+10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 18%-48%, 11 min) to give the title compound (0.075 g, 5% yield, 82% purity on LCMS) as a white solid.

(281) .sup.1H NMR (DMSO-d.sub.6): δ 9.47 (br s, 1H), 8.29 (d, 1H), 7.93 (d, 1H), 6.95 (s, 1H), 6.75 (d, 1H), 4.98 (dd, 1H), 4.24-3.97 (m, 3H), 2.82 (t, 4H), 2.74-2.66 (m, 4H), 1.99-1.94 (m, 4H) and 1.08 (dd, 3H).

(282) LCMS: m/z 411.1 (M+Na).sup.+ (ES.sup.+).

Step B: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfonimidamide

(283) ##STR00133##

(284) To a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide (0.07 g, 180.19 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (25 mg, 162.17 mol, 0.9 eq) under N.sub.2 atmosphere. Then the mixture was stirred for 0.5 hour. This solution was added dropwise over 10 minutes to a saturated ammonia solution of THF (5 mL) at −70° C., which had been prepared by bubbling NH.sub.3 gas into THF (5 mL) at −70° C. for 5 minutes. After stirring for 25 minutes, the mixture was warmed to 25° C. for 2 hours. Then the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.04% NH.sub.3.H.sub.2O+10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 22%-52%, 11 min) to give the title compound (0.0148 g, 20% yield, 100% purity on LCMS) as a white solid.

(285) .sup.1H NMR (CD.sub.3OD): δ 7.74 (s, 1H), 6.92 (s, 1H), 6.76 (s, 1H), 4.24-4.08 (m, 3H), 2.92-2.79 (m, 8H), 2.10-2.00 (m, 4H) and 1.20 (dd, 3H).

(286) LCMS: m/z 404.2 (M+H).sup.+ (ES.sup.+).

Example 4: tert-Butylethyl(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfinimidoyl)propyl)carbamate

(287) ##STR00134##

Step A: tert-Butylethyl(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfinamoyl)propyl)carbamate

(288) ##STR00135##

(289) To a solution of tert-butyl ethyl(3-sulfinamoylpropyl)carbamate (intermediate L3) (5.8 g, 23.17 mmol, 1 eq) in THF (60 mL) was added NaOMe (1.50 g, 27.80 mmol, 1.2 eq) in one portion at 25° C. The reaction mixture was stirred for 10 minutes. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate R1) (4.62 g, 23.17 mmol, 1 eq) was added and the reaction mixture was stirred at 25° C. for 50 minutes under nitrogen. The mixture was concentrated in vacuo. The residue was diluted with EtOAc (300 mL) and water (100 mL). The two layers were separated and the aqueous layer was 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 trituration with a mixture of PE and EtOAc (20:1, 500 mL) to give the title compound (5.9 g, 57% yield) as a white solid.

(290) .sup.1H NMR (DMSO-d.sub.6): δ 8.83-8.81 (m, 1H), 8.32-8.28 (m, 1H), 6.94 (s, 1H), 3.27 (t, 2H), 3.20-3.16 (m, 2H), 2.89-2.83 (m, 2H), 2.80 (t, 4H), 2.69 (t, 4H), 1.99-1.94 (m, 4H), 1.81-1.75 (m, 2H), 1.40 (s, 9H) and 1.04 (t, 3H).

Step B: tert-Butylethyl(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfinimidoyl)propyl)carbamate

(291) ##STR00136##

(292) To a solution of tert-butyl ethyl(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfinamoyl)propyl)carbamate (0.5 g, 1.11 mmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (154 mg, 1.00 mmol, 0.9 eq) in one portion under nitrogen. The mixture became homogeneous and turned yellow after 10 minutes and then was stirred for another 20 minutes. This solution was added dropwise over 10 minutes to a solution of ammonia in THF (5 mL) at −70° C., which had been prepared by NH.sub.3 gas bubbling into THF (5 mL) at −65° C. for 5 minutes. After stirring for 15 minutes, the mixture was warmed to 20° C. for 2 hours. Then the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc:MeOH=50:1 to 20:1) to give the title compound (0.55 g, 99% yield, 92.9% purity on LCMS) as a white solid.

(293) .sup.1H NMR (DMSO-d.sub.6): δ 6.87 (s, 1H), 3.24 (t, 2H), 3.17-3.14 (m, 2H), 2.80-2.65 (m, 10H), 1.99-1.89 (m, 6H), 1.39 (s, 9H) and 1.05-1.01 (m, 3H).

(294) LCMS: m/z 465.2 (M+H).sup.+ (ES.sup.+).

Example 5: 3-(Ethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) propane-1-sulfonimidamide

(295) ##STR00137##

(296) To a solution of tert-butyl ethyl(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamimidoyl)propyl)carbamate (example 4) (0.5 g, 1.08 mmol, 1 eq) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 25.10 eq) in one portion. Then the reaction mixture was stirred at 25° C. for 0.5 hour. The mixture was concentrated in vacuo to give the title compound (0.5 g, crude, TFA salt) as a yellow oil.

(297) .sup.1H NMR (DMSO-d.sub.6): δ 8.42-837 (m, 1H), 7.08-7.06 (m, 1H), 6.88 (s, 1H), 3.53-350 (m, 2H), 3.07-3.04 (m, 2H), 2.96-2.92 (m, 2H), 2.79 (t, 4H), 2.72 (t, 4H), 2.05-2.01 (m, 2H), 1.98-1.93 (m, 4H) and 1.18-1.14 (m, 3H).

(298) LCMS: m/z 365.2 (M+H).sup.+ (ES.sup.+).

Example 6: 3-(Diethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) propane-1-sulfonimidamide

(299) ##STR00138##

(300) To a solution of 3-(ethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) propane-1-sulfonimidamide (example 5) (0.4 g, 835.90 μmol, 1 eq, TFA salt) and TEA (727 mg, 7.18 mmol, 1 mL, 8.59 eq) in DMF (4 mL) was added iodoethane (156 mg, 1.00 mmol, 80.23 μL, 1.2 eq) in one portion. Then the reaction mixture was stirred at 25° C. for 12 hours. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3); B: MeCN]; B %: 25%-55%, 10 min) to give the title compound (30.88 mg, 9% yield, 98.6% purity on LCMS) as a white solid.

(301) .sup.1H NMR (DMSO-d.sub.6): δ 8.19 (br s, 1H), 6.86 (s, 1H), 6.80 (br s, 1H), 3.46-3.40 (m, 2H), 2.78 (q, 4H), 2.71-2.66 (m, 4H), 2.47-2.41 (m, 6H), 1.97-1.89 (m, 4H), 1.83-1.76 (m, 2H) and 0.93 (t, 6H).

(302) LCMS: m/z 393.2 (M+H).sup.+ (ES.sup.+).

Example 7: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-azetidine-3-sulfonimidamide

(303) ##STR00139##

Step A: tert-Butyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfinamoyl) azetidine-1-carboxylate

(304) ##STR00140##

(305) To a solution of tert-butyl 3-sulfinamoylazetidine-1-carboxylate (intermediate L4) (1.35 g, 6.13 mmol, 1 eq) in THF (40 mL) was added NaOMe (397 mg, 7.35 mmol, 1.2 eq) and the resulting mixture was stirred for 10 minutes. To this reaction mixture was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate R1) (1.22 g, 6.13 mmol, 1 eq). The mixture was stirred at 70° C. for 50 minutes. Then the reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was redissolved in MeOH and the mixture was stirred for another 10 minutes. Then the mixture was filtered and the filter cake was concentrated in vacuo to give 1.4 g of the title compound. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=3:1 to 0:1) to give a further 500 mg of the title compound. The title compound (1.9 g, 74% yield, 100% purity on LCMS) was obtained as a white solid.

(306) .sup.1H NMR (DMSO-d.sub.6): δ 9.28 (s, 1H), 8.19 (s, 1H), 6.96 (s, 1H), 4.18-4.11 (m, 3H), 3.99-3.96 (m, 1H), 3.85-3.82 (m, 1H), 2.84-2.67 (m, 8H), 2.02-1.96 (m, 4H) and 1.40 (s, 9H).

(307) LCMS: m/z 420.2 (M+H).sup.+ (ES.sup.+).

Step B: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfinamide

(308) ##STR00141##

(309) To a solution of tert-butyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfinamoyl)azetidine-1-carboxylate (640 mg, 1.53 mmol) in DCM (10 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL, 26.56 eq). The mixture was stirred at 25° C. for 1 hour. Then the reaction mixture was concentrated in vacuo to give the title compound (661 mg, TFA salt), which was used in the next step without further purification.

(310) LCMS: m/z 320.2 (M+H).sup.+ (ES.sup.+).

Step C: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropylazetidine-3-sulfinamide

(311) ##STR00142##

(312) To a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-sulfinamide (661 mg, 1.52 mmol, 1 eq, TFA salt) in DMF (5 mL) was added TEA (1.54 g, 15.25 mmol, 2.12 mL, 10 eq) and 2-iodopropane (337 mg, 1.98 mmol, 198.24 μL, 1.3 eq). The mixture was stirred at 50° C. for 2 hours. Then the reaction mixture was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (80 mg, 14% yield, 96.3% purity on LCMS) as a white solid.

(313) .sup.1H NMR (DMSO-d.sub.6): δ 8.29 (s, 1H), 6.96 (s, 1H), 3.79-3.75 (m, 1H), 3.40-3.37 (m, 3H), 3.09-3.06 (m, 1H), 2.82 (t, 4H), 2.70 (t, 4H), 2.32-2.29 (m, 1H), 2.02-1.96 (m, 4H) and 0.89-0.82 (m, 6H).

(314) LCMS: m/z 362.2 (M+H).sup.+ (ES.sup.+).

Step D: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropylazetidine-3-sulfonimidamide

(315) ##STR00143##

(316) To a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropylazetidine-3-sulfinamide (210 mg, 580.91 μmol, 1 eq) in THF (10 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (80 mg, 522.82 μmol, 0.9 eq) at 20° C. The mixture was stirred at 20° C. for 30 minutes. NH.sub.3 was bubbled into THF (30 mL) at −78° C. for 10 minutes and the above reaction mixture was added into the NH.sub.3/THF solution over 10 minutes at −70° C. The resulting mixture was stirred at 20° C. for another 130 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3); B: MeCN]; B %: 26%-56%, 10 min) to give the title compound (39.99 mg, 18% yield, 97.1% purity on LCMS) as a white solid.

(317) .sup.1H NMR (DMSO-d.sub.6): δ 8.25 (br s, 1H), 7.05 (br s, 2H), 6.87 (s, 1H), 4.34-4.26 (m, 1H), 3.48-3.42 (m, 2H), 3.27-3.23 (m, 2H), 2.79 (t, 4H), 2.70 (t, 4H), 2.35-2.31 (m, 1H), 1.98-1.90 (m, 4H) and 0.83 (d, 6H).

Example 8: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-sulfonimidamide

(318) ##STR00144##

Step A: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-sulfinamide

(319) ##STR00145##

(320) To a solution of 1-(2-hydroxyethyl)-1H-pyrazole-3-sulfinamide (intermediate L5) (0.9 g, 5.14 mmol, 1 eq) in THF (50 mL) was added t-BuONa (148 mg, 1.54 mmol, 0.3 eq) at 25° C. and stirred for 0.5 hour. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate R1) (1.02 g, 5.14 mmol, 1 eq) was added and the mixture was heated to 70° C. and stirred for another 21.5 hours. Then the mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (basic condition, 0.05% NH.sub.3.H.sub.2O in water/MeCN) to give the title compound (0.58 g, 30% yield, 98% purity on LCMS) as a light yellow solid.

(321) .sup.1H NMR (DMSO-d.sub.6): δ 7.91 (s, 1H), 6.93 (s, 1H), 6.70 (s, 1H), 4.99 (br s, 1H), 4.23 (t, 2H), 3.78-3.73 (m, 2H), 2.81 (t, 4H), 2.74-2.69 (m, 4H) and 2.01-1.95 (m, 4H).

(322) LCMS: m/z 375.3 (M+H).sup.+ (ES.sup.+).

Step B: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-sulfonimidamide

(323) ##STR00146##

(324) To a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-sulfinamide (0.25 g, 667.63 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (102 mg, 667.63 μmol, 1 eq) under N.sub.2 atmosphere. Then the mixture was stirred for 0.5 hour. This solution was added dropwise over 10 minutes at −70° C. to a saturated solution of ammonia in THF (5 mL), which had been prepared by bubbling NH.sub.3 gas into THF (5 mL) at −70° C. for 5 minutes. After stirring for 25 minutes, the mixture was warmed to 25° C. for 2 hours. Then the mixture was concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH=10:1) and then purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.04% NH.sub.3.H.sub.2O+10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 16%-46%, 10 min) to give the title compound (0.02 g, 8% yield, 100% purity on LCMS) as a white solid.

(325) .sup.1H NMR (DMSO-d.sub.6): δ 8.31 (br s, 1H), 7.84 (d, 1H), 7.41 (br s, 2H), 6.86 (s, 1H), 6.61 (s, 1H), 5.00 (t, 1H), 4.21 (t, 2H), 3.78-3.73 (m, 2H), 2.77 (t, 4H), 2.68 (t, 4H) and 1.97-1.89 (m, 4H).

(326) LCMS: m/z 390.2 (M+H).sup.+ (ES.sup.+).

Example A: 2-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamimidoyl)-1H-pyrazol-1-yl)ethyl methanesulfonate

(327) ##STR00147##

(328) To a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-sulfonimidamide (example 8) (0.02 g, 51.35 μmol, 1 eq) in THF (2 mL) was added MsCl (6 mg, 51.35 μmol, 3.97 μL, 1 eq) followed by TEA (16 mg, 154.06 μmol, 21.44 μL, 3 eq). Then the mixture was stirred at 25° C. for 6 hours. The reaction mixture was diluted with H.sub.2O (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (0.024 g, 59% yield, 59% purity on LCMS) as a white solid, which was used to prepare the compound of example 10 without further purification.

(329) LCMS: m/z 468.1 (M+H).sup.+ (ES.sup.+).

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

(330) ##STR00148##

(331) To a solution of 2-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamimidoyl)-1H-pyrazol-1-yl)ethyl methanesulfonate (example 9) (0.2 g with 51% purity, 218.15 μmol, 1 eq) in THF (1 mL) was added dimethylamine (2 M, 10.2 mL, 93.51 eq). The mixture was heated to 60° C. for 12 hours. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.225% HCOOH); B: MeCN]; B %: 8%-38%, 10 min) to give the title compound (0.85 mg, 1% yield, 95% purity on LCMS, HCOOH salt) as a white solid.

(332) .sup.1H NMR (CDCl.sub.3): δ 7.53 (d, 1H), 6.91 (s, 1H), 6.69 (s, 1H), 6.56 (br s, 1H), 4.29 (t, 2H), 2.86 (t, 2H), 2.79 (t, 4H), 2.74-2.70 (m, 4H), 2.78 (s, 6H) and 1.98-1.93 (m, 4H).

(333) LCMS: m/z 417.2 (M+H).sup.+ (ES.sup.+).

Example 11: 4-Chloro-1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide

(334) ##STR00149##

Step A: 4-Chloro-1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfinamide

(335) ##STR00150##

(336) To a solution of 4-chloro-1-isopropyl-1H-pyrazole-3-sulfinamide (intermediate L6) (150 mg, 722.26 μmol, 1 eq) in THF (2 mL) was added t-BuONa (69 mg, 722.26 μmol, 1 eq). The mixture was stirred at 20° C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate R2) (192 mg, 722.26 μmol, 1 eq) was added. The mixture was stirred at 20° C. for 20 minutes and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (290 mg, 83% yield, 98% purity on LCMS) as a white solid.

(337) .sup.1H NMR (CD.sub.3OD): δ 8.11 (d, 1H), 8.00 (s, 1H), 7.27 (d, 1H), 7.16 (d, 1H), 6.96-6.94 (m, 1H), 6.79 (s, 1H), 4.61-4.53 (m, 1H), 3.90 (s, 3H), 3.01 (t, 2H), 2.92 (t, 2H), 2.17-2.09 (m, 2H) and 1.50 (d, 6H).

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

Step B: 4-Chloro-1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide

(339) ##STR00151##

(340) 4-Chloro-1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfinamide (200 mg, 421.96 μmol, 1 eq) was dissolved in THF (4 mL) under nitrogen. Then 1-chloro-1H-benzo[d][1,2,3]triazole (58 mg, 379.77 μmol, 0.9 eq) was added in one portion. The resulting mixture was stirred for 30 minutes. The reaction mixture was added dropwise over 10 minutes at −70° C. to a solution of ammonia in THF (10 mL), which had been prepared by bubbling NH.sub.3 gas (15 psi) into THF (10 mL) at −70° C. for 5 minutes. After stirring for 15 minutes, the mixture was warmed to 20° C. for 2 hours and then concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH=10:1) and then purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 32%-62%, 10 min) to give the title compound (61.15 mg, 30% yield, 100% purity on LCMS) as a white solid.

(341) .sup.1H NMR (DMSO-d.sub.6): δ 8.19 (s, 2H), 8.10 (d, 1H), 7.36 (br s, 2H), 7.15 (d, 1H), 7.08 (d, 1H), 6.95 (d, 1H), 6.77 (s, 1H), 4.55-4.47 (m, 1H), 3.87 (s, 3H), 2.90 (t, 2H), 2.75-2.67 (m, 2H), 2.01-1.94 (m, 2H) and 1.41 (d, 6H).

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

Example 12: 4-Chloro-N-((2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(343) ##STR00152##

Step A: 4-Chloro-N-((2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide

(344) ##STR00153##

(345) To a solution of 4-chloro-1-isopropyl-1H-pyrazole-3-sulfinamide (intermediate L6) (150 mg, 722.26 μmol, 1 eq) in THF (2 mL) was added t-BuONa (69 mg, 722.26 μmol, 1 eq). The mixture was stirred at 20° C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate R3) (203 mg, 722.26 μmol, 1 eq) was added. The mixture was stirred at 20° C. for 20 minutes and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (320 mg, 70% yield, 77% purity on LCMS) as a yellow solid.

(346) .sup.1H NMR (CD.sub.3OD): δ 8.73 (d, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 7.70-7.68 (m, 1H), 7.29 (dd, 1H), 7.10 (dd, 1H), 4.64-4.57 (m, 1H), 3.28-3.24 (m, 1H), 1.52 (dd, 6H) and 1.29-1.26 (m, 6H).

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

Step B: 4-Chloro-N-((2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(348) ##STR00154##

(349) 4-Chloro-N-((2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide (200 mg, 409.03 μmol, 1 eq) was dissolved in THF (4 mL) under nitrogen. Then 1-chloro-1H-benzo[d][1,2,3]triazole (57 mg, 368.12 μmol, 0.9 eq) was added in one portion. The resulting mixture was stirred for 30 minutes. The mixture was added dropwise over 10 minutes at −70° C. to a solution of ammonia in THF (6 mL), which had been prepared by bubbling NH.sub.3 gas (15 psi) into THF (10 mL) at −70° C. for 5 minutes. After stirring for 15 minutes, the mixture was warmed to 20° C., stirred for 2 hours and then concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH=10:1) and then purified by prep-HPLC (column: Waters Xbridge 150 mm*50 mm*10 μm; mobile phase: [A: water (1 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 30%-60%, 11.5 min) to give the title compound (41.11 mg, 20% yield, 99% purity on LCMS) as a white solid.

(350) .sup.1H NMR (DMSO-d.sub.6): δ 8.70 (d, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.69 (d, 1H), 7.23 (dd, 1H), 7.12 (dd, 1H), 6.71 (br s, 2H), 4.51-4.43 (m, 1H), 3.20-3.16 (m, 1H), 1.44-1.38 (m, 6H) and 1.19-1.11 (m, 6H).

(351) LCMS: m/z 504.2 (M+H).sup.+ (ES.sup.+).

Example 13: 4-Chloro-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(352) ##STR00155##

Step A: 4-Chloro-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide

(353) ##STR00156##

(354) To a solution of 4-chloro-1-isopropyl-1H-pyrazole-3-sulfinamide (intermediate L6) (150 mg, 722.26 μmol, 1 eq) in THF (2 mL) was added t-BuONa (69 mg, 722.26 μmol, 1 eq). The mixture was stirred at 20° C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate R4) (207 mg, 722.26 μmol, 1 eq) was added. The mixture was stirred at 20° C. for 20 minutes and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (300 mg, 74% yield, 88% purity on LCMS) as a white solid.

(355) .sup.1H NMR (CD.sub.3OD): δ 8.12 (d, 1H), 8.00 (s, 1H), 7.20 (dd, 1H), 7.00-6.95 (m, 2H), 6.81 (s, 1H), 4.62-4.55 (m, 1H), 3.90 (s, 3H), 3.24-3.20 (m, 1H), 1.52-1.47 (m, 6H) and 1.29-1.22 (m, 6H).

(356) LCMS: m/z 494.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Chloro-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(357) ##STR00157##

(358) 4-Chloro-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide (200 mg, 404.87 μmol, 1 eq) was dissolved in THF (4 mL) under nitrogen. Then 1-chloro-1H-benzo[d][1,2,3]triazole (56 mg, 364.39 μmol, 0.9 eq) was added in one portion. The resulting reaction mixture was stirred for 30 minutes. Then the mixture was added dropwise over 10 minutes at −70° C. to a solution of ammonia in THF (1 mL), which had been prepared by bubbling NH.sub.3 gas (15 psi) into THF (10 mL) at −70° C. for 5 minutes. After stirring for 15 minutes, the reaction mixture was warmed to 20° C., stirred for 2 hours and then concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH=10:1) and then purified by prep-HPLC (column: Waters Xbridge 150 mm*50 mm*10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 35%-65%, 11.5 min) to give the title compound (71.14 mg, 35% yield, 100% purity in LCMS) as a white solid.

(359) .sup.1H NMR (DMSO-d.sub.6): δ 8.22-8.10 (m, 3H), 7.54 (br s, 2H), 7.17-7.14 (m, 1H), 7.00-6.80 (m, 2H), 6.78 (m, 1H), 4.53-4.46 (m, 1H), 3.85 (s, 3H), 3.19-3.14 (m, 1H), 1.42-1.33 (m, 6H) and 1.11-1.02 (m, 6H).

(360) LCMS: m/z 509.2 (M+H).sup.+ (ES.sup.+).

Example 14: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide

(361) ##STR00158##

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

(362) ##STR00159##

(363) To a solution of 1-iso-propyl-1H-pyrazole-3-sulfinamide (intermediate L1) (100 mg, 577.25 μmol, 1 eq) in THF (6 mL) was added t-BuONa (55 mg, 577.25 μmol, 1 eq) and 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate R2) (154 mg, 577.25 μmol, 1 eq). The mixture was stirred at 10° C. for 1 hour and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (210 mg, 80% yield, 96.4% purity on LCMS) as a white solid.

(364) .sup.1H NMR (DMSO-d.sub.6): δ 8.15 (d, 1H), 7.94 (s, 1H), 7.21 (d, 1H), 7.13 (d, 1H), 6.95 (d, 1H), 6.77 (s, 1H), 6.61 (s, 1H), 4.61-4.54 (m, 1H), 3.87 (s, 3H), 2.94 (t, 2H), 2.81 (t, 2H), 2.07-2.00 (m, 2H) and 1.44 (d, 6H).

(365) LCMS: m/z 440.2 (M+H).sup.+ (ES.sup.+).

Step B: 1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide

(366) ##STR00160##

(367) To a solution of 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfinamide (200 mg, 455.03 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (70 mg, 455.03 μmol, 1 eq) and the mixture was stirred at 10° C. for 30 minutes. NH.sub.3 was bubbled into THF (30 mL) at −75° C. for 10 minutes. The above reaction mixture was added into the NH.sub.3/THF solution at −75° C. and the resulting mixture was stirred for another 20 minutes. The mixture was slowly warmed to 10° C. and stirred at 10° C. for 1 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3); B: MeCN]; B %: 30%-60%, 12 min) to give the title compound (68.64 mg, 33% yield, 100% purity on LCMS) as a white solid.

(368) .sup.1H NMR (DMSO-d.sub.6): δ 8.26 (br s, 1H), 8.12 (d, 1H), 7.91 (d, 1H), 7.41 (br s, 2H), 7.16 (d, 1H), 7.09 (d, 1H), 6.95 (d, 1H), 6.77 (s, 1H), 6.51 (s, 1H), 4.64-4.53 (m, 1H), 3.88 (s, 3H), 2.91 (t, 2H), 2.73-2.67 (m, 2H), 2.00-1.95 (m, 2H) and 1.44 (d, 6H).

(369) LCMS: m/z 455.2 (M+H).sup.+ (ES.sup.+).

Example 15: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(370) ##STR00161##

Step A: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide

(371) ##STR00162##

(372) To a solution of 1-iso-propyl-1H-pyrazole-3-sulfinamide (intermediate L1) (100 mg, 577.25 μmol, 1 eq) in THF (5 mL) was added t-BuONa (61 mg, 634.97 μmol, 1.1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate R3) (162 mg, 577.25 μmol, 1 eq). The mixture was stirred at 25° C. for 1 hour and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (200 mg, 76% yield) as a white solid.

(373) .sup.1H NMR (DMSO-d.sub.6): δ 8.77 (d, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 8.02 (d, 1H), 7.75-773 (m, 1H), 7.35 (d, 1H), 7.23 (dd, 1H), 6.66 (d, 1H), 4.67-4.51 (m, 1H), 3.17-313 (m, 1H), 1.45 (d, 6H) and 1.20 (dd, 6H).

(374) LCMS: m/z 455.2 (M+H).sup.+ (ES.sup.+).

Step B: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(375) ##STR00163##

(376) To a solution of N-((2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide (160 mg, 352.02 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (54 mg, 352.02 μmol, 1 eq) and the mixture was stirred for 30 minutes. The above solution was added into a NH.sub.3/THF solution, which had been prepared by bubbling NH.sub.3 into THF (30 mL) at −78° C. for 10 minutes. The reaction mixture was stirred at −70 to −60° C. for 30 minutes and then stirred at 25° C. for 3.5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3); B: MeCN]; B %: 30%-60%, 12 min) to give the title compound (7.76 mg, 5% yield, 100% purity on LCMS) as an off-white solid.

(377) .sup.1H NMR (DMSO-d.sub.6): δ 8.69 (d, 1H), 7.97 (s, 1H), 7.80 (d, 1H), 7.71 (d, 1H), 7.22-7.17 (m, 3H), 7.08 (dd, 1H), 6.39 (s, 1H), 4.62-4.51 (m, 1H), 3.27-3.21 (m, 1H), 1.46 (d, 6H) and 1.17 (dd, 6H).

(378) LCMS: m/z 470.2 (M+H).sup.+ (ES.sup.+).

Example 16: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(379) ##STR00164##

Step A: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide

(380) ##STR00165##

(381) To a solution of 1-iso-propyl-1H-pyrazole-3-sulfinamide (intermediate L1) (100 mg, 577.25 μmol, 1 eq) in THF (6 mL) was added t-BuONa (55 mg, 577.25 μmol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate R4) (165 mg, 577.25 μmol, 1 eq). The mixture was stirred at 10° C. for 1 hour and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (180 mg, 66% yield, 96.6% purity on LCMS) as a white solid.

(382) .sup.1H NMR (DMSO-d.sub.6): δ 8.12 (d, 1H), 7.88 (s, 1H), 7.22 (d, 1H), 7.06-7.00 (m, 2H), 6.85 (s, 1H), 6.50 (s, 1H), 4.59-4.51 (m, 1H), 3.86 (s, 3H), 3.20-3.17 (m, 1H), 1.43 (d, 6H) and 1.16 (d, 6H).

(383) LCMS: m/z 460.3 (M+H).sup.+ (ES.sup.+).

Step B: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(384) ##STR00166##

(385) To a solution of N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide (160 mg, 348.18 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (53 mg, 348.18 μmol, 1 eq) and the mixture was stirred at 10° C. for 30 minutes. NH.sub.3 was bubbled into THF (30 mL) at −75° C. for 10 minutes. The above reaction mixture was added into the NH.sub.3/THF solution at −75° C. and stirred another 20 minutes. The mixture was slowly warmed to ° C. and stirred at 10° C. for 1 hour. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3); B: MeCN]; B %: 33%-63%, 12 min) to give the title compound (28.24 mg, 17% yield, 99.5% purity on LCMS) as a white solid.

(386) .sup.1H NMR (DMSO-d.sub.6): δ 8.11 (d, 1H), 8.00 (br s, 1H), 7.82 (d, 1H), 7.15-7.11 (m, 3H), 6.99-6.93 (m, 2H), 6.81 (s, 1H), 6.42 (s, 1H), 4.61-4.52 (m, 1H), 3.91 (s, 3H), 3.25-3.20 (m, 1H), 1.46 (d, 6H) and 1.17-1.09 (m, 6H).

(387) LCMS: m/z 475.2 (M+H).sup.+ (ES.sup.+).

Example 17: 1-((R)-2-Hydroxypropyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide

(388) ##STR00167##

Step A: 1-((R)-2-Hydroxypropyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfinamide

(389) ##STR00168##

(390) To a solution of 1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide (intermediate L2) (0.06 g, 317.07 μmol, 1 eq) in THF (2 mL) was added t-BuONa (37 mg, 380.48 μmol, 1.2 eq) at 25° C. The mixture was stirred for 0.5 hour. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate R2) (101 mg, 380.48 μmol, 1.2 eq) was added. The mixture was heated to 70° C., stirred for another 0.1 hour and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (basic condition, 0.1% NH.sub.3.H.sub.2O in water/MeCN) to give the title compound (0.1 g, 67% yield, 97% purity on LCMS) as a white solid.

(391) .sup.1H NMR (CDCl.sub.3): δ 7.93 (s, 1H), 7.39 (m, 1H), 7.12-7.08 (m, 1H), 7.03-7.00 (m, 1H), 6.77 (s, 1H), 6.62 (s, 1H), 6.38 (s, 1H), 4.13-3.89 (m, 3H), 3.82 (s, 3H), 2.98-2.61 (m, 4H), 1.99-1.95 (m, 2H) and 1.07-1.04 (m, 3H).

(392) LCMS: m/z 456.2 (M+H).sup.+ (ES.sup.+)

Step B: 1-((R)-2-Hydroxypropyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide

(393) ##STR00169##

(394) To a solution of 1-((R)-2-hydroxypropyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfinamide (0.1 g, 219.52 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (33.71 mg, 219.52 μmol, 1 eq) under N.sub.2 atmosphere. Then the mixture was stirred for 0.5 hour. This solution was added dropwise over 10 minutes at −70° C. to a solution of ammonia in THF (5 mL), which had been prepared by bubbling NH.sub.3 gas into THF (5 mL) at −70° C. for 5 minutes. After stirring for 25 minutes, the mixture was warmed to 25° C. for 2 hours and then concentrated in vacuo. The residue was purified by prep-TLC (dichloromethane:methanol=10:1) and then purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.04% NH.sub.3.H.sub.2O+10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 18%-48%, 10 min) to give the title compound (9.05 mg, 9% yield, 100% purity on LCMS) as a white solid.

(395) .sup.1H NMR (DMSO-d.sub.6): δ 8.23 (br s, 1H), 8.12 (d, 1H), 7.79 (d, 1H), 7.34 (br s, 2H), 7.16 (d, 1H), 7.08 (d, 1H), 6.95 (d, 1H), 6.77 (s, 1H), 6.47 (s, 1H), 5.02-5.00 (m, 1H), 4.08 (d, 2H), 4.04-3.96 (m, 1H), 3.88 (s, 3H), 2.91 (t, 2H), 2.78-2.74 (m, 2H), 2.03-1.96 (m, 2H) and 1.05 (dd, 3H).

(396) LCMS: m/z 471.2 (M+H).sup.+ (ES.sup.+).

Example 8: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfonimidamide

(397) ##STR00170##

Step A: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide

(398) ##STR00171##

(399) To a solution of 1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide (intermediate L2) (0.07 g, 369.91 μmol, 1 eq) in THF (2 mL) was added t-BuONa (43 mg, 443.89 mol, 1.2 eq) at 25° C. The mixture was stirred for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate R3) (125 mg, 443.89 mol, 1.2 eq) was added and the resulting mixture was heated to 70° C. and stirred for 0.1 hour. Then the mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (basic condition, 0.1% NH.sub.3.H.sub.2O in water/MeCN) to give the title compound (0.11 g, 55% yield, 87% purity on LCMS) as a white solid.

(400) .sup.1H NMR (CDCl.sub.3): δ 8.58 (d, 1H), 8.02-7.85 (m, 1H), 7.68-7.64 (m, 1H), 7.55-7.44 (m, 2H), 7.11 (dd, 1H), 6.85 (d, 1H), 6.49 (s, 1H), 4.18-4.10 (m, 2H), 3.99-3.92 (m, 1H), 3.15-3.10 (m, 1H) and 1.20-1.02 (m, 9H).

(401) LCMS: m/z 471.2 (M+H).sup.+ (ES.sup.+).

Step B: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfonimidamide

(402) ##STR00172##

(403) To a solution of N-((2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide (0.11 g, 233.78 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (36 mg, 233.78 μmol, 1 eq) under N.sub.2 atmosphere. Then the mixture was stirred for 0.5 hour. This mixture was added dropwise over 10 minutes to a solution of ammonia in THF (5 mL) at −70° C. The ammonia solution had been prepared by bubbling NH.sub.3 gas into THF (5 mL) at −70° C. for 5 minutes. After stirring at −70° C. for 25 minutes, the mixture was warmed to 25° C. for 2 hours and then concentrated in vacuo. The residue was purified by prep-TLC (dichloromethane:methanol=10:1) and then purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.04% NH.sub.3.H.sub.2O+10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 18%-51%, 10 min) to give the title compound (15.84 mg, 14% yield, 99% purity on LCMS) as a white solid.

(404) .sup.1H NMR (DMSO-d.sub.6): δ 8.72 (d, 1H), 8.36 (br s, 1H), 8.08-7.96 (m, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.31 (br s, 2H), 7.24 (d, 1H), 7.15-7.12 (m, 1H), 6.36-6.26 (m, 1H), 4.99 (d, 1H), 4.06 (d, 2H), 3.99-3.92 (m, 1H), 3.19-3.15 (m, 1H) and 1.26-0.93 (m, 9H).

(405) LCMS: m/z 486.2 (M+H).sup.+ (ES.sup.+).

Example 19: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfonimidamide

(406) ##STR00173##

Step A: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide

(407) ##STR00174##

(408) To a solution of 1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide (intermediate L2) (0.07 g, 369.91 μmol, 1 eq) in THF (2 mL) was added t-BuONa (43 mg, 443.89 μmol, 1.2 eq) at 25° C. The mixture was stirred for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate R4) (127 mg, 443.89 μmol, 1.2 eq) was added. The mixture was heated to 70° C., stirred for another 0.1 hour and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (basic condition, 0.1% NH.sub.3.H.sub.2O in water/MeCN) to give the title compound (0.09 g, 50% yield, 97% purity on LCMS) as a white solid.

(409) .sup.1H NMR (CDCl.sub.3): δ 7.89 (s, 1H), 7.66 (br s, 1H), 7.46 (s, 1H), 7.05 (d, 1H), 6.84-6.80 (m, 2H), 6.63 (s, 1H), 6.46-6.41 (m, 1H), 4.12-4.00 (m, 2H), 3.99-3.66 (m, 4H), 3.19-3.12 (m, 1H) and 1.25-1.04 (m, 9H).

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

Step B: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfonimidamide

(411) ##STR00175##

(412) To a solution of N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide (0.09 g, 189.26 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (29 mg, 189.26 μmol, 1 eq) under N.sub.2 atmosphere. Then the mixture was stirred for 0.5 hour. This solution was added dropwise over 10 minutes at −70° C. to a solution of ammonia in THF (5 mL), which had been prepared by bubbling NH.sub.3 gas into THF (5 mL) at −70° C. for 5 minutes. After stirring for 25 minutes, the mixture was warmed to 25° C. for 2 hours and then concentrated in vacuo. The residue was purified by prep-TLC (dichloromethane:methanol=10:1) and then purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.04% NH.sub.3.H.sub.2O+10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 23%-53%, 10 min) to give the title compound (4.45 mg, 5% yield, 100% purity on LCMS) as a white solid.

(413) .sup.1H NMR (DMSO-d.sub.6): δ 8.11 (d, 1H), 7.95 (br s, 1H), 7.74 (d, 1H), 7.23 (br s, 2H), 7.13 (dd, 1H), 6.98 (d, 1H), 6.94 (dd, 1H), 6.81 (s, 1H), 6.41 (s, 1H), 4.72 (d, 1H), 4.10-4.08 (m, 2H), 4.05-3.99 (m, 1H), 3.91 (s, 3H), 3.25-3.19 (m, 1H), 1.19-1.14 (m, 6H) and 1.08 (d, 3H).

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

Example 20: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(1-hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfonimidamide

(415) ##STR00176##

Step A: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(1-hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfinamide

(416) ##STR00177##

(417) To a solution of 5-(1-hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfinamide (intermediate L7) (855 mg, 4.52 mmol, 1 eq) in THF (10 mL) was added t-BuONa (434 mg, 4.52 mmol, 1 eq). The reaction mixture was stirred at 20° C. for 10 minutes. To the above mixture was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate R1) (900 mg, 4.52 mmol, 1 eq). The resulting mixture was stirred at 20° C. for 1 hour and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% NH.sub.3.H.sub.2O)-MeCN) to give the title compound (450 mg, 26% yield) as a yellow solid.

(418) .sup.1H NMR (DMSO-d.sub.6): δ 9.19 (br s, 1H), 6.90 (s, 1H), 6.71 (s, 1H), 5.47-5.46 (m, 1H), 4.86-4.83 (m, 1H), 3.88 (s, 3H), 2.80 (t, 4H), 2.71 (t, 4H), 1.98-1.96 (m, 4H) and 1.46-1.43 (m, 3H).

(419) LCMS: m/z 389.2 (M+H).sup.+ (ES.sup.+).

Step B: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(1-hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfonimidamide

(420) ##STR00178##

(421) To a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(1-hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfinamide (310 mg, 797.98 μmol, 1 eq) in THF (6 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (110 mg, 718.18 μmol, 0.9 eq). The mixture was stirred at 20° C. for 30 minutes. Then the mixture was added dropwise over 10 minutes at −70° C. to a saturated solution of ammonia in THF (10 mL), which had been prepared by bubbling NH.sub.3 gas (15 psi) into THF (10 mL) at −70° C. for 5 minutes. After stirring for 15 minutes, the mixture was warmed to 20° C. for 2 hours and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% NH.sub.3.H.sub.2O)-MeCN) to give the title compound (113 mg, 35% yield) as a white solid.

(422) .sup.1H NMR (DMSO-d.sub.6): δ 8.28 (br s, 1H), 7.39 (br s, 2H), 6.86 (s, 1H), 6.53 (s, 1H), 5.49 (d, 1H), 4.87-4.83 (m, 1H), 3.88 (s, 3H), 2.78 (t, 4H), 2.69-2.65 (m, 4H), 1.97-1.92 (m, 4H) and 1.42 (d, 3H).

(423) LCMS: m/z 404.2 (M+H).sup.+ (ES.sup.+).

Example 21: 5-(1-Chloroethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonimidamide

(424) ##STR00179##

(425) To a solution of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(1-hydroxyethyl)-1-methyl-1H-pyrazole-3-sulfonimidamide (example 20) (80 mg, 198.27 μmol, 1 eq) in THF (2 mL) was added SOCl.sub.2 (35 mg, 297.40 μmol, 21.57 μL, 1.5 eq) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then concentrated in vacuo to give the title compound (95 mg, crude) as a yellow solid, which was used to prepare the compound of example 22 without further purification.

(426) LCMS: m/z 422.2 (M+H).sup.+ (ES.sup.+).

Example 22: 5-(1-(Azetidin-1-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonimidamide

(427) ##STR00180##

(428) To a solution of 5-(1-chloroethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonimidamide (example 21) (84 mg, 198.27 μmol, 1 eq) in THF (2 mL) was added azetidine (68 mg, 1.19 mmol, 80.28 μL, 6 eq). The reaction mixture was stirred at 35° C. for 7 hours and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 25%-55%, 11 min) to give the title compound (13.9 mg, 16% yield, 98% purity on LCMS) as a white solid.

(429) .sup.1H NMR (DMSO-d.sub.6): δ 8.30 (br s, 1H), 7.23 (br s, 2H), 6.86 (s, 1H), 6.48 (s, 1H), 3.90 (s, 3H), 3.62-3.60 (m, 1H), 3.11-3.06 (m, 4H), 2.77 (t, 4H), 2.67 (t, 4H), 1.94-1.90 (m, 6H) and 1.12 (d, 3H).

(430) LCMS: m/z 443.3 (M+H).sup.+ (ES.sup.+).

Example 23: 5-(Azetidin-1-ylmethyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonimidamide

(431) ##STR00181##

Step A: 5-(Azetidin-1-ylmethyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfinamide

(432) ##STR00182##

(433) To a solution of 5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazole-3-sulfinamide (intermediate L8) (270 mg, 1.02 mmol, 1 eq) in THF (5 mL) was added t-BuONa (98 mg, 1.02 mmol, 1 eq). The mixture was stirred at 20° C. for 10 minutes. Then 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (intermediate R5) (226 mg, 1.02 mmol, 1 eq) was added. The resulting mixture was stirred at 20° C. for 20 minutes and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% NH.sub.3.H.sub.2O)-MeCN) to give the title compound (250 mg, 50% yield, 89% purity on LCMS) as a white solid.

(434) .sup.1H NMR (DMSO-d.sub.6): δ 6.88 (d, 2H), 6.41 (s, 1H), 3.85 (s, 3H), 3.58 (s, 2H), 3.26-3.16 (m, 6H), 2.07-2.02 (m, 2H) and 1.16-1.13 (m, 12H).

(435) LCMS: m/z 458.2 (M+Na).sup.+ (ES.sup.+).

Step B: 5-(Azetidin-1-ylmethyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonimidamide

(436) ##STR00183##

(437) To a solution of 5-(azetidin-1-ylmethyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfinamide (170 mg, 390.30 μmol, 1 eq) in THF (2 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (54 mg, 351.27 μmol, 0.9 eq). The reaction mixture was stirred at 20° C. for 30 minutes. Then the above mixture was added dropwise over 10 minutes at −70° C. to a saturated solution of ammonia in THF (5 mL), which had been prepared by bubbling NH.sub.3 gas (15 psi) into THF (10 mL) at −70° C. for 5 minutes. After stirring for 15 minutes, the reaction mixture was warmed to 20° C. for 2 hours and then concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH=10:1) and then purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 25%-55%, 11 min) to give the title compound (12.2 mg, 7% yield, 100% purity on LCMS) as a white solid.

(438) .sup.1H NMR (DMSO-d.sub.6): δ 7.82 (br s, 1H), 7.19 (br s, 2H), 6.82 (d, 2H), 6.47 (s, 1H), 3.83 (s, 3H), 3.57 (s, 2H), 3.20-3.16 (m, 6H), 2.03-1.99 (m, 2H) and 1.12-1.09 (m, 12H).

(439) LCMS: m/z 451.1 (M+H).sup.+ (ES.sup.+).

Example 24: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(440) ##STR00184##

Step A: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide

(441) ##STR00185##

(442) To a solution of 1-iso-propyl-1H-pyrazole-3-sulfinamide (intermediate L1) (100 mg, 577.25 μmol, 1 eq) in THF (6 mL) was added t-BuONa (55 mg, 577.25 μmol, 1 eq) and 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate R6) (147 mg, 577.25 μmol, 1 eq). The reaction mixture was stirred at 10° C. for 1.5 hours and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/MeCN) to give the title compound (170 mg, yield 68%, 98.9% purity on LCMS) as an off-white solid.

(443) .sup.1H NMR (DMSO-d.sub.6): δ 9.68 (br s, 1H), 8.61 (d, 2H), 8.00 (d, 1H), 7.37 (d, 2H), 7.07 (d, 1H), 6.67 (d, 1H), 4.64-4.55 (m, 1H), 3.00 (t, 2H), 2.86 (t, 2H), 2.15-2.07 (m, 2H) and 1.45 (d, 6H).

(444) LCMS: m/z 428.2 (M+H).sup.+ (ES.sup.+).

Step B: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-H-pyrazole-3-sulfonimidamide

(445) ##STR00186##

(446) To a solution of N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide (160 mg, 374.27 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (57 mg, 374.27 μmol, 1 eq). The reaction mixture was stirred at 10° C. for 30 minutes. Then the reaction mixture was added at −75° C. into a NH.sub.3/THF solution, which had been prepared by bubbling NH.sub.3 into THF (30 mL) at −75° C. for 10 minutes. Then the reaction mixture was stirred for another 20 minutes, slowly warmed to 10° C., stirred at 10° C. for 1 hour and then concentrated in vacuo. The residue was purified prep-TLC (SiO.sub.2, DCM:MeOH=1:0 to 10:1) and then purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.4HCO.sub.3 v/v); B: MeCN]; B %: 23%-53%, 10 min) to give the title compound (28.09 mg, yield 17%, 100% purity on LCMS) as a white solid.

(447) 1H NMR (DMSO-d.sub.6): δ 8.57-8.54 (m, 2H), 8.27 (br s, 1H), 7.91 (d, 1H), 7.41-7.36 (m, 4H), 6.98 (d, 1H), 6.50 (s, 1H), 4.64-4.53 (m, 1H), 2.95 (t, 2H), 2.81-2.77 (m, 2H), 2.09-2.02 (m, 2H) and 1.46-1.41 (m, 6H).

(448) LCMS: m/z 443.2 (M+H).sup.+ (ES.sup.+).

Example 25: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfonimidamide

(449) ##STR00187##

Step A: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide

(450) ##STR00188##

(451) A solution of 1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide (intermediate L2) (160 mg, 845.51 μmol, 1 eq) and t-BuONa (81 mg, 845.51 μmol, 1 eq) in THF (3 mL) was stirred at 25° C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate R6) (215 mg, 845.51 μmol, 1 eq) was added. The resulting mixture was stirred at 25° C. for 10 minutes and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.05% NH.sub.3.H.sub.2O, H.sub.2O/MeCN) to give the title compound (150 mg, 40% yield, 99% purity on LCMS) as a red solid.

(452) .sup.1H NMR (DMSO-d.sub.6): δ 8.54 (d, 2H), 7.70 (s, 1H), 7.41 (d, 2H), 6.98 (d, 1H), 6.42 (s, 1H), 4.95 (br s, 1H), 4.06-3.94 (m, 3H), 2.96 (t, 2H), 2.87 (t, 2H), 2.10-2.04 (m, 2H) and 1.04 (d, 3H).

(453) LCMS: m/z 444.3 (M+H).sup.+ (ES.sup.+).

Step B: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfonimidamide

(454) ##STR00189##

(455) To a solution of N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfinamide (150 mg, 338.22 μmol, 1 eq) in THF (2 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (47 mg, 304.40 μmol, 0.9 eq). The reaction mixture was stirred at 20° C. for 30 minutes. Then the reaction mixture was added dropwise over 10 minutes at −70° C. to a saturated solution of ammonia in THF (8 mL), which had been prepared by bubbling NH.sub.3 gas (15 psi) into THF (10 mL) at −70° C. for 5 minutes. After stirring for 15 minutes, the reaction mixture was warmed to 20° C., stirred for 2 hours and then concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH=10:1) and then further purified by prep-HPLC (column: Waters Xbridge 150 mm*25 mm*5 μm; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 10%-30%, 8 min) to give the title compound (27.61 mg, 18% yield, 99% purity on LCMS) as a white solid.

(456) .sup.1H NMR (DMSO-d.sub.6): δ 8.55 (d, 2H), 8.28 (br s, 1H), 7.79 (s, 1H), 7.49-7.30 (m, 4H), 6.98 (d, 1H), 6.47 (s, 1H), 5.02 (s, 1H), 4.08-4.00 (m, 2H), 3.99-3.95 (m, 1H), 2.94 (t, 2H), 2.88-2.70 (m, 2H), 2.07-2.01 (m, 2H) and 1.05 (dd, 3H).

(457) LCMS: m/z 459.2 (M+H).sup.+ (ES.sup.+).

Example 26: 4-Chloro-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(458) ##STR00190##

Step A: 4-Chloro-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide

(459) ##STR00191##

(460) To a solution of 4-chloro-1-isopropyl-1H-pyrazole-3-sulfinamide (intermediate L6) (150 mg, 722.26 μmol, 1 eq) in THF (3 mL) was added t-BuONa (69 mg, 722.26 μmol, 1 eq). The mixture was stirred at 20° C. for 10 minutes. To the above mixture was added a solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate R6) (184 mg, 722.26 μmol, 1 eq) in THF (2 mL). The resulting mixture was stirred at 20° C. for 20 minutes and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (water (0.05% NH.sub.3.H.sub.2O)-MeCN) to give the title compound (260 mg, 76% yield, 97% purity on LCMS) as a yellow solid.

(461) .sup.1H NMR (DMSO-d.sub.6): δ 9.87 (br s, 1H), 8.59 (d, 2H), 8.33-8.30 (m, 2H), 7.37 (dd, 2H), 7.08 (d, 1H), 4.61-4.53 (m, 1H), 2.99 (t, 2H), 2.85 (t, 2H), 2.13-2.09 (m, 2H) and 1.44 (d, 6H).

(462) LCMS: m/z 462.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Chloro-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

(463) ##STR00192##

(464) Toa solution of 4-chloro-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfinamide (200 mg, 432.96 μmol, 1 eq) in THF (2 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (60 mg, 389.66 μmol, 0.9 eq). The mixture was stirred at 20° C. for 30 minutes. Then the reaction mixture was added dropwise over 10 minutes at −70° C. to a saturated solution of ammonia in THF (8 mL), which had been prepared by bubbling NH.sub.3 gas (15 psi) into THF (10 mL) at −70° C. for 5 minutes. After stirring for 15 minutes, the reaction mixture was warmed to 20° C. for 2 hours and then concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH=10:1) and then further purified by prep-HPLC (column: Xtimate C18 250 mm*50 mm*10 μm; mobile phase: [A: water (0.05% ammonia hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (33.6 mg, 16% yield, 99% purity on LCMS) as a white solid.

(465) .sup.1H NMR (DMSO-d.sub.6): δ 8.56-8.53 (m, 2H), 8.24 (br s, 1H), 8.19 (s, 1H), 7.43 (br s, 2H), 7.38 (d, 2H), 6.99 (d, 1H), 4.53-4.47 (m, 1H), 2.95 (t, 2H), 2.85-2.75 (m, 2H), 2.07-2.02 (m, 2H) and 1.42 (d, 6H).

(466) LCMS: m/z 477.2 (M+H).sup.+ (ES.sup.+).

Examples 27 and 28: (R)-1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide and (S)-1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide

(467) ##STR00193##

(468) Racemic 1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide (example 14) (24.9 mg) was separated by preparative chiral HPLC (Gilson, basic (0.1% ammonium bicarbonate), Chiralpak® IC (Daicel Ltd.) column (2×25 cm), flow rate 15 mL/min eluting with 40% MeCN in 10 mM aqueous ammonium bicarbonate (isocratic)) to afford (R)-1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide (example 27) (9.3 mg, 37% yield) as a white solid and (S)-1-isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide (example 28) (9.0 mg, 36% yield), also as a white solid.

Example 27: (R)-1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide

(469) .sup.1H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.11 (d, J=5.3 Hz, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 6.94 (dd, J=5.2, 1.5 Hz, 1H), 6.77 (s, 1H), 6.49 (d, J=2.3 Hz, 1H), 5-79 (br s, 2H), 4.58 (sept, J=6.7 Hz, 1H), 3.87 (s, 3H), 2.90 (t, J=7.5 Hz, 2H), 2.80-2.68 (m, 2H), 1.97 (p, J=7.6 Hz, 2H), 1.44 (d, J=6.7 Hz, 6H).

(470) LCMS; m/z 455.2 (M+H).sup.+ (ES.sup.+).

Example 28: (S)-1-Isopropyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide

(471) .sup.1H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.11 (d, J=5.3 Hz, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 6.94 (dd, J=5.2, 1.5 Hz, 1H), 6.77 (s, 1H), 6.49 (d, J=2.3 Hz, 1H), 5.79 (br s, 2H), 4.58 (sept, J=6.7 Hz, 1H), 3.87 (s, 3H), 2.90 (t, J=7.5 Hz, 2H), 2.80-2.68 (m, 2H), 1.97 (p, J=7.6 Hz, 2H), 1.44 (d, J=6.7 Hz, 6H).

(472) LCMS; m/z 455.2 (M+H).sup.+ (ES.sup.+); 453.1 (M−H).sup.− (ES.sup.−).

Examples—Biological Studies

(473) NLRP3 and Pyroptosis

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

(475) THP-1 Cells: Culture and Preparation

(476) 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.

(477) THP-1 Cells Pyroptosis Assay

(478) 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)

(479) 96-Well Plate Map

(480) TABLE-US-00001 1 2 3 4 5 6 7 8 9 10 11 12 A High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low B High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low C High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low D High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low E High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low F High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low G High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low H High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low High MCC950 (10 uM) Low Drug free control Compound 8-point half-log dilution

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

(482) Human Whole Blood IL1β Release Assay

(483) 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.

(484) 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 AL220F-5000) 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

(485) The results of the human whole blood assay are summarised in Table 1 below as HWB IC.sub.50.

(486) TABLE-US-00002 TABLE 1 NLRP3 inhibitory activity (≤0.1 μm = ‘+++++’, ≤0.5 μm = ‘++++’, ≤1 μm = ‘+++’, ≤5 μm = ‘++’, ≤10 μm = ‘+’, not determined = ‘ND’) Example No Structure THP IC.sub.50 HWB IC.sub.50 1 ++++ ++ 2 +++++ ++ 3 +++++ ++++ 6 + ND 7 ++ ++ 10 ++++ ++++ 11 00 +++++ +++ 12 01 +++++ ++++ 13 02 +++++ +++ 14 03 +++++ ++++ 15 04 +++ +++ 16 05 +++++ +++ 17 06 +++++ ++++ 18 07 ++++ ++++ 19 08 +++++ +++ 22 09 +++++ ++++ 23 0 +++++ ++ 24 +++++ ++++ 25 +++++ ++++ 26 +++++ ++++ 27 +++++ ++++ 28 +++ ++

(487) PK Protocol

(488) Pharmacokinetic parameters were determined in male Sprague Dawley rats (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.

(489) For intravenous administration, compounds were formulated as a solution in DMSO:PBS [10:90] in 2 mL/kg dosing volume and administered via tail vein.

(490) Serial blood samples (about 200 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 (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 Phoenix WinNonlin 6.3 software.

(491) TABLE-US-00003 TABLE 2 PK data (intravenous administration) Example Dose AUC T.sub.1/2 V.sub.dss Cl No (mg/kg) (ng•hr/mL) (hr) (L/kg) (mL/min/kg) 3 1 2248.6 2.7 0.75 7.4 11 1 2718.2 1.0 0.45 6.1 14 1 1738.5 0.9 0.34 9.6

(492) As is evident from the results presented in Table 1, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and in the human whole blood assay.

(493) As is evident from the results presented in Table 2, 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.

(494) 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.