NOVEL SULFONAMIDE CARBOXAMIDE COMPOUNDS

Abstract

The present invention relates to sulfonylureas and sulfonylthioureas comprising as-membered nitrogen-containing heteroaryl ring attached to the sulfonyl group, wherein the heteroaryl ring is substituted with at least one group containing an oxygen atom, and wherein said oxygen atom is attached to the heteroaryl ring via at least two other atoms. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP3.

##STR00001##

Claims

1. A compound of formula (I): ##STR00344## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is selected from O or S; W, X, Y and Z are each independently N, O, S, NH or CH, wherein at least one of W, X, Y and Z is N or NH; L is a saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbylene group may optionally be substituted, and wherein the hydrocarbylene group may optionally include one or more heteroatoms N, O or S in its carbon skeleton; R.sup.1 is hydrogen or 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; optionally L and R.sup.1 together with the oxygen atom to which they are attached may form a 3- to 12-membered saturated or unsaturated cyclic group, wherein the cyclic group may optionally be substituted; optionally R.sup.1O-L-, and any two adjacent W, X, Y or Z, may together form a 3- to 12-membered saturated or unsaturated cyclic group fused to ring A, wherein the cyclic group fused to ring A may optionally be substituted; R.sup.2 is a cyclic group substituted at the -position, wherein R.sup.2 may optionally be further substituted; each R.sup.3 is independently a halo, OH, NO.sub.2, NH.sub.2, N.sub.3, SH, or 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; m is 0, 1, 2 or 3; and optionally any R.sup.3, and any two adjacent W, X, Y or Z, may together form a 3- to 12-membered saturated or unsaturated cyclic group fused to ring A, wherein the cyclic group fused to ring A may optionally be substituted; provided that any atom of L or R.sup.1 that is directly attached to W, X, Y or Z is not the same atom of L or R that is directly attached to the oxygen atom of R.sup.1O-L-; and provided that the compound is not: ##STR00345##

2. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein ring A is monocyclic.

3. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein: (i) W, X, Y and Z are each independently N, NH or CH; and/or (ii) at least two of W, X, Y and Z are N or NH.

4. (canceled)

5. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein R.sup.1O-L- is directly attached to a ring nitrogen atom of ring A.

6. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein (i) the group R.sup.1O-L-, including any optional substituents, contains only atoms selected from the group consisting of carbon, hydrogen, oxygen and halogen atoms; and/or (ii) the oxygen atom of R.sup.1O-L- is not directly attached to a sp.sup.2 hybridised atom.

7. (canceled)

8. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein the group ##STR00346## contains from 8 to 16 atoms other than hydrogen or halogen.

9. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein (i) Q is O; and/or (ii) each R.sup.3 is independently selected from halo; CN; NO.sub.2; N.sub.3; R.sup.; OH; OR.sup.; R.sup.-halo; R.sup.CN; R.sup.NO.sub.2; R.sup.N.sub.3; R.sup.R.sup.; R.sup.OH; R.sup.OR.sup.; SH; SR.sup.; SOR.sup.; SO.sub.2H; SO.sub.2R.sup.; SO.sub.2NH.sub.2; SO.sub.2NHR.sup.; SO.sub.2N(R.sup.).sub.2; R.sup.SH; R.sup.SR.sup.; R.sup.SOR.sup.; R.sup.SO.sub.2H; R.sup.SO.sub.2R.sup.; R.sup.SO.sub.2NH.sub.2; R.sup.SO.sub.2NHR.sup.; R.sup.SO.sub.2N(R.sup.).sub.2; NH.sub.2; NHR.sup.; N(R.sup.).sub.2; R.sup.NH.sub.2; R.sup.NHR.sup.; R.sup.N(R.sup.).sub.2; CHO; COR.sup.; COOH; COOR.sup.; OCOR.sup.; R.sup.CHO; R.sup.COR.sup.; R.sup.COOH; R.sup.COOR.sup.; or R.sup.OCOR.sup.; wherein each R.sup. 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. groups; and wherein each R.sup. is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group, and wherein any R.sup. may optionally be substituted with one 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, CCH, oxo (O), or 4- to 6-membered heterocyclic group.

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

11. (canceled)

12. (canceled)

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

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

15. (canceled)

16. (canceled)

17. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein: Q is O; W, X, Y and Z are each independently N, NH or CH, wherein at least one of W, X, Y and Z is N or NH; R.sup.1O-L- is directly attached to X or Y; m is 0, 1 or 2; each R.sup.3 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, wherein any 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 may optionally be substituted with one or more halo groups; R.sup.2 is a phenyl or a 5- or 6-membered heteroaryl group, wherein: (i) the phenyl or 5- or 6-membered heteroaryl group is substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the , positions and which is optionally substituted with one or more halo groups; and the phenyl or 5- or 6-membered heteroaryl group is further substituted at the position with a substituent selected from R.sup.4, OR.sup.4 and COR.sup.4, wherein R.sup.4 is 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 R.sup.4 is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted with one or two substituents independently selected from halo, NO.sub.2, CN, COOR.sup.45, CONH.sub.2, CONHR.sup.45 or CON(R.sup.45).sub.2, wherein each R.sup.45 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group; or (ii) the phenyl or 5- or 6-membered heteroaryl group is substituted with a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the , positions and which is optionally substituted with one or more halo groups; and the phenyl or 5- or 6-membered heteroaryl group is substituted with a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the , positions and which is optionally substituted with one or more halo groups; and optionally the phenyl group is further substituted with a substituent selected from halo, NO.sub.2, CN, COOR.sup.45, CONH.sub.2, CONHR.sup.45 or CON(R.sup.45).sub.2, wherein each R.sup.45 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group; or (iii) the phenyl or 5- or 6-membered heteroaryl group is substituted at the -position with a monovalent heterocyclic group or a monovalent aromatic group selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group may optionally be substituted with one or two substituents independently selected from halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, R.sup.42OR.sup.43, R.sup.42N(R.sup.43).sub.2, R.sup.42CN or R.sup.42CCR.sup.43, and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to the -ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein each R.sup.42 is independently selected from a bond or a C.sub.1-C.sub.3 alkylene group; and each R.sup.43 is independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl group; and the phenyl or 5- or 6-membered heteroaryl group is further substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the , positions and which is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted with one or two substituents independently selected from halo, NO.sub.2, CN, COOR.sup.45, CONH.sub.2, CONHR.sup.45 or CON(R.sup.45).sub.2, wherein each R.sup.45 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group; and L is an alkylene group, wherein the alkylene group may be straight-chained or branched, wherein the alkylene group may optionally include one or two heteroatoms N or O in its carbon skeleton, and wherein the alkylene group may be optionally substituted with (i) one or more substituents independently selected from halo and OH, and/or (ii) a divalent bridging substituent selected from O and C.sub.1-C.sub.3 alkylene, wherein the C.sub.1-C.sub.3 alkylene group may be straight-chained or branched, wherein the C.sub.1-C.sub.3 alkylene group may optionally be substituted with one or more substituents independently selected from halo and OH, and wherein the C.sub.1-C.sub.3 alkylene group may optionally include one heteroatom N or O in its carbon skeleton; and R.sup.i is hydrogen or a C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl group, wherein the C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl group is optionally substituted with one or more substituents independently selected from halo, OH and NH.sub.2; provided that L contains from 2 to 8 atoms other than hydrogen or halogen, and that the atom of L that is directly attached to X or Y is a carbon atom and is not the same atom of L that is directly attached to the oxygen atom of R.sup.1O-L-; or R.sup.1O-L- has the formula R.sup.10-L.sup.2-, wherein: R.sup.10 is a 4- to 6-membered saturated monocyclic group, wherein R.sup.10 includes at least one oxygen atom in the ring structure, wherein R.sup.10 optionally includes one or two additional heteroatoms N or O in the ring structure, wherein R.sup.10 is optionally substituted with one or more substituents independently selected from halo, OH, NH.sub.2, R.sup.20, OR.sup.20, NHR.sup.2 and N(R.sup.2).sub.2, wherein each R.sup.2 is independently selected from a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.4 cycloalkyl or C.sub.3-C.sub.4 halocycloalkyl group, or any two R.sup.20 directly attached to the same nitrogen atom may together form a C.sub.2-C.sub.5 alkylene or C.sub.2-C.sub.5 haloalkylene group; and L.sup.2 is a bond or a (C(R.sup.15).sub.2).sub.x group, wherein x is 1 or 2, and each R.sup.15 is independently selected from hydrogen or a halo, methyl or halomethyl group, or any two R.sup.15 directly attached to the same carbon atom may together form a C.sub.2 alkylene or C.sub.2 haloalkylene group; provided that the atom of R.sup.10-L.sup.2- that is directly attached to X or Y is a carbon atom and at least one oxygen atom in the ring structure of R.sup.10 is not directly attached to the same atom of R.sup.10-L.sup.2- that is directly attached to X or Y.

18. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein the compound is selected from the group consisting of: ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370##

19. (canceled)

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

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

22. (canceled)

23. The method as claimed in claim 21, 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.

24. The method as claimed in claim 23, wherein the disease, disorder or condition is selected from: (i) inflammation; (ii) an infection; (iii) a cardiovascular disease; (iv) a respiratory disease; (v) a liver disease; (vi) a renal disease; (vii) an ocular disease; (viii) a skin disease; (ix) a psychological disorder; (x) a lymphatic condition; and/or (xi) any disease, disorder or condition in which an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

25. The method as claimed in claim 21, 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).

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

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

28. The method as claimed in claim 21, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

Description

EXAMPLESCOMPOUND SYNTHESIS

[0513] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0514] 2-MeTHF 2-methyltetrahydrofuran [0515] Ac.sub.2O acetic anhydride [0516] AcOH acetic acid [0517] aq aqueous [0518] Boc tert-butyloxycarbonyl [0519] br broad [0520] Cbz carboxybenzyl [0521] CDI 1,1-carbonyl-diimidazole [0522] conc concentrated [0523] d doublet [0524] DABCO 1,4-diazabicyclo[2.2.2]octane [0525] DCE 1,2-dichloroethane, also called ethylene dichloride [0526] DCM dichloromethane [0527] DIPEA N,N-diisopropylethylamine, also called Hnig's base [0528] DMA dimethylacetamide [0529] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0530] DME dimethoxyethane [0531] DMF N,N-dimethylformamide [0532] DMSO dimethyl sulfoxide [0533] eq or equiv equivalent [0534] (ES+) electrospray ionization, positive mode [0535] Et ethyl [0536] EtOAc ethyl acetate [0537] EtOH ethanol [0538] h hour(s) [0539] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0540] HPLC high performance liquid chromatography [0541] LC liquid chromatography [0542] m multiplet [0543] m-CPBA 3-chloroperoxybenzoic acid [0544] Me methyl [0545] MeCN acetonitrile [0546] MeOH methanol [0547] (M+H)+ protonated molecular ion [0548] MHz megahertz [0549] min minute(s) [0550] MS mass spectrometry [0551] Ms mesyl, also called methanesulfonyl [0552] MsCl mesyl chloride, also called methanesulfonyl chloride [0553] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0554] m/z mass-to-charge ratio [0555] NaO.sup.tBu sodium tert-butoxide [0556] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0557] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0558] NMP N-methylpyrrolidine [0559] NMR nuclear magnetic resonance (spectroscopy) [0560] Pd(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o) [0561] Pd(dppf)Cl.sub.2 [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [0562] PE petroleum ether [0563] Ph phenyl [0564] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0565] prep-HPLC preparative high performance liquid chromatography [0566] prep-TLC preparative thin layer chromatography [0567] PTSA p-toluenesulfonic acid [0568] q quartet [0569] RP reversed phase [0570] RT room temperature [0571] s singlet [0572] Sept septuplet [0573] sat saturated [0574] SCX solid supported cation exchange (resin) [0575] t triplet [0576] T3P propylphosphonicanhydride [0577] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0578] TEA triethylamine [0579] TFA 2,2,2-trifluoroaceticacid [0580] THF tetrahydrofuran [0581] TLC thin layer chromatography [0582] wt % weight percent or percent by weight

Experimental Methods

Nuclear Magnetic Resonance

[0583] NMR spectra were recorded at 300, 400 or 500 MHz. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Spectra were recorded using one of the following machines: [0584] a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe, [0585] a Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control, [0586] a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe, [0587] an Agilent VNMRS 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, indirect detection probe and direct drive console including PFG module, or [0588] an Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

[0589] LC-MS

[0590] LC-MS Methods: Using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200G6110A, Agilent 1200 LC & Agilent 6110 MSD. Mobile Phase: A: 0.025% NH.sub.3H.sub.2 in water (v/v); B: acetonitrile. Column: Kinetex EVO C18 2.130 mm, 5 m.

Reversed Phase HPLC Conditions for the LCMS Analytical Methods

[0591] Methods 1a and 1b:

[0592] Waters Xselect CSH C18 XP column (4.630 mm, 2.5 m) at 40 C.; flow rate 2.5-4.5 mL min-1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 1a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 1b) over 4 min employing UV detection at 254 nm. Gradient information: 0-3.00 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 3.00-3.01 min, held at 5% water-95% acetonitrile, flow rate increased to 4.5 mL min.sup.1; 3.01-3.50 min, held at 5% water-95% acetonitrile; 3.50-3.60 min, returned to 95% water-5% acetonitrile, flow rate reduced to 3.50 mL min.sup.1; 3.60-3.90 min, held at 95% water-5% acetonitrile; 3.90-4.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 2.5 mL min.sup.1.

[0593] Method 1c:

[0594] Agilent 1290 series with UV detector and HP 6130 MSD mass detector using Waters XBridge BEH C18 XP column (2.150 mm, 2.5 m) at 35 C.; flow rate 0.6 mL/min; mobile phase A: ammonium acetate (10 mM); water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM); water/MeOH/acetonitrile (100:540:360); over 4 min employing UV detection at 215 and 238 nm. Gradient information: 0-0.5 min, held at 80% A-20% B; 0.5-2.0 min, ramped from 80% A-20% B to 100% B.

Reversed Phase HPLC Conditions for the UPLC Analytical Methods

[0595] Methods 2a and 2b:

[0596] Waters BEH C18 (2.130 mm, 1.7 m) at 40 C.; flow rate 0.77 mL min-1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 2a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 2b) over 3 min employing UV detection at 254 nm. Gradient information: 0-0.11 min, held at 95% water-5% acetonitrile, flow rate 0.77 mL min.sup.1; 0.11-2.15 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 2.15-2.49 min, held at 5% water-95% acetonitrile, flow rate 0.77 mL min.sup.1; 2.49-2.56 min, returned to 95% water-5% acetonitrile; 2.56-3.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 0.77 mL min.sup.1.

Preparative Reversed Phase HPLC General Methods

[0597] Method 1 (Acidic Preparation):

[0598] Waters X-Select CSH column C18, 5 m (1950 mm), flow rate 28 mL min-1 eluting with a H.sub.2O-MeCN gradient containing 0.1% v/v formic acid over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 20% MeCN; 0.2-5.5 min, ramped from 20% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0599] Method 2 (Basic Preparation):

[0600] Waters X-Bridge Prep column C18.5 m (1950 mm), flow rate 28 mL min-1 eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 10% MeCN; 0.2-5.5 min, ramped from 10% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0601] Method 3:

[0602] Phenomenex Gemini column, 10 m (15025 mm), flow rate=25 mL/min eluting with a water-acetonitrile gradient containing 0.04% NH.sub.3 at pH 10 over 9 minutes using UV detection at 220 and 254 nm. Gradient information: 0-9 minutes, ramped from 8% to 35% acetonitrile; 9-9.2 minutes, ramped from 35% to 100% acetonitrile; 9.2-15.2 minutes, held at 100% acetonitrile.

[0603] Method 4:

[0604] Revelis C18 reversed-phase 12 g cartridge [carbon loading 18%; surface area 568 m.sup.2/g; pore diameter 65 Angstrom; pH (5% slurry) 5.1; average particle size 40 m], flow rate=30 mL/min eluting with a water-methanol gradient over 35 minutes using UV detection at 215, 235, 254 and 280 nm. Gradient information: 0-5 minutes, held at 0% methanol; 5-30 minutes, ramped from 0% to 70% methanol; 30-30.1 minutes, ramped from 70% to 100% methanol; 30.1-35 minutes, held at 100% methanol.

Synthesis of Intermediates

Intermediate P1: 1-(Tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide

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

[0605] ##STR00072##

[0606] A solution of BuLi (100 mL, 250 mmol, 2.5M in hexanes) was added slowly to a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (36.2 g, 238 mmol) in THF (500 mL) keeping the temperature below 65 C. The mixture was stirred for 1.5 hours, then sulfur dioxide was bubbled through for 10 minutes. The mixture was allowed to warm to room temperature, the solvent evaporated and the residue triturated with TBME (300 mL) and filtered. The solid was washed with TBME and isohexane and dried to afford the crude title compound (54.89 g, 99%).

[0607] .sup.1H NMR (DMSO-d6) 7.26 (d, J=1.6 Hz, 1H), 6.10 (d, J=1.7 Hz, 1H), 5.99 (dd, J=10.0, 2.5 Hz, 1H), 3.92-3.87 (m, 1H), 3.56-3.49 (m, 1H), 2.25-2.15 (m, 1H), 2.00-1.91 (m, 1H), 1.75-1.69 (m, 1H), 1.66-1.46 (m, 3H).

[0608] LCMS; m/z 215 (MH).sup. (ES.sup.).

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

[0609] ##STR00073##

[0610] NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (20 g, 90 mmol) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 4 hours, quenched with water (100 mL), and then partitioned between DCM (300 mL) and water (200 mL). The organic phase was washed with water (200 mL), dried (MgSO.sub.4), filtered and evaporated to-50 mL. The solution was added to a mixture of bis(4-methoxybenzyl)amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL) cooled in an ice bath. After stirring for 1 hour, the mixture was warmed to room temperature, and then partitioned between DCM (300 mL) and water (250 mL). The organic layer was washed with water (250 mL), aq 1M HCl (2250 mL), water (250 mL), dried (MgSO.sub.4), filtered, and evaporated to afford the crude title compound (41.02 g, 97%) as a brown oil.

[0611] LCMS; m/z 494.2 (M+Na).sup.+ (ES.sup.+).

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

[0612] ##STR00074##

[0613] A mixture of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (41 g, 87 mmol) and aq 1M HCl (30 mL) in THF (300 mL) and MeOH (50 mL) was stirred at room temperature for 18 hours. The solvent was evaporated and the residue partitioned between EtOAc (400 mL) and aq 1M HCl (200 mL). The organic layer was washed with 10% brine (200 mL), dried (MgSO.sub.4), filtered and evaporated. The residue was triturated with TBME, filtered and dried to afford the title compound (24.87 g, 69%) as an off white solid.

[0614] .sup.1H NMR (CDCl.sub.3) 7.88 (d, J=2.4 Hz, 1H), 7.06-7.02 (m, 4H), 6.79-6.75 (m, 4H), 6.63 (d, J=2.4 Hz, 1H), 4.31 (s, 4H), 3.78 (s, 6H). Exchangeable proton not visible.

[0615] LCMS; m/z 388 (M+H).sup.+ (ES.sup.+); 386 (MH).sup. (ES.sup.).

Step D: N,N-Bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide

[0616] ##STR00075##

[0617] Under nitrogen, a mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.5 g, 1.290 mmol) and K.sub.2CO.sub.3 (0.35 g, 2.53 mmol) was suspended in dry acetonitrile (5 mL). 3-Bromotetrahydrofuran (0.25 g, 1.656 mmol) was added in a single portion and the cloudy mixture was heated to 65 C. (bath temperature) for 16 hours. The mixture was diluted with water (5 mL) and extracted with DCM (325 mL). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (461 mg, 77%) as a colourless solid.

[0618] .sup.1H NMR (CDCl.sub.3) 7.51 (d, J=2.4 Hz, 1H), 7.10-7.04 (m, 4H), 6.80-6.75 (m, 4H), 6.67 (d, J=2.4 Hz, 1H), 5.05-4.98 (m, 1H), 4.32 (s, 4H), 4.13-4.06 (m, 1H), 4.04 (d, J=4.6 Hz, 2H), 3.94 (td, J=8.6, 5.4 Hz, 1H), 3.78 (s, 6H), 2.54-2.42 (m, 1H), 2.33-2.23 (m, 1H).

[0619] LCMS; m/z 458 (M+H).sup.+ (ES.sup.+).

Step E: 1-(Tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide

[0620] ##STR00076##

[0621] N,N-Bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (0.455 g, 0.994 mmol) was dissolved in DCM (1 mL) and TFA (2 mL, 26.0 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, suspended in toluene (5 mL) and concentrated again. The residue was dissolved in DCM and purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford the title compound (187 mg, 87%) as a thick colourless oil.

[0622] .sup.1H NMR (DMSO-d6) 7.93 (d, J=2.4 Hz, 1H), 7.41 (s, 2H), 6.61 (d, J=2.4 Hz, 1H), 5.14-5.07 (m, 1H), 4.03-3.96 (m, 2H), 3.91 (dd, J=9.6, 3.5 Hz, 1H), 3.82 (td, J=8.3, 5.6 Hz, 1H), 2.48-2.38 (m, 1H), 2.32-2.23 (m, 1H). LCMS; m/z 218 (M+H).sup.+ (ES.sup.+); 216 (MH).sup. (ES.sup.)

Intermediate P2: 1-(2-Methoxyethyl)-1H-pyrazole-3-sulfonamide

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

[0623] ##STR00077##

[0624] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 1-bromo-2-methoxyethane to afford the title compound (417 mg, 54%) as a pale yellow oil.

[0625] .sup.1H NMR (CDCl.sub.3) 7.55 (d, J=2.3 Hz, 1H), 7.11-7.04 (m, 4H), 6.82-6.76 (m, 4H), 6.65 (d, J=2.3 Hz, 1H), 4.40-4.32 (m, 2H), 4.33 (s, 4H), 3.81 (s, 6H), 3.80-3.72 (m, 2H), 3.37 (s, 3H).

[0626] LCMS; m/z 468.4 (M+Na).sup.+ (ES.sup.+).

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

[0627] ##STR00078##

[0628] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(2-methoxyethyl)-1H-pyrazole-3-sulfonamide to afford the title compound (95 mg, 62%) as a solid.

[0629] LCMS; m/z 206 (M+H).sup.+ (ES.sup.+).

Intermediate P3: 1-((Tetrahydrofuran-2-yl)methyl)-1H-pyrazole-3-sulfonamide

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

[0630] ##STR00079##

[0631] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-(bromomethyl)tetrahydrofuran to afford the title compound (486 mg, 74%) as a colourless oil.

[0632] .sup.1H NMR (CDCl.sub.3) 7.57 (d, J=2.3 Hz, 1H), 7.07-7.01 (m, 4H), 6.79-6.74 (m, 4H), 6.64 (d, J=2.3 Hz, 1H), 4.37-415 (m, 2H), 4.31 (s, 2H), 4.29 (s, 2H), 3.88-3.74 (m, 2H), 3.78 (s, 6H), 2.07-1.96 (m, 1H), 1.94-1.82 (m, 1H), 1.82-1.70 (m, 1H), 1.65-1.51 (m, 2H).

[0633] LCMS; m/z 472 (M+H).sup.+ (ES.sup.+).

Step B: 1-((Tetrahydrofuran-2-yl)methyl)-1H-pyrazole-3-sulfonamide

[0634] ##STR00080##

[0635] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-pyrazole-3-sulfonamide to afford the title compound (215 mg, 87%) as a thick colourless oil.

[0636] .sup.1H NMR (DMSO-d6) 7.83 (d, J=2.3 Hz, 1H), 7.39 (s, 2H), 6.57 (d, J=2.3 Hz, 1H), 4.29-4.13 (m, 3H), 3.78-3.71 (m, 1H), 3.68-3.61 (m, 1H), 2.01-1.90 (m, 1H), 1.86-1.71 (m, 2H), 1.64-1.54 (m, 1H).

[0637] LCMS; m/z 232 (M+H).sup.+ (ES.sup.+); 230 (MH).sup. (ES.sup.).

Intermediate P4: 1-((Tetrahydrofuran-3-yl)methyl)-1H-pyrazole-3-sulfonamide

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

[0638] ##STR00081##

[0639] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 3-(bromomethyl)tetrahydrofuran to afford the title compound (445 mg, 72%) as a colourless oil.

[0640] .sup.1H NMR (DMSO-d6) 8.01 (d, J=2.3 Hz, 1H), 7.07-6.97 (m, 4H), 6.85-6.78 (m, 4H), 6.73 (d, J=2.3 Hz, 1H), 4.22, d, J=9.1 Hz, 2H), 4.21 (s, 4H), 3.77 (td, J=8.1, 5.5 Hz, 1H), 3.72 (s, 6H), 3.70-3.60 (m, 2H), 3.45 (dd, J=8.7, 5.6 Hz, 1H), 2.77-2.64 (m, 1H), 1.96-1.85 (m, 1H), 1.65-1.54 (m, 1H).

[0641] LCMS; m/z 494 (M+Na).sup.+ (ES.sup.+); 470 (MH).sup. (ES.sup.).

Step B: 1-((Tetrahydrofuran-3-yl)methyl)-1H-pyrazole-3-sulfonamide

[0642] ##STR00082##

[0643] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazole-3-sulfonamide to afford the title compound (205 mg, 90%) as a pale brown oil.

[0644] .sup.1H NMR (DMSO-d6) 7.92 (d, J=2.3 Hz, 1H), 7.39 (s, 2H), 6.59 (d, J=2.3 Hz, 1H), 4.17 (d, J=7.5 Hz, 2H), 3.77 (td, J=8.1, 5.6 Hz, 1H), 3.69-3.61 (m, 2H), 3.47 (dd, J=8.7, 5.4 Hz, 1H), 2.77-2.66 (m, 1H), 1.97-1.87 (m, 1H), 1.65-1.55 (m, 1H).

Intermediate P5: 1-(3-Hydroxypropyl)-1H-pyrazole-3-sulfonamide Step A: 1-(3-Hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0645] ##STR00083##

[0646] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 3-bromopropan-1-ol to afford the title compound (355 mg, 60%) as an oil.

[0647] LCMS; m/z 446 (M+Na).sup.+ (ES.sup.+).

Step B: 1-(3-Hydroxypropyl)-1H-pyrazole-3-sulfonamide

[0648] ##STR00084##

[0649] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-(3-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (56 mg, 32%) as a white solid.

[0650] .sup.1H NMR (DMSO-d6) 7.86 (d, J=2.3 Hz, 1H), 7.37 (s, 2H), 6.57 (d, J=2.3 Hz, 1H), 4.63 (t, J=5.1 Hz, 1H), 4.27-4.18 (m, 2H), 3.40 (td, J=6.1, 5.0 Hz, 2H), 1.95-1.92 (m, 2H).

Intermediate P6: 1-(2-Hydroxyethyl)-1H-pyrazole-3-sulfonamide

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

[0651] ##STR00085##

[0652] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-bromoethanol to afford the title compound (3.50 g, 68%) as a yellow oil.

[0653] .sup.1H NMR (DMSO-d6) 7.93 (d, J=2.3 Hz, 1H), 7.03-6.98 (m, 4H), 6.84-6.78 (m, 4H), 6.71 (d, J=2.4 Hz, 1H), 5.01 (t, J=5.2 Hz, 1H), 4.27 (t, J=5.5 Hz, 2H), 4.19 (s, 4H), 3.81-3.74 (m, 2H), 3.72 (s, 6H).

[0654] LCMS; m/z 454.5 (M+Na).sup.+ (ES.sup.+).

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

[0655] ##STR00086##

[0656] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (273 mg, 54%) as a yellow oil.

[0657] .sup.1H NMR (DMSO-d6) 7.84 (d, J=2.3 Hz, 1H), 7.39 (s, 2H), 6.57 (d, J=2.3 Hz, 1H), 4.99 (t, J=5.2 Hz, 1H), 4.21 (t, J=5.5 Hz, 2H), 3.78-3.71 (m, 2H).

[0658] LCMS; m/z 192.0 (M+H).sup.+ (ES.sup.+).

Intermediate P7: 1-((3-Methyloxetan-3-yl)methyl)-1H-pyrazole-3-sulfonamide

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

[0659] ##STR00087##

[0660] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 3-(bromomethyl)-3-methyloxetane to afford the title compound (450 mg, 76%) as a colourless oil.

[0661] LCMS; m/z 472 (M+H).sup.+ (ES.sup.+).

Step B: 1-((3-Methyloxetan-3-yl)methyl)-1H-pyrazole-3-sulfonamide

[0662] ##STR00088##

[0663] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole-3-sulfonamide to afford the title compound (20 mg, 10%) as a white solid.

[0664] .sup.1H NMR (DMSO-d6) 8.28 (d, J=2.8 Hz, 1H), 6.77 (d, J=2.7 Hz, 1H), 5.28 (br s, 2H), 4.51-4.44 (m, 2H), 4.25-4.23 (m, 2H), 3.44 (s, 2H), 1.26 (s, 3H).

Intermediate P8: 1-(2-Hydroxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide Step A: 1-(2-Hydroxy-2-methylpropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0665] ##STR00089##

[0666] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2,2-dimethyloxirane to afford the title compound (6.09 g, 92%) as a thick colourless oil.

[0667] .sup.1H NMR (DMSO-d6) 7.86 (d, J=2.4 Hz, 1H), 7.04-6.97 (m, 4H), 6.82-6.76 (m, 4H), 6.72 (d, J=2.4 Hz, 1H), 4.81 (s, 1H), 4.18 (s, 4H), 4.13 (s, 2H), 3.71 (s, 6H), 1.07 (s, 6H).

[0668] LCMS; m/z 482.5 (M+Na).sup.+ (ES.sup.+).

Step B: 1-(2-Hydroxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide

[0669] ##STR00090##

[0670] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-(2-hydroxy-2-methylpropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (2.48 g, 80%) as a clear crystalline solid.

[0671] .sup.1H NMR (DMSO-d6) 7.76 (d, J=2.3 Hz, 1H), 7.36 (s, 2H), 6.57 (d, J=2.3 Hz, 1H), 4.74 (s, 1H), 4.07 (s, 2H), 1.07 (s, 6H).

[0672] LCMS; m/z 242.3 (M+Na).sup.+ (ES.sup.+).

Intermediate P9: (S)-1-(2-Hydroxypropyl)-1H-pyrazole-3-sulfonamide Step A: (S)-1-(2-Hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0673] ##STR00091##

[0674] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and (S)-2-methyloxirane to afford the title compound (180 mg, 40%) as a clear colourless oil.

[0675] .sup.1H NMR (CDCl.sub.3) 7.50 (d, J=2.3 Hz, 1H), 7.13-7.05 (m, 4H), 6.84-6.75 (m, 4H), 6.69 (d, J=2.3 Hz, 1H), 4.35 (s, 4H), 4.27-3.99 (m, 3H), 3.81 (s, 6H), 1.28 (d, J=6.3 Hz, 3H).

Step B: (S)-1-(2-Hydroxypropyl)-1H-pyrazole-3-sulfonamide

[0676] ##STR00092##

[0677] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from (S)-1-(2-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (58 mg, 69%) as a white solid.

[0678] .sup.1H NMR (DMSO-d6) 7.80 (d, J=2.3 Hz, 1H), 7.37 (br s, 2H), 6.56 (d, J=2.3 Hz, 1H), 4.98 (d, J=4.9 Hz, 1H), 4.15-4.01 (m, 2H), 4.04-3.93 (m, 1H), 1.06 (d, J=6.1 Hz, 3H).

Intermediate P10: 1-(Oxetan-3-yl)-1H-pyrazole-3-sulfonamide

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

[0679] ##STR00093##

[0680] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C), 3-bromooxetane and KI (1 equiv.) to afford the title compound (289 mg, 49%) as a clear colourless oil.

[0681] .sup.1H NMR (CDCl.sub.3) 7.62 (d, J=2.4 Hz, 1H), 7.15-7.10 (m, 4H), 6.83-6.77 (m, 4H), 6.76 (d, J=2.4 Hz, 1H), 5.54-5.46 (m, 1H), 5.08-4.98 (m, 4H), 4.38 (s, 4H), 3.81 (s, 6H).

[0682] LCMS; m/z 466 (M+Na).sup.+ (ES.sup.+); 442 (MH).sup. (ES.sup.).

Step B: 1-(Oxetan-3-yl)-1H-pyrazole-3-sulfonamide

[0683] ##STR00094##

[0684] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(oxetan-3-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (64 mg, 64%) as a white solid.

[0685] .sup.1H NMR (DMSO-d6) 8.04 (d, J=2.4 Hz, 1H), 7.48 (s, 2H), 6.65 (d, J=2.4 Hz, 1H), 5.68-5.64 (m, 1H), 5.00-4.80 (m, 4H).

[0686] LCMS; m/z 204 (M+H).sup.+ (ES.sup.+).

Intermediate P1: (R)-1-(1-Hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

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

[0687] ##STR00095##

[0688] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and (S)-2-bromopropan-1-ol to afford the title compound (410 mg, 70%) as a clear colourless oil.

Step B: (R)-1-(1-Hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

[0689] ##STR00096##

[0690] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from (R)-1-(1-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (110 mg, 41%) as a white solid.

[0691] .sup.1H NMR (DMSO-d6) 7.80 (d, J=2.3 Hz, 1H), 7.37 (s, 2H), 6.56 (d, J=2.3 Hz, 1H), 5.03-4.95 (m, 1H), 4.16-4.01 (m, 2H), 1.06 (d, J=6.1 Hz, 3H).

[0692] LCMS; m/z 206 (M+H).sup.+ (ES.sup.+).

Intermediate P12: 1-(2-Methoxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide

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

[0693] ##STR00097##

[0694] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 1-bromo-2-methoxy-2-methylpropane to afford the title compound (775 mg, 60%) as a clear colourless oil.

[0695] .sup.1H NMR (CDCl.sub.3) 7.57 (d, J=2.4 Hz, 1H), 7.11-7.05 (m, 4H), 6.82-6.75 (m, 4H), 6.67 (d, J=2.4 Hz, 1H), 4.32 (s, 4H), 4.19 (s, 2H), 3.80 (s, 6H), 3.27 (s, 3H), 1.14 (s, 6H).

[0696] LCMS; m/z 496 (M+Na).sup.+ (ES.sup.+); 472 (MH).sup. (ES.sup.).

Step B: 1-(2-Methoxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide

[0697] ##STR00098##

[0698] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-(2-methoxy-2-methylpropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (119 mg, 79%) as a light brown gum.

[0699] .sup.1H NMR (DMSO-d6) 7.73 (d, J=2.3 Hz, 1H), 7.38 (br s, 2H), 6.58 (d, J=2.3 Hz, 1H), 4.19 (s, 2H), 3.17 (s, 3H), 1.09 (s, 6H).

[0700] LCMS; m/z 234 (M+H).sup.+ (ES.sup.+); 232 (MH).sup. (ES.sup.).

Intermediate P13: (S)-1-(1-Hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

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

[0701] ##STR00099##

[0702] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and (R)-2-bromopropan-1-ol to afford the title compound (225 mg, 37%) as a clear colourless oil.

[0703] .sup.1H NMR (CDCl.sub.3) 7.52 (d, J=2.3 Hz, 1H), 7.13-7.04 (m, 4H), 6.84-6.76 (m, 4H), 6.69 (d, J=2.3 Hz, 1H), 4.35 (s, 4H), 4.28-4.11 (m, 2H), 4.09-3.99 (m, 1H), 3.81 (s, 6H), 1.25 (d, J=6.3 Hz, 3H).

Step B: (S)-1-(1-Hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

[0704] ##STR00100##

[0705] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from (S)-1-(1-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (150 mg, 30%) as a white solid.

[0706] .sup.1H NMR (DMSO-d6) 7.80 (d, J=2.3 Hz, 1H), 7.37 (s, 2H), 6.56 (d, J=2.3 Hz, 1H), 5.02-4.97 (m, 1H), 4.13-3.91 (m, 3H), 1.06 (d, J=6.1 Hz, 3H).

[0707] LCMS; m/z 206 (M+H).sup.+ (ES.sup.+).

Intermediate P14: (R)-1-(2-Hydroxypropyl)-1H-pyrazole-3-sulfonamide

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

[0708] ##STR00101##

[0709] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and (R)-2-methyloxirane to afford the title compound (210 mg, 46%) as a clear colourless oil.

[0710] .sup.1H NMR (CDCl.sub.3) 7.50 (d, J=2.3 Hz, 1H), 7.13-7.05 (m, 4H), 6.87-6.75 (m, 4H), 6.69 (d, J=2.3 Hz, 1H), 4.35 (s, 4H), 4.28-3.99 (m, 3H), 3.81 (s, 6H), 1.28 (d, J=6.3 Hz, 3H).

[0711] LCMS; m/z 446 (M+H).sup.+ (ES.sup.+).

Step B: (R)-1-(2-Hydroxypropyl)-1H-pyrazole-3-sulfonamide

[0712] ##STR00102##

[0713] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from (R)-1-(2-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (56 mg, 49%) as a white solid.

[0714] .sup.1H NMR (DMSO-d6) 7.80 (d, J=2.3 Hz, 1H), 7.37 (s, 2H), 6.56 (d, J=2.3 Hz, 1H), 4.98 (d, J=4.9 Hz, 1H), 4.09-3.95 (m, 3H), 1.06 (d, J=6.1 Hz, 3H).

Intermediate P15: 1-(1-Hydroxy-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide

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

[0715] ##STR00103##

[0716] A solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) (2.00 g, 5.16 mmol) and 1,1,1-trichloro-2-methylpropan-2-ol hemihydrate (2.00 g, 10.37 mmol) in THF (50 mL) at 0 C. was treated portionwise with sodium hydroxide (1.04 g, 26.0 mmol). The reaction was then left to warm to room temperature and stirred for 3 days.

[0717] Additional 1,1,1-trichloro-2-methylpropan-2-ol hemihydrate (0.6 g) and sodium hydroxide (0.6 g) were added and the reaction was left to stir for a further 24 hours. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (250 mL). The aqueous layer was acidified to pH1 with 1M HCl, and extracted with EtOAc (250 mL). The combined organic layers were dried (MgSO.sub.4), filtered and evaporated under reduced pressure to afford the title compound (490 mg, 17%) as a dark yellow oil.

[0718] LCMS; m/z 496.5 (M+Na).sup.+ (ES.sup.+).

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

[0719] ##STR00104##

[0720] 2M Lithium aluminium hydride in THF (1.4 mL, 2.80 mmol) was added dropwise to a stirred solution of 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid (0.49 g, 0.880 mmol) in THF (15 mL) cooled to 0 C. The mixture was stirred at room temperature for 4 hours. Further 2M lithium aluminium hydride in THF (1.4 mL, 2.80 mmol) was added, and the reaction was stirred for a further 3 days at room temperature. The mixture was quenched carefully at 0 C. with saturated aqueous ammonium chloride. The reaction mixture was diluted with water (20 mL) and EtOAc (30 mL) and precipitated salts filtered. The organic layer was separated and the aqueous layer was washed with EtOAc (220 mL). The combined organic layers were dried (MgSO.sub.4), filtered and evaporated to give a yellow oil. The crude product was purified by chromatography on silica gel (12 g column, 0-100% EtOAc/isohexane) to afford the title compound (130 mg, 30.2%) as a colourless oil. .sup.1H NMR (CD.sub.3OD) 7.88 (d, J=2.5 Hz, 1H), 7.08-6.99 (m, 4H), 6.82-6.72 (m, 4H), 6.66 (d, J=2.5 Hz, 1H), 4.28 (s, 4H), 3.76 (s, 6H), 3.75 (s, 2H), 1.57 (s, 6H).

[0721] Exchangeable proton not visible.

[0722] LCMS; m/z 482.1 (M+Na).sup.+ (ES.sup.+).

Step C: 1-(1-Hydroxy-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide

[0723] ##STR00105##

[0724] 1-(1-Hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (130 mg, 0.283 mmol) was dissolved in TFA (5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 18 hours. Additional TFA (3 mL) was added and the reaction left to stir at room temperature for 4 hours. A further portion of TFA (3 mL) was added and the reaction left to stir at room temperature for a further 19 hours. The reaction mixture was evaporated to dryness and purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford the title compound (43 mg, 68%) as a colourless film.

[0725] .sup.1H NMR (CD.sub.3OD) 7.80 (d, J=2.5 Hz, 1H), 6.61 (d, J=2.5 Hz, 1H), 3.73 (s, 2H), 1.54 (s, 6H). Three exchangeable protons not visible.

[0726] LCMS; m/z 220.3 (M+H).sup.+ (ES.sup.+).

Intermediate P16: (S)-1-(2-Hydroxybutyl)-1H-pyrazole-3-sulfonamide

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

[0727] ##STR00106##

[0728] A mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) (1 g, 2.58 mmol), (S)-2-ethyloxirane (0.29 mL, 3.37 mmol), Cs.sub.2CO.sub.3 (2.52 g, 7.74 mmol) and acetonitrile (10 mL) was subjected to microwave irradiation at 100 C. for 6 hours. The mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (340 mL). The combined organic extracts were washed with brine (30 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (1.13 g, 85%) as a clear colourless oil. .sup.1H NMR (DMSO-d6) 7.89 (d, J=2.3 Hz, 1H), 7.01 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.70 (d, J=2.3 Hz, 1H), 4.96 (d, J=5.6 Hz, 1H), 4.23-413 (m, 5H), 4.10 (dd, J=13.7, 7.3 Hz, 1H), 3.78-3.72 (m, 1H), 3.71 (s, 6H), 1.46-1.24 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

[0729] LCMS; m/z 482.3 (M+Na).sup.+ (ES.sup.+).

Step B: (S)-1-(2-Hydroxybutyl)-1H-pyrazole-3-sulfonamide

[0730] ##STR00107##

[0731] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from (S)-1-(2-hydroxybutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (128 mg, 48%) as a clear colourless oil.

[0732] .sup.1H NMR (DMSO-d6) 7.79 (d, J=2.3 Hz, 1H), 7.36 (s, 2H), 6.55 (d, J=2.3 Hz, 1H), 4.93 (s, 1H), 4.14 (dd, J=13.7, 4.4 Hz, 1H), 4.03 (dd, J=13.7, 7.5 Hz, 1H), 3.76-3.67 (m, 1H), 1.46-1.25 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).

[0733] LCMS; m/z 220.3 (M+H).sup.+ (ES.sup.+).

Intermediate P17: 1-(2-Hydroxycyclopentyl)-1H-pyrazole-3-sulfonamide (racemic anti)

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

[0734] ##STR00108##

[0735] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 6-oxabicyclo[3.1.0]hexane to afford the title compound (1.06 g, 82%) as a pale yellow oil.

[0736] .sup.1H NMR (DMSO-d6) 7.98 (d, J=2.4 Hz, 1H), 7.01 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.70 (d, J=2.4 Hz, 1H), 5.18 (d, J=5.1 Hz, 1H), 4.47 (td, J=7.9, 5.9 Hz, 1H), 4.22-4.20 (m, 1H), 4.19 (s, 4H), 3.71 (s, 6H), 2.24-2.13 (m, 1H), 2.00-1.88 (m, 2H), 1.77 (dq, J=8.3, 7.0 Hz, 2H), 1.64-1.51 (m, 1H).

[0737] LCMS; m/z 494.8 (M+Na).sup.+ (ES.sup.+).

Step B: 1-(2-Hydroxycyclopentyl)-1H-pyrazole-3-sulfonamide (racemic anti)

[0738] ##STR00109##

[0739] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-(2-hydroxycyclopentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (racemic anti) to afford the title compound (29.5 mg, 11%) as a clear colourless oil.

[0740] .sup.1H NMR (DMSO-d6) 7.89 (d, J=2.3 Hz, 1H), 7.37 (s, 2H), 6.57 (d, J=2.3 Hz, 1H), 5.14 (s, 1H), 4.41 (td, J=8.3, 6.2 Hz, 1H), 4.20 (q, J=6.7 Hz, 1H), 2.23-2.10 (m, 1H), 2.02-1.88 (m, 2H), 1.82-1.70 (m, 2H), 1.63-1.50 (m, 1H).

[0741] LCMS; m/z 232.3 (M+H).sup.+ (ES.sup.+).

Intermediate P18: 1-(3-Hydroxybutan-2-yl)-1H-pyrazole-3-sulfonamide (racemicR,R and S,S enantiomers)

Step A: 1-(3-Hydroxybutan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (racemicR,R and S,S enantiomers)

[0742] ##STR00110##

[0743] A mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) (1 g, 2.58 mmol), (2S,3S)-2,3-dimethyloxirane (0.3 mL, 3.35 mmol) and Cs.sub.2CO.sub.3 (2.52 g, 7.74 mmol) in acetonitrile (15 mL) was heated to 80 C. and stirred for 4 days. The mixture was transferred into a microwave vial and irradiated at 130 C. for 6 hours, then diluted with H.sub.2O (20 mL) and extracted with EtOAc (340 mL). The combined organic extracts were washed with brine (30 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (452 mg, 3%) as a sticky yellow oil.

[0744] .sup.1H NMR (DMSO-d6) 7.95 (d, J=2.4 Hz, 1H), 7.02 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.70 (d, J=2.4 Hz, 1H), 5.06 (d, J=5.2 Hz, 1H), 4.30-4.20 (m, 1H), 4.19 (s, 2H), 4.18 (s, 2H), 3.89-3.79 (m, 1H), 3.71 (s, 6H), 1.46 (d, J=6.9 Hz, 3H), 0.88 (d, J=6.3 Hz, 3H).

[0745] LCMS; m/z 482.5 (M+Na).sup.+ (ES.sup.+).

Step B: 1-(3-Hydroxybutan-2-yl)-1H-pyrazole-3-sulfonamide (racemicR,R and S,S enantiomers)

[0746] ##STR00111##

[0747] A solution of 1-(3-hydroxybutan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (racemicR,R and S,S enantiomers) (450 mg, 0.979 mmol) in TFA (3 mL, 47.1 mmol), H.sub.2O (0.1 mL) and DCM (5 mL) was stirred at room temperature overnight. The solvent was removed and the residue loaded onto silica and purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford the title compound (72.9 mg, 33%) as a clear colourless oil.

[0748] .sup.1H NMR (DMSO-d6) 7.85 (d, J=2.4 Hz, 1H), 7.36 (s, 2H), 6.56 (d, J=2.4 Hz, 1H), 5.01 (s, 1H), 4.26-4.14 (m, 1H), 3.88-376 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.3 Hz, 3H).

[0749] LCMS; m/z 220.3 (M+H).sup.+ (ES.sup.+).

Intermediate P1: 1-(1-(Hydroxymethyl)cyclobutyl)-1H-pyrazole-3-sulfonamide

Step A: Ethyl 1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)cyclobutanecarboxylate

[0750] ##STR00112##

[0751] A solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C (1 g, 2.58 mmol) in DMF (15 mL) was cooled to 0 C. before sodium hydride (60% in mineral oil) (134 mg, 3.35 mmol) was added. The mixture was warmed to room temperature and stirred for 30 minutes before ethyl 1-bromocyclobutanecarboxylate (0.46 mL, 2.84 mmol) was added slowly. The resulting mixture was stirred at room temperature for 5 days, then diluted with EtOAc (80 mL), H.sub.2O (40 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (280 mL) and the combined organic extracts were washed with brine (450 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (711 mg, 40%) as a 3:1 mixture of regioisomers as a clear colourless oil.

[0752] LCMS; m/z 536.1 (M+Na).sup.+ (ES.sup.+).

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

[0753] ##STR00113##

[0754] To a solution of ethyl 1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)cyclobutanecarboxylate (710 mg, 1.037 mmol) in THF (20 mL) at 0 C. was added slowly LiAlH.sub.4 (2M in THF) (2.1 mL, 4.20 mmol) and the mixture was warmed to room temperature and stirred overnight. The reaction was sequentially quenched with H.sub.2O (0.2 mL), 2M NaOH (0.5) and H.sub.2O (1 mL). Na.sub.2SO.sub.4 was added, the mixture was stirred for 30 minutes and then filtered through a plug of Celite with EtOAc. The filtrate was evaporated and the residue loaded onto silica and purified by chromatography on silica gel (40 g column, 15-100% EtOAc/isohexane) to afford the title compound (410 mg, 83%) as a clear colourless oil.

[0755] .sup.1H NMR (DMSO-d6) 7.89 (d, J=2.4 Hz, 1H), 7.01 (d, J=8.7 Hz, 4H), 6.82 (d, J=8.7 Hz, 4H), 6.70 (d, J=2.4 Hz, 1H), 5.20 (t, J=5.6 Hz, 1H), 4.20 (s, 4H), 3.75 (d, J=5.6 Hz, 2H), 3.72 (s, 6H), 2.48-2.39 (m, 2H), 2.39-2.27 (m, 2H), 1.95-1.80 (m, 2H).

[0756] LCMS; m/z 494.0 (M+Na).sup.+ (ES.sup.+).

Step C: 1-(1-(Hydroxymethyl)cyclobutyl)-1H-pyrazole-3-sulfonamide

[0757] ##STR00114##

[0758] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-(1-(hydroxymethyl)cyclobutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (31-5 mg, 14%) as a clear colourless crystalline solid.

[0759] .sup.1H NMR (DMSO-d6) 7.80 (d, J=2.4 Hz, 1H), 7.37 (s, 2H), 6.56 (d, J=2.4 Hz, 1H), 5.16 (s, 1H), 3.73 (s, 2H), 2.48-2.43 (m, 2H), 2.33-2.27 (m, 2H), 1.92-1.80 (m, 2H).

[0760] LCMS; m/z 232.2 (M+H).sup.+ (ES.sup.+).

Intermediate P20: (R)-1-(2-Hydroxybutyl)-1H-pyrazole-3-sulfonamide

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

[0761] ##STR00115##

[0762] A mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) (1 g, 2.58 mmol), (R)-2-ethyloxirane (0.29 mL, 3.37 mmol), Cs.sub.2CO.sub.3 (2.52 g, 7.74 mmol) and acetonitrile (10 mL) was subjected to microwave irradiation at 110 C. for 6 hours. The mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (340 mL). The combined organic extracts were washed with brine (30 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (1.01 g, 83%) as a clear colourless oil. .sup.1H NMR (DMSO-d6) 7.90 (d, J=2.3 Hz, 1H), 7.01 (d, J=8.6 Hz, 4H), 6.81 (d, J=8.6 Hz, 4H), 6.70 (d, J=2.3 Hz, 1H), 4.96 (d, J=5.6 Hz, 1H), 4.24-4.06 (m, 6H), 3.79-372 (m, 1H), 3.71 (s, 6H), 1.46-1.36 (m, 1H), 1.35-1.25 (m, 1H), 0.91 (t, J=7.4 Hz, 3H).

[0763] LCMS; m/z 482.6 (M+Na).sup.+ (ES.sup.+).

Step B: (R)-1-(2-Hydroxybutyl)-1H-pyrazole-3-sulfonamide

[0764] ##STR00116##

[0765] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from (R)-1-(2-hydroxybutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (113 mg, 40%) as a clear colourless oil.

[0766] .sup.1H NMR (DMSO-d6) 7.79 (d, J=2.3 Hz, 1H), 7.36 (s, 2H), 6.55 (d, J=2.3 Hz, 1H), 4.92 (s, 1H), 4.14 (dd, J=13.7, 4.3 Hz, 1H), 4.04 (dd, J=13.7, 7.5 Hz, 1H), 3.76-3.67 (m, 1H), 1.47-1.35 (m, 1H), 1.35-1.25 (m, 1H), 0.90 (t, J=7.5 Hz, 3H).

[0767] LCMS; m/z 220.3 (M+H).sup.+ (ES.sup.+).

Intermediate P21: 1-(3-Hydroxybutan-2-yl)-1H-pyrazole-3-sulfonamide (racemicR,S and S,R enantiomers)

Step A: 1-(3-Hydroxybutan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (racemicR,S and S,R enantiomers)

[0768] ##STR00117##

[0769] A mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) (1 g, 2.58 mmol), (2S,3R)-2,3-dimethyloxirane (0.3 mL, 3.35 mmol) and Cs.sub.2CO.sub.3 (2.52 g, 7.74 mmol) in acetonitrile (10 mL) was subjected to microwave irradiation at 110 C. for 8 hours. The mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (340 mL). The combined organic extracts were washed with brine (30 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (1.05 g, 85%) as a sticky yellow oil.

[0770] .sup.1H NMR (DMSO-d6) 7.91 (d, J=2.4 Hz, 1H), 7.00 (d, J=8.6 Hz, 4H), 6.80 (d, J=8.6 Hz, 4H), 6.69 (d, J=2.4 Hz, 1H), 4.95 (d, J=5.1 Hz, 1H), 4.37-4.25 (m, 1H), 4.18 (s, 4H), 3.93-3.81 (m, 1H), 3.71 (s, 6H), 1.41 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.3 Hz, 3H).

[0771] LCMS; m/z 482.6 (M+Na).sup.+ (ES.sup.+).

Step B: 1-(3-Hydroxybutan-2-yl)-1H-pyrazole-3-sulfonamide (racemicR,S and S,R enantiomers)

[0772] ##STR00118##

[0773] A solution of 1-(3-hydroxybutan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (racemicR,S and S,R enantiomers) (515 mg, 1.121 mmol) in TFA (3 mL, 47.1 mmol), H.sub.2O (0.1 mL) and DCM (5 mL) was stirred at room temperature overnight. The solvent was removed and the residue loaded onto silica and purified by chromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford the title compound (110 mg, 36%) as a clear colourless oil.

[0774] .sup.1H NMR (DMSO-d6) 7.81 (d, J=2.3 Hz, 1H), 7.34 (s, 2H), 6.55 (d, J=2.3 Hz, 1H), 4.85 (s, 1H), 4.30-4.20 (m, 1H), 3.92-3.79 (m, 1H), 1.39 (d, J=7.0 Hz, 3H), 1.00 (d, J=6.3 Hz, 3H).

[0775] LCMS; m/z 220.6 (M+H).sup.+ (ES.sup.+).

Intermediate P22: (R)-1-(2-Hydroxypropyl)-1H-imidazole-4-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide

[0776] ##STR00119##

[0777] A solution of 1H-imidazole-4-sulfonyl chloride (2.5 g, 15.01 mmol) in DCM (10 mL) was added slowly to a solution of bis(4-methoxybenzyl)amine (4 g, 15.54 mmol) and Et.sub.3N (4.5 mL, 32.3 mmol) in DCM (50 mL) cooled in an ice bath. The mixture was stirred for 30 minutes, warmed to room temperature and stirred for 2 hours. The DCM was removed under pressure and replaced with dioxane (50 mL) and the mixture heated under reflux for 48 hours, cooled, and then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was dried (MgSO.sub.4), filtered and evaporated to give an oil that was purified by chromatography on silica gel (120 g column, 0-100% EtOAc/isohexane). The product was triturated in TBME/EtOAc, filtered and dried to afford the title compound (2.864 g, 48%) as a solid.

[0778] .sup.1H NMR (CDCl.sub.3) 7.92 (d, J=1.3 Hz, 1H), 7.52 (d, J=1.3 Hz, 1H), 7.06-7.02 (m, 4H), 6.79-6.75 (m, 4H), 4.30 (s, 4H), 3.77 (s, 6H). Exchangeable proton not visible.

[0779] LCMS; m/z 388 (M+H).sup.+ (ES.sup.+); 386 (MH).sup. (ES.sup.).

Step B: (R)-1-(2-Hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide

[0780] ##STR00120##

[0781] A mixture of N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide (500 mg, 1.29 mmol), (R)-2-methyloxirane (0.18 ml, 2.57 mmol) and K.sub.2CO.sub.3 (535 mg, 3.87 mmol) in acetonitrile (10 mL) was stirred at 60 C. overnight. Upon cooling to room temperature, the reaction mixture was diluted with H.sub.2O (20 mL) and extracted with EtOAc (350 mL). The combined organic extracts were washed with brine (30 mL), passed through a phase separator, and concentrated in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (468 mg, 68%) as a clear colourless oil.

[0782] .sup.1H NMR (DMSO-d6) 7.82 (d, J=1.3 Hz, 1H), 7.81 (d, J=1.3 Hz, 1H), 7.03 (d, J=8.6 Hz, 4H), 6.80 (d, J=8.6 Hz, 4H), 4.18 (s, 4H), 4.06-4.00 (m, 2H), 3.95-3.86 (m, 2H), 3.71 (s, 6H), 1.04 (d, J=5.9 Hz, 3H).

[0783] LCMS; m/z 446.4 (M+H).sup.+ (ES.sup.+).

Step C: (R)-1-(2-Hydroxypropyl)-1H-imidazole-4-sulfonamide

[0784] ##STR00121##

[0785] A mixture of (R)-1-(2-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide (460 mg, 0.857 mmol) and TFA (5.5 mL) was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo and the residue loaded onto silica and purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford a clear colourless oil, which was further purified by prep-HPLC to afford the title compound (123 mg, 68%) as a clear colourless oil.

[0786] .sup.1H NMR (DMSO-d6) 7.71 (d, J=1.3 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 7.12 (s, 2H), 5.00 (d, J=4.1 Hz, 1H), 4.07-3.96 (m, 1H), 3.93-3.79 (m, 2H), 1.03 (d, J=6.0 Hz, 3H).

[0787] LCMS; m/z 206.2 (M+H).sup.+ (ES.sup.+).

Intermediate P23: (S)-1-(2-Hydroxypropyl)-1H-imidazole-4-sulfonamide

Step A: (S)-1-(2-Hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide

[0788] ##STR00122##

[0789] Prepared according to the general procedure of (R)-1-(2-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide (Intermediate P22, Step B) from N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide (Intermediate P22, Step A) and (S)-2-methyloxirane to afford the title compound (160 mg, 37%) as a clear colourless oil.

[0790] .sup.1H NMR (DMSO-d6) 7.81 (d, J=1.2 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H), 7.02 (d, J=8.7 Hz, 4H), 6.80 (d, J=8.7 Hz, 4H), 5.04 (d, J=4.6 Hz, 1H), 4.18 (s, 4H), 4.06-3.99 (m, 1H), 3.97-3.84 (m, 2H), 3.71 (s, 6H), 1.04 (d, J=5.9 Hz, 3H).

[0791] LCMS; m/z 446.2 (M+H).sup.+ (ES.sup.+).

Step B: (S)-1-(2-Hydroxypropyl)-1H-imidazole-4-sulfonamide

[0792] ##STR00123##

[0793] Prepared according to the general procedure of (R)-1-(2-hydroxypropyl)-1H-imidazole-4-sulfonamide (Intermediate P22, Step C) from (S)-1-(2-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide to afford the title compound (56 mg, 70%1 as a clear colourless oil.

[0794] .sup.1H NMR (DMSO-d6) 7.71 (d, J=1.3 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 7.11 (s, 2H), 5.00 (d, J=4.6 Hz, 1H), 4.04-3.95 (m, 1H), 3.92-3.80 (m, 2H), 1.03 (d, J=6.0 Hz, 3H).

[0795] LCMS; m/z 206.2 (M+H).sup.+ (ES.sup.+).

Intermediate P24: 1-(3,3,3-Trifluoro-2-hydroxypropyl)-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazole-3-sulfonamide

[0796] ##STR00124##

[0797] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 3-bromo-1,1,1-trifluoropropan-2-ol to afford the title compound (183 mg, 28%) as a clear colourless oil.

[0798] .sup.1H NMR (DMSO-d6) 8.01 (d, J=2.4 Hz, 1H), 7.02 (d, J=8.7 Hz, 4H), 6.84-6.78 (m, 5H), 6.74 (d, J=2.4 Hz, 1H), 4.56-4.35 (m, 3H), 4.19 (s, 4H), 3.71 (s, 6H).

[0799] LCMS; m/z 522.4 (M+Na).sup.+ (ES.sup.+).

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

[0800] ##STR00125##

[0801] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazole-3-sulfonamide to afford the title compound (74 mg, 89%) as a pale yellow oil.

[0802] .sup.1H NMR (DMSO-d6) 7.92 (d, J=2.3 Hz, 1H), 7.43 (s, 2H), 6.79 (d, J=6.5 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 4.51-4.28 (m 3H).

[0803] LCMS; m/z 260.1 (M+H).sup.+ (ES.sup.+); 258.0 (MH).sup. (ES.sup.).

Intermediate P25: 1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-sulfonamide

Step A: 3-Nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole

[0804] ##STR00126##

[0805] 3-Nitro-1H-pyrazole (1.5 g, 13.27 mmol) was combined with K.sub.2CO.sub.3 (3.67 g, 26.5 mmol) and tetrabutylammonium iodide (0.588 g, 1.592 mmol) in DMF (30 mL) and treated with 4-bromotetrahydro-2H-pyran (1.791 mL, 15.92 mmol). The resultant mixture was heated at 60 C. for 24 hours, then additional K.sub.2CO.sub.3 (1.8 g) and 4-bromotetrahydro-2H-pyran (0.8 mL) were added and the reaction stirred another 18 hours. The reaction mixture was diluted with TBME (50 mL), water (100 mL) and brine (100 mL). The organic layer was washed with water (2100 mL), dried (MgSO.sub.4), filtered and concentrated to give a brown oil. The brown oil was purified by chromatography on silica gel (80 g column, 0-100% EtOAc/isohexane) to afford the title compound (1.02 g, 37.0%) as a thick yellow oil.

[0806] .sup.1H NMR (CDCl.sub.3) 7.51 (d, J=2.6 Hz, 1H), 6.92 (d, J=2.6 Hz, 1H), 4.52-4.28 (m, 1H), 4.25-3.99 (m, 2H), 3.67-3.37 (m, 2H), 2.34-1.90 (m, 4H).

[0807] LCMS; m/z 198.1 (M+H).sup.+ (ES.sup.+).

Step B: 1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-amine

[0808] ##STR00127##

[0809] In a 30-mL vial, 3-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (1 g, 4.82 mmol) and 10% Pd/C (wet) Type 87 L (0.021 g) were suspended in methanol (10 mL) and ethyl acetate (10 mL). The Baskerville vessel was purged with N.sub.2 three times, and then filled with H.sub.2 three times. The reaction mixture was stirred at room temperature under 5 bar of H.sub.2 for 17 hours. The reaction mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc (210 mL). The combined filtrates were concentrated to dryness to give the title compound (0.662 g, 94%) as a white solid.

[0810] .sup.1H NMR (CDCl.sub.3) 7.18 (d, J=2.4 Hz, 1H), 5.60 (d, J=2.4 Hz, 1H), 4.18-3.99 (m, 3H), 3.50 (td, J=11.8, 2.5 Hz, 2H), 3.07 (s, 2H), 2.15-1.85 (m, 4H).

[0811] LCMS; m/z 168.0 (M+H).sup.+ (ES.sup.+).

Step C: 1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-sulfonyl chloride

[0812] ##STR00128##

[0813] In a 100-mL 3-necked round-bottomed flask, a mixture of HCl (1.42 mL, 46.8 mmol) in water (0.95 mL) and acetonitrile (4.75 mL) was cooled to 10 C. (acetone/dry ice bath) and treated dropwise with an aqueous solution of NaNO.sub.2 (0.314 g, 4.55 mmol) in water (0.570 mL), maintaining internal temperature below 0 C. The solution was stirred for 10 minutes and then treated with a solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-amine (0.66 g, 3.79 mmol) in acetonitrile (4.75 mL) (with 0.2 mL of concentrated HCl for solubility) (which was pre-cooled to 0 C.) at 0 C. over 15 minutes. The resulting reaction mixture was stirred at 0 C. for 45 minutes. Cold AcOH (1.9 mL, 33.2 mmol), Cu(II)Cl (0.255 g, 1.895 mmol) and Cu(I)Cl (0.019 g, 0.189 mmol) were sequentially added to the reaction mixture and the reaction mixture was purged with sulfur dioxide gas for 20 minutes at 0 C. (exotherm). The reaction was stirred for a further 50 minutes at 0 C., diluted with water (15 mL) and extracted with EtOAc (330 mL), then dried (MgSO.sub.4), filtered and concentrated to dryness to give a black paste. The crude product was purified by chromatography on silica gel (40 g column, 0-100% DCM/isohexane, monitored at 215 nm) to afford the title compound (250 mg, 21%) as a clear yellow oil.

[0814] .sup.1H NMR (CDCl.sub.3) 7.58 (d, J=2.5 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 4.58-4.45 (m, 1H), 4.18-4.06 (m, 2H), 3.62-3.50 (m, 2H), 2.26-2.04 (m, 4H).

Step D: 1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-sulfonamide

[0815] ##STR00129##

[0816] A solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-sulfonyl chloride (0.250 g, 0.798 mmol) in THF (1.6 mL) was treated with 0.5 M ammonia in dioxane (4.79 mL, 2.393 mmol). The reaction mixture was then left to stir at room temperature for 17 hours. The reaction mixture was concentrated to dryness and the residue obtained was quenched with water (1 mL) and extracted with EtOAc (210 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated to dryness. The white residue obtained was taken up in DCM (1 mL) and precipitated by addition of isohexane (3 mL). The remaining liquid was removed by pipette and the solid washed with isohexane (23 mL) and the decantation process repeated. The residual solid was then dried under vacuum to give the title compound (170 mg, 91%) as a white solid. .sup.1H NMR (DMSO-d6) 7.96 (d, J=2.4 Hz, 1H), 7.39 (s, 2H), 6.59 (d, J=2.4 Hz, 1H), 4.49 (dt, J=10.4, 5.2 Hz, 1H), 4.11-3.74 (m, 2H), 3.57-3.37 (m, 2H), 2.04-1.82 (m, 4H).

[0817] LCMS; m/z 231.9 (M+H).sup.+ (ES.sup.+); 229.9 (MH).sup. (ES.sup.).

Intermediate P26: (R)-2-(2-Hydroxypropyl)-2H-1,2,3-triazole-4-sulfonamide

Step A: (R)-1-(4-(Benzylthio)-2H-1,2,3-triazol-2-yl)propan-2-ol

[0818] ##STR00130##

[0819] A mixture of 4-(benzylthio)-1H-1,2,3-triazole (6 g, 31.4 mmol), K.sub.2CO.sub.3 (13 g, 94 mmol) and (R)-2-methyloxirane (3 ml, 42.8 mmol) in MeCN (100 ml) was heated at 50 C. for 3 days. A further portion of (R)-2-methyloxirane (1 ml) was added and heated for a further 3 days. The mixture was cooled to room temperature and partitioned between EtOAc (400 ml) and water (300 ml). The organic layer was washed with brine (300 ml), dried (MgSO.sub.4), filtered and evaporated. The residue was purified by chromatography on silica gel (120 g column, 0-50% EtOAc/isohexane) to afford the title compound (2.83 g, 17%), (R)-1-(5-(benzylthio)-1H-1,2,3-triazol-1-yl)propan-2-ol (1.47 g, 17%) and (R)-1-(4-(benzylthio)-1H-1,2,3-triazol-1-yl)propan-2-ol (2.37 g, 30%) all as colourless oils.

[0820] .sup.1H NMR (CDCl.sub.3) 7.38 (s, 1H), 7.33-7.24 (m, 5H), 4.49-4.26 (m, 3H), 4.12 (s, 2H), 1.24 (d, J=6.3 Hz, 3H). Exchangeable proton not visible.

[0821] LCMS; m/z 250.0 (M+H).sup.+ (ES.sup.+); 248.7 (MH).sup. (ES.sup.).

Step B: (R)-2-(2-(Benzyloxy)propyl)-4-(benzylthio)-2H-1,2,3-triazole

[0822] ##STR00131##

[0823] To a solution of (R)-1-(4-(benzylthio)-2H-1,2,3-triazol-2-yl)propan-2-ol (2.83 g, 11.35 mmol) in THF (50 ml) at 0 C. was added sodium hydride (60% in mineral oil) (0.6 g, 15.00 mmol) and the mixture was stirred for 15 minutes. (Bromomethyl)benzene (1.5 ml, 12.61 mmol) was added and the mixture was warmed to room temperature and stirred overnight. Additional sodium hydride (60% in mineral oil) (0.6 g, 11.35 mmol) was added and the mixture was stirred at room temperature for 4 days. The mixture was quenched with water (30 mL) and extracted with EtOAc (360 mL). The combined organic extracts were washed with brine (50 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (80 g column, 0-100% EtOAc/isohexane) to afford the title compound (2.92 g, 73%) as a pale yellow oil.

[0824] .sup.1H NMR (DMSO-d6) 7.71 (s, 1H), 7.29-7.20 (m, 8H), 7.17-7.12 (m, 2H), 4.47-4.41 (m, 3H), 4.31 (d, J=12.0 Hz, 1H), 4.17 (s, 2H), 4.04-3.92 (m, 1H), 1.13 (d, J=6.3 Hz, 3H).

[0825] LCMS; m/z 340.3 (M+H).sup.+ (ES.sup.+).

Step C: (R)-2-(2-(Benzyloxy)propyl)-2H-1,2,3-triazole-4-sulfonamide

[0826] ##STR00132##

[0827] To a mixture of (R)-2-(2-(benzyloxy)propyl)-4-(benzylthio)-2H-1,2,3-triazole (2.91 g, 8.32 mmol) in AcOH (60 mL) and H.sub.2O (30 mL) was added NCS (4.5 g, 33.7 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc (300 ml) and H.sub.2O (300 ml) and the organic layer was sequentially washed with sat aq NaHCO.sub.3 (2200 ml) and brine (300 ml), passed through a phase separator and the solvent was removed in vacuo. TBME (60 mL) was added to the residue and the white solid removed by filtration. The filtrate was concentrated to give a pale yellow oil which as was dissolved in TBME (30 mL). Ammonia (0.5 M in dioxane) (so mL, 25.00 mmol) was added and the mixture was stirred at room temperature overnight. The volatiles were evaporated and the residue was partitioned between EtOAc (500 mL) and H.sub.2 (150 mL). The organic layer was washed with brine (100 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (80 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (1.99 g, 77%) as a pale yellow oil.

[0828] .sup.1H NMR (DMSO-d6) 8.11 (s, 1H), 7.81 (s, 2H), 7.34-7.21 (m, 3H), 7.17-7.12 (m, 2H), 4.64 (dd, J=13.9, 4.4 Hz, 1H), 4.55 (dd, J=13.9, 7.3 Hz, 1H), 4.48 (d, J=12.0 Hz, 1H), 4.36 (d, J=12.0 Hz, 1H), 4.12-3.99 (m, 1H), 1.20 (d, J=6.3 Hz, 3H).

[0829] LCMS; m/z 297.2 (M+H).sup.+ (ES.sup.+).

Step D: (R)-2-(2-Hydroxypropyl)-2H-1,2,3-triazole-4-sulfonamide

[0830] ##STR00133##

[0831] A mixture of (R)-2-(2-(benzyloxy)propyl)-2H-1,2,3-triazole-4-sulfonamide (1.99 g, 6.38 mmol) and 5% Pd/C (Type 87L, 58-5% moisture) (1.73 g, 0-337 mmol) in EtOH (15 mL) was hydrogenated at 5 bar overnight. The mixture was filtered through Celite and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (40 g cartridge, 0-10% MeOH/DCM) to afford the title compound (1.235 g, 90%) as a clear colourless oil.

[0832] .sup.1H NMR (DMSO-d6) 8.08 (s, 1H), 7.77 (s, 2H), 5.04 (d, J=5.3 Hz, 1H), 4.41 (dd, J=13.5, 5.0 Hz, 1H), 4.36 (dd, J=13.5, 7.3 Hz, 1H), 4.19-4.09 (m, 1H), 1.11 (d, J=6.3 Hz, 3H).

[0833] LCMS; m/z 207.0 (M+H).sup.+ (ES.sup.+).

Intermediate P27: 1-(3-Hydroxycyclobutyl)-1H-pyrazole-3-sulfonamide

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

[0834] ##STR00134##

[0835] To a solution of 3-(benzyloxy)cyclobutanol (0.52 ml, 3.14 mmol) in DCM (15 mL) at 0 C. was added N-ethyl-N-isopropylpropan-2-amine (0.72 ml, 4.12 mmol) and methanesulfonyl chloride (0.28 ml, 3.59 mmol). The mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched with aqueous NaHCO.sub.3 (15 mL) and extracted with DCM (220 mL). The combined organic extracts were washed with brine (15 mL), passed through a phase separator and the solvent was concentrated in vacuo. The residue was dissolved in THF (7-5 mL) and added to a mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) (1 g, 2.58 mmol) and K.sub.2CO.sub.3 (1.4 g, 10.13 mmol) in THF (7-5 mL). The resulting mixture was stirred at 60 C. overnight for 4 days. The mixture was quenched with H.sub.2O (30 mL) and extracted with EtOAc (360 mL). The combined organic extracts were washed with brine (50 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (725 mg, 49%) as a pale yellow oil.

[0836] .sup.1H NMR (DMSO-d6) 8.03 (d, J=2.4 Hz, 1H), 7.36-7.27 (m, 5H), 7.03 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.72 (d, J=2.4 Hz, 1H), 5.14-5.03 (m, 1H), 4.43 (s, 2H), 4.37-4.31 (m, 1H), 4.21 (s, 4H), 3.71 (s, 6H), 2.66-2.52 (m, 4H).

[0837] LCMS; m/z 570.4 (M+Na).sup.+ (ES.sup.+).

Step B: 1-(3-(Benzyloxy)cyclobutyl)-1H-pyrazole-3-sulfonamide

[0838] ##STR00135##

[0839] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-(3-(benzyloxy)cyclobutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (379 mg, 87%) as a pale yellow oil.

[0840] .sup.1H NMR (DMSO-d6) 7.96 (d, J=2.3 Hz, 1H), 7.41 (s, 2H), 7.38-7.34 (m, 4H), 7.33-7.27 (m, 1H), 6.59 (d, J=2.4 Hz, 1H), 5.14-5.02 (m, 1H), 4.44 (s, 2H), 4.39-4.31 (m, 1H), 2.71-2.61 (m, 2H), 2.61-2.52 (m, 2H).

[0841] LCMS; m/z 308.2 (M+H).sup.+ (ES.sup.+).

Step C: 1-(3-Hydroxycyclobutyl)-1H-pyrazole-3-sulfonamide

[0842] ##STR00136##

[0843] Prepared according to the general procedure of (R)-2-(2-hydroxypropyl)-2H-1,2,3-triazole-4-sulfonamide (Intermediate P26, Step D) from 1-(3-(benzyloxy) cyclobutyl)-1H-pyrazole-3-sulfonamide to afford the title compound (156 mg, 91%) as a colourless solid.

[0844] .sup.1H NMR (DMSO-d6) 7.94 (d, J=2.3 Hz, 1H), 7.39 (s, 2H), 6.58 (d, J=2.3 Hz, 1H), 5.26 (d, J=5.0 Hz, 1H), 5.05-4.97 (m, 1H), 4.49-4.40 (m, 1H), 2.66-2.58 (m, 2H), 2.41-2.33 (m, 2H).

[0845] LCMS; m/z 218.1 (M+H).sup.+ (ES.sup.+).

Intermediate P28:5-(3-Hydroxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

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

[0846] ##STR00137##

[0847] A solution of 1-methyl-1H-pyrazole-3-sulfonyl chloride (13.0 g, 72.0 mmol) in DCM (30 mL) was added slowly to a solution of bis-(4-methoxybenzyl)amine (20 g, 78 mmol) and triethylamine (20 mL, 143 mmol) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 30 minutes, warmed to room temperature and stirred for 2 hours. The mixture was washed with water (200 mL), hydrochloric acid (aqueous, 1 M, 200 mL) and water (200 mL), then dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was triturated with TBME (250 mL), filtered, and then purified by chromatography on silica gel (330 g column, 0-60% EtOAc/iso-hexane) to afford the title compound (27.66 g, 93%) as a white solid.

[0848] .sup.1H NMR (CDCl.sub.3) 7.42 (d, J=2.3, 1H), 7.11-7.07 (m, 4H), 6.81-6.77 (m, 4H), 6.65 (d, J=2.3, 1H), 4.33 (s, 4H), 3.99 (s, 3H) and 3.81 (s, 6H).

[0849] LCMS m/z 402 (M+H).sup.+ (ES.sup.+).

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

[0850] ##STR00138##

[0851] A solution of n-BuLi (2.5 M in hexanes; 2.0 mL, 5.00 mmol) was added dropwise to a stirred solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (2 g, 4.98 mmol) in THF (35 mL) cooled to 78 C. The reaction mixture was stirred for 1 hour and then a solution of oxetan-3-one (0.292 mL, 4.98 mmol) in THF (16 mL) was added. The reaction mixture was left at 78 C. for 5 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with saturated aq NH.sub.4Cl solution (20 mL) and extracted with EtOAc (350 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO.sub.4), filtered and evaporated in vacuo to give an orange oil. The crude product was purified by chromatography on silica gel (80 g column, 0-75% EtOAc/isohexane) to afford the title compound (1.44 g, 61%) as a colourless solid.

[0852] 1H NMR (DMSO-d6) 7.10-7.00 (m, 4H), 6.90 (s, 1H), 6.85-6.78 (m, 4H), 6.75 (s, 1H), 4.89 (d, J=7.3 Hz, 2H), 4.76 (d, J=7.2 Hz, 2H), 4.23 (s, 4H), 3.81 (s, 3H), 3.71 (s, 6H).

[0853] LCMS; m/z 496.1 (M+Na).sup.+ (ES.sup.+).

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

[0854] ##STR00139##

[0855] A solution of ceric ammonium nitrate (289 mg, 0.528 mmol) in water (0.5 mL) was added portionwise over 5 minutes to a stirred solution of 5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (50 mg, 0.106 mmol) in MeCN (2 mL). The orange mixture was stirred at room temperature for 17 hours and then diluted with water (2 mL) and extracted with EtOAc (35 mL). The combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica gel (4 g column, 0-8% MeOH/DCM) to afford the title compound (21 mg, 77%) as an orange residue.

[0856] 1H NMR (DMSO-d6) 7.41 (s, 2H), 6.77 (s, 1H), 6.73 (s, 1H), 4.90-4.85 (m, 2H), 4.78-4.73 (m, 2H), 3.79 (s, 3H).

[0857] LCMS; m/z 234.0 (M+H).sup.+ (ES.sup.+).

Intermediate P29: 5-(3-Methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

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

[0858] ##STR00140##

[0859] Sodium hydride (60% in mineral oil) (71.5 mg, 1.787 mmol) was added portionwise to 5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step B) (705 mg, 1.489 mmol) in dry DMF (9 mL) at 0 C. The reaction mixture was stirred for 30 minutes at 0 C., then iodomethane (2M in MTBE; 2.98 mL, 5.96 mmol) was added in a single portion and the mixture was stirred for a further 2 hours while warming to room temperature. The reaction mixture was quenched by slow addition of saturated aqueous ammonium chloride (10 mL) and then partitioned between EtOAc (30 mL) and brine (100 mL). The aqueous layer was separated and the organic layer was washed with brine (100 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-70% EtOAc/isohexane) to afford the title compound (620 mg, 78%) as a colourless oil.

[0860] .sup.1H NMR (CDCl.sub.3) 7.22-7.06 (m, 4H), 6.83-6.75 (m, 4H), 6.57 (s, 1H), 4.90 (dd, J=6.8, 0.7 Hz, 2H), 4.78 (dd, J=6.8, 0.8 Hz, 2H), 4.35 (s, 4H), 3.81-3.74 (m, 9H), 3.04 (s, 3H).

[0861] LCMS m/z 488.2 (M+H).sup.+ (ES.sup.+).

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

[0862] ##STR00141##

[0863] Prepared according to the general procedure of 5-(3-hydroxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step C) from N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (357 mg, 40%) as a colourless solid. 1H NMR (DMSO-d6) 7.46 (s, 2H), 6.92 (s, 1H), 4.94-4.82 (m, 2H), 4.83-4.70 (m, 2H), 3.73 (s, 3H), 2.99 (s, 3H).

[0864] LCMS m/z 248.3 (M+H).sup.+ (ES.sup.+).

Intermediate P30: (R)-1-(2-Hydroxypropyl)-1H-1,2,4-triazole-3-sulfonamide

Step A: (R)-1-(3-(Benzylthio)-1H-1,2,4-triazol-1-yl)propan-2-ol

[0865] ##STR00142##

[0866] Prepared according to the general procedure of (R)-1-(4-(benzylthio)-2H-1,2,3-triazol-2-yl)propan-2-ol (Intermediate P26, Step A) from 3-(benzylthio)-1H-1,2,4-triazole and (R)-2-methyloxirane to afford the title compound (1.01 g, 35.6%) and (R)-1-(3-(benzylthio)-4H-1,2,4-triazol-4-yl)propan-2-ol (783 mg, 30%), both as yellow oils. .sup.1H NMR (DMSO-d6) 8.43 (s, 1H), 7.38 (d, J=7.2 Hz, 2H), 7.34-7.20 (m, 3H), 4.98 (d, J=4.7 Hz, 1H), 4.32 (s, 2H), 4.10-3.90 (m, 3H), 1.05 (d, J=5.8 Hz, 3H).

[0867] LCMS; m/z 250.3 (M+H).sup.+ (ES.sup.+).

Step B: (R)-1-(2-(Benzyloxy)propyl)-3-(benzylthio)-1H-1,2,4-triazole

[0868] ##STR00143##

[0869] Prepared according to the general procedure of (R)-2-(2-(benzyloxy)propyl)-4-(benzylthio)-2H-1,2,3-triazole (Intermediate P26, Step B) from (R)-1-(3-(benzylthio)-1H-1,2,4-triazol-1-yl)propan-2-ol to afford the title compound (923 mg, 65%) as a colourless oil.

[0870] .sup.1H NMR (DMSO-d6) 8.47 (s, 1H), 7.39-7.33 (m, 2H), 7.32-7.18 (m, 6H), 7.16-7.11 (m, 2H), 4.47 (d, J=12.0 Hz, 1H), 4.32-4.28 (m, 3H), 4.23 (dd, J=14.1, 4.3 Hz, 1H), 4.17 (dd, J=14.1, 7.1 Hz, 1H), 3.89-3.80 (m, 1H), 1.13 (d, J=6.3 Hz, 3H).

[0871] LCMS; m/z 340.2 (M+H).sup.+ (ES.sup.+).

Step C: (R)-1-(2-(Benzyloxy)propyl)-1H-1,2,4-triazole-3-sulfonamide

[0872] ##STR00144##

[0873] Prepared according to the general procedure of (R)-2-(2-(benzyloxy)propyl)-2H-1,2,3-triazole-4-sulfonamide (Intermediate P26, Step C) from (R)-1-(2-(benzyloxy)propyl)-3-(benzylthio)-1H-1,2,4-triazole to afford the title compound (314 mg, 37%) as a colourless solid.

[0874] .sup.1H NMR (DMSO-d6) 8.66 (s, 1H), 7.76 (bs, 2H), 7.34-7.23 (m, 3H), 7.19-7.13 (m, 2H), 4.53 (d, J=12.1 Hz, 1H), 4.41-4.29 (m, 3H), 3.96-3.88 (m, 1H), 1.18 (d, J=6.3 Hz, 3H).

[0875] LCMS; m/z 297.2 (M+H).sup.+ (ES.sup.+).

Step D: (R)-1-(2-Hydroxypropyl)-1H-1,2,4-triazole-3-sulfonamide

[0876] ##STR00145##

[0877] Prepared according to the general procedure of (R)-2-(2-hydroxypropyl)-2H-1,2,3-triazole-4-sulfonamide (Intermediate P26, Step D) from (R)-1-(2-(benzyloxy)propyl)-1H-1,2,4-triazole-3-sulfonamide to afford the title compound (178 mg, 69%) as a colourless oil.

[0878] 1H NMR (DMSO-d6) 8.61 (s, 1H), 7.82-7.66 (m, 2H), 5.09 (d, J=5.0 Hz, 1H), 4.21 (dd, J=13.7, 4.0 Hz, 1H), 4.14-4.07 (m, 2H), 1.10 (d, J=6.2 Hz, 3H).

[0879] LCMS; m/z 207.4 (M+H).sup.+ (ES.sup.+).

Intermediate P31: 1-Cyclopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

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

[0880] ##STR00146##

[0881] To a solution of cyclopropylboronic acid (36.77 g, 428.04 mmol) in 1,2-dichloroethane (500 mL) was added 3-nitro-1H-pyrazole (44 g, 389.12 mmol), 2,2-bipyridine (60.77 g, 389.12 mmol) and Na.sub.2CO.sub.3 (64.59 g, 609.44 mmol) at 25 C. The mixture was stirred at 25 C. for 30 minutes. Then Cu(OAc).sub.2 (70.68 g, 389.12 mmol) was added and the reaction mixture was warmed to 70 C. and stirred at 70 C. for 15.5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography on silica gel (3-25% EtOAc/petroleum ether) to give crude product (26.7 g). The crude product was dissolved in pyrrolidine (10 mL) and the resulting mixture was stirred at 70 C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyrrolidine. The residue was diluted with H.sub.2O (33 mL) and the pH was adjusted to 5-6 with aqueous HCl solution (1 N). The mixture was extracted with EtOAc (350 mL). The combined organic layers were washed with brine (233 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (17.7 g, 30%) as a yellow oil.

[0882] .sup.1H NMR (CDCl.sub.3) 7.54 (d, 1H), 6.84 (d, 1H), 3.73-3.67 (m, 1H), 1.24-1.22 (m, 2H), 1.13-1.07 (m, 2H).

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

[0883] ##STR00147##

[0884] To a solution of 1-cyclopropyl-3-nitro-1H-pyrazole (36 g, 235.08 mmol) in EtOH (400 mL) was added a solution of NH.sub.4Cl (62.87 g, 1.18 mol, 41.09 mL) in H.sub.2 (150 mL). Then the reaction mixture was warmed to 60 C. and iron powder (39.38 g, 705.24 mmol) was added in portions. The reaction mixture was stirred at 60 C. for 16 hours and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3500 mL). The combined organic layers were washed with brine (2250 mL dried over NaSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3-50% EtOAc/petroleum ether) to give the title compound (20 g, 69%) as a yellow oil.

[0885] .sup.1H NMR (CDCl.sub.3) 7.14 (d, 1H), 5.11 (d, 1H), 3.57 (br s, 2H), 3.38-3.32 (m, 1H), 0.99-0.95 (m, 2H), 0.90-0.87 (m, 2H).

[0886] LCMS m/z 124.2 (M+H).sup.+ (ES.sup.+).

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

[0887] ##STR00148##

[0888] To a solution of 1-cyclopropyl-1H-pyrazol-3-amine (19 g, 154.28 mmol) in MeCN (500 mL) and H.sub.2O (50 mL) at 0 C. was added concentrated HCl solution (50 mL). Then an aqueous solution of NaNO.sub.2 (12.77 g, 185.13 mmol) in H.sub.2O (50 mL) was added slowly. The resulting solution was stirred at 0 C. for 40 minutes. AcOH (50 mL), CuCl.sub.2 (10.37 g, 77.14 mmol) and CuCl (763 mg, 7.71 mmol, 184.46 L) were added into the reaction mixture. Then SO.sub.2 gas (15 psi) was bubbled into the reaction mixture for 20 minutes at 0 C. The reaction mixture was stirred at 0 C. for 1 hour and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (250 mL) and extracted with EtOAc (3250 mL). The combined organic layers were washed with brine (2150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/petroleum ether) to give the title compound (14 g, 44%) as a yellow oil.

[0889] .sup.1H NMR (CDCl.sub.3) 7.62 (d, 1H), 6.83 (d, 1H), 3.78-3.72 (m, 1H), 1.28-1.24 (m, 2H), 1.16-1.12 (m, 2H).

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

[0890] ##STR00149##

[0891] To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride (28 g, 135.49 mmol) in THF (300 mL) was added triethylamine (27.42 g, 270.99 mmol, 37.72 mL) and bis(4-methoxybenzyl)amine (34.87 g, 135-49 mmol). The mixture was stirred at 25 C. for 1 hour. Then the reaction mixture was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3500 mL). The combined organic layers were washed with brine (2500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography (MeCN/NH.sub.3.H.sub.2O (0.5% NH.sub.3.H.sub.2O)) and the collected eluting solution was concentrated under reduced pressure to remove most of the MeCN. Then the mixture was extracted with EtOAc (31000 mL). The combined organic layers were washed with brine (2500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (30 g, 52%).

[0892] .sup.1H NMR (CDCl.sub.3) 7.49 (d, 1H), 7.08-7.06 (m, 4H), 6.79-6.77 (m, 4H), 6.62 (d, 1H), 4.32 (s, 4H), 3.80 (s, 6H), 3.68-3.64 (m, 1H), 1.15-1.13 (m, 2H), 1.09-1.06 (m, 2H).

[0893] LCMS m/z 428.2 (M+H).sup.+ (ES.sup.+).

Step E: 1-Cyclopropyl-5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0894] ##STR00150##

[0895] Prepared according to the general procedure of 5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step B) from 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide and oxetan-3-one to afford the title compound (830 mg, 63%) as a colourless solid.

[0896] 1H NMR (DMSO-d6) =7.08-7.03 (m, 4H), 6.89 (s, 1H), 6.84-6.79 (m, 4H), 6.77 (s, 1H), 4.95 (d, J=7.0 Hz, 2H), 4.78 (d, J=7.0 Hz, 2H), 4.21 (s, 4H), 3.77-3.69 (m, 1H), 3.72 (s, 6H), 1.09-0.93 (m, 4H).

[0897] LCMS; m/z 522.1 (M+Na).sup.+ (ES.sup.+).

Step F: 1-Cyclopropyl-N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[0898] ##STR00151##

[0899] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P29, Step A) from 1-cyclopropyl-5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (450 mg, 97%) as a pale yellow oil.

[0900] LCMS; m/z 536.4 (M+Na).sup.+ (ES.sup.+).

Step G: 1-Cyclopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[0901] ##STR00152##

[0902] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (101 mg, 87%) as a colourless solid.

[0903] LCMS m/z 273.9 (M+H).sup.+ (ES.sup.+).

Intermediate P32: 1-(tert-Butyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

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

[0904] ##STR00153##

[0905] To a solution of 1-(tert-butyl)-1H-pyrazole-3-sulfonyl chloride (40 g, 179.6 mmol) in THF (400 mL) was added TEA (54.53 g, 538.9 mmol, 75.00 mL) and bis(4-methoxybenzyl)amine (13.87 g, 53.9 mmol). The mixture was stirred at 25 C. for 16 hours. The reaction mixture was poured into H.sub.2O (1 L) and extracted with EtOAc (31 L). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30:1 to 2:1 petroleum ether/EtOAc) and then purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/CH.sub.3CN) to give the title compound (15 g, 19%) as a yellow oil. 1H NMR (CDCl.sub.3) 7.54 (d, 1H), 7.07 (d, 4H), 6.77 (d, 4H), 6.66 (d, 1H), 4.32 (s, 4H), 3.79 (s, 6H), and 1.60 (s, 9H).

[0906] LCMS: m/z 444.1 (M+H).sup.+ (ES.sup.+).

Step B: 1-(tert-Butyl)-5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0907] ##STR00154##

[0908] Prepared according to the general procedure of 5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step B) from 1-(tert-butyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide and oxetan-3-one to afford the title compound (330 mg, 19%) as a colourless solid.

[0909] 1H NMR (DMSO-d6) =7.09-7.03 (m, 4H), 6.90 (s, 1H), 6.86 (s, 1H), 6.85-6.79 (m, 4H), 4.95 (d, J=7.0, 2H), 4.68 (d, J=7.2, 2H), 4.24 (s, 4H), 3.72 (s, 6H), 1.53 (s, 9H).

[0910] LCMS; m/z 516.2 (M+H).sup.+ (ES.sup.+).

Step C: 1-(tert-Butyl)-N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[0911] ##STR00155##

[0912] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P29, Step A) from 1-(tert-butyl)-5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (310 mg, 94%) as a yellow oil.

[0913] LCMS; m/z 530.2 (M+H).sup.+ (ES.sup.+).

Step D: 1-(tert-Butyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[0914] ##STR00156##

[0915] Prepared according to the general procedure of 5-(3-hydroxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step C) from 1-(tert-butyl)-N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (80 mg, 7%) as a colourless solid.

[0916] 1H NMR (DMSO-d6) =7.43 (s, 2H), 6.88 (s, 1H), 4.91 (d, J=7.5 Hz, 2H), 4.76 (d, J=7.5 Hz, 2H), 3.00 (s, 3H), 1.52 (s, 9H).

Intermediate P33: 5-(3-Ethoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

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

[0917] ##STR00157##

[0918] A solution of n-BuLi (2.5 M in hexanes; 1.519 ml, 3.80 mmol) was added dropwise to a stirred solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (1.51 g, 3.72 mmol) in THF (30 ml) at 78 C. The reaction was stirred for 1 hour at 78 C. Then a solution of oxetan-3-one (0.268 ml, 4.10 mmol) in THF (1.5 mL) was added and the mixture was stirred for 10 minutes at 78 C., before warming to room temperature and stirring for 18 hours. Then the reaction mixture was cooled to 0 C. and sodium hydride (60% in mineral oil) (0.179 g, 4.47 mmol) was added portionwise. After 15 minutes, ethyl iodide (0.391 ml, 4.84 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 20 hours. A further portion of ethyl iodide (0.391 ml, 4.84 mmol) was added and the mixture was heated at 45 C. for 4 days. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution (10 mL) and diluted with EtOAc (50 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (250 mL) and the combined organic phases were washed with brine (30 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give a yellow oil. The crude material was purified by chromatography on silica gel (40 g column, 0-70% EtOAc/isohexane) to afford the title compound (1.394 g, 73%) as a white solid.

[0919] 1H NMR (DMSO-d6) 7.10-7.03 (m, 4H), 7.00 (s, 1H), 6.85-6.78 (m, 4H), 4.87 (d, J=7.3 Hz, 2H), 4.78 (d, J=7.3 Hz, 2H), 4.24 (s, 4H), 3.74 (s, 3H), 3.72 (s, 6H), 3.07 (q, J=7.0 Hz, 2H), 1.10 (t, J=7.0 Hz, 3H).

[0920] LCMS m/z 524.4 (M+Na).sup.+ (ES.sup.+).

Step B: 5-(3-Ethoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[0921] ##STR00158##

[0922] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 5-(3-ethoxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (555 mg, 76%) as a colourless solid.

[0923] LCMS m/z 262.4 (M+H).sup.+ (ES.sup.+).

Intermediate P34: 5-(3-Hydroxyoxetan-3-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide

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

[0924] ##STR00159##

[0925] Prepared according to the general procedure of N,N-bis-(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step A) from 1-isopropyl-1H-pyrazole-3-sulfonyl chloride to afford the title compound as a white solid (16.6 g, 80%). 1H NMR (DMSO-d6) 8.00 (d, J=2.4 Hz, 1H), 7.07-6.96 (m, 4H), 6.85-6.76 (m, 4H), 6.70 (d, J=2.4 Hz, 1H), 4.61 (sept, J=6.7 Hz, 1H), 4.20 (s, 4H), 3.71 (s, 6H), 1.44 (d, J=6.7 Hz, 6H).

[0926] LCMS m/z 452.2 (M+Na).sup.+ (ES.sup.+).

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

[0927] ##STR00160##

[0928] Prepared according to the general procedure of 5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step B) from N,N-bis-(4-methoxybenzyl)-1-isopropyl-1H-pyrazole-3-sulfonamide and oxetan-3-one to afford the title compound (1.8 g, 61%) as a colourless solid.

[0929] 1H NMR (DMSO-d6) 7.10-7.00 (m, 4H), 6.87 (s, 1H), 6.86-6.80 (m, 4H), 6.78 (s, 1H), 4.88 (d, J=7.1 Hz, 2H), 4.78 (d, J=6.9 Hz, 2H), 4.53-4.36 (m, 1H), 4.23 (s, 4H), 3.72 (s, 6H), 1.37 (d, J=6.5 Hz, 6H).

[0930] LCMS; m/z 524.4 (M+Na).sup.+ (ES.sup.+).

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

[0931] ##STR00161##

[0932] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 5-(3-hydroxyoxetan-3-yl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (260 mg, 95%) as a colourless solid.

[0933] 1H NMR (DMSO-d6) 7.41 (s, 2H), 6.75 (s, 1H), 6.72 (s, 1H), 4.89-4.82 (m, 2H), 4.81-4.73 (m, 2H), 4.42 (sept, J=6.5 Hz, 1H), 1.39 (d, J=6.5 Hz, 6H).

[0934] LCMS m/z 260.1 (MH).sup. (ES.sup.).

Intermediate P35: 1-Isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

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

[0935] ##STR00162##

[0936] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P29, Step A) from 5-(3-hydroxyoxetan-3-yl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P34, Step B) to afford the title compound (911 mg, 88%) as a colourless solid.

[0937] 1H NMR (DMSO-d6) 6.36-6.25 (m, 4H), 6.06-5.97 (m, 4H), 5.95 (s, 1H), 4.13-4.07 (m, 4H), 3.58-3.50 (m, 5H), 2.97 (s, 6H), 2.27 (s, 3H), 0.62 (d, J=6.5 Hz, 6H).

[0938] LCMS m/z 538.2 (M+Na).sup.+ (ES.sup.+).

Step B: 1-Isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[0939] ##STR00163##

[0940] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-isopropyl-N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (241 mg, 86%) as a colourless solid.

[0941] 1H NMR (DMSO-d6) 7.46 (s, 2H), 6.87 (s, 1H), 4.91-4.78 (m, 4H), 4.26 (sept, J=6.6 Hz, 1H), 3.32 (s, 3H), 1.38 (d, J=6.5 Hz, 6H).

[0942] LCMS m/z 276.30 (M+H).sup.+ (ES.sup.+).

Intermediate P36: 1-Ethyl-5-(3-hydroxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

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

[0943] ##STR00164##

[0944] To a solution of 1-ethyl-1H-pyrazole-3-sulfonyl chloride (41.0 g, 210 mmol) in THF (400 mL) was added TEA (63.9 g, 631 mmol) and bis(4-methoxybenzyl)amine (10.8 g, 42.1 mmol). The mixture was stirred at 25 C. for 1.5 hours. The reaction mixture was diluted with water (800 mL) and extracted with EtOAc (3800 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 in water/MeCN) to give the title compound (18.7 g, 21%) as a yellow oil.

[0945] .sup.1H NMR (CDCl.sub.3) 7.44 (d, 1H), 7.06 (d, 4H), 6.77 (d, 4H), 6.64 (d, 1H), 4.32 (s, 4H), 4.27-4.21 (m, 2H), 3.79 (s, 6H), 1.52 (t, 3H).

[0946] LCMS: m/z 416.1 (M+H).sup.+ (ES.sup.+).

Step B: 1-Ethyl-5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0947] ##STR00165##

[0948] Prepared according to the general procedure of 5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step B) from 1-ethyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide and oxetan-3-one to afford the title compound (902 mg, 78%) as a pale yellow oil. 1H NMR (DMSO-d6) 7.09-7.02 (m, 4H), 6.88 (s, 1H), 6.85-6.77 (m, 5H), 4.87 (d, 2H), 4.76 (d, 2H), 4.23 (s, 4H), 4.07 (q, 2H), 3.72 (s, 6H), 1.34 (t, 3H). Exchangeable proton not visible.

[0949] LCMS; m/z 510.4 (M+Na).sup.+ (ES.sup.+).

Step C: 1-Ethyl-5-(3-hydroxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[0950] ##STR00166##

[0951] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-ethyl-5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (127 mg, 83%) as a colourless solid.

[0952] LCMS m/z 248.4 (M+H).sup.+ (ES.sup.+).

Intermediate P37: 1-Ethyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

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

[0953] ##STR00167##

[0954] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P29, Step A) from 1-ethyl-5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P36, Step B) to afford the title compound (480 mg, 77%) as a pale yellow oil.

[0955] LCMS m/z 524.5 (M+Na).sup.+ (ES.sup.+).

Step B: 1-Ethyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[0956] ##STR00168##

[0957] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 1-ethyl-N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (189 mg, 76%) as a colourless solid.

[0958] LCMS m/z 262.4 (M+H).sup.+ (ES.sup.+).

Intermediate P38: 5-(3-Methoxytetrahydrofuran-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

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

[0959] ##STR00169##

[0960] Prepared according to the general procedure of 5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step B) from N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide and dihydrofuran-3(2H)-one to afford the title compound (114 mg, 16%) as a colourless solid.

[0961] 1H NMR (DMSO-d6) 7.06 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.57 (s, 1H), 4.21 (s, 4H), 3.98 (s, 3H), 3.99-3.80 (m, 3H), 3.71 (s, 6H), 3.33 (s, 2H), 2.27 (dd, J=7.8, 6.2 Hz, 2H).

[0962] LCMS; m/z 510.3 (M+Na).sup.+ (ES.sup.+).

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

[0963] ##STR00170##

[0964] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P29, Step A) from 5-(3-hydroxytetrahydrofuran-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (80 mg, 71%) as a yellow oil. 1H NMR (DMSO-d6) 7.07 (d, J=8.7 Hz, 4H), 6.82 (d, J=8.7 Hz, 4H), 6.69 (s, 1H), 4.23 (s, 4H), 4.13 (dd, J=9.7, 1.0 Hz, 1H), 3.91 (s, 3H), 3.90-3.79 (m, 3H), 3.71 (s, 6H), 2.93 (s, 3H), 2.48-2.41 (m, 1H), 2.25 (dt, J=13.2, 8.3 Hz, 1H).

[0965] LCMS m/z 502.1 (M+H).sup.+ (ES.sup.+).

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

[0966] ##STR00171##

[0967] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-5-(3-methoxytetrahydrofuran-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (43 mg, 98%) as a brown oil.

[0968] 1H NMR (DMSO-d6) 7.41 (s, 2H), 6.67 (s, 1H), 4.14 (dd, J=9.7, 1.0 Hz, 1H), 3.91 (s, 3H), 3.91-3.81 (m, 3H), 2.96 (s, 3H), 2.50-2.42 (m, 1H), 2.28 (dt, J=13.1, 8.3 Hz, 1H).

[0969] LCMS m/z 262.4 (M+H).sup.+ (ES.sup.+).

Intermediate P39: 5-(3-Fluorooxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

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

[0970] ##STR00172##

[0971] 5-(3-Hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step B) (0.5 g, 1.003 mmol) was dissolved in DCM (10 mL) and DBU (0.3 ml, 1.990 mmol) was added follow by XtalFluor-E (0.35 g, 1.528 mmol) as a solid in a single portion. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with sat aq NaHCO.sub.3 (5 mL) and stirred for 1 hour at room temperature. The organic phase was dried by passing through a hydrophobic frit and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (0.113 g, 22%) as a colourless solid on standing. 1H NMR (CDCl.sub.3) 7.14-7.07 (m, 4H), 6.82-6.76 (m, 4H), 6.57 (d, J=2.4 Hz, 1H), 5.11 (ddd, J=20.1, 8.1, 1.3 Hz, 2H), 4.90 (ddd, J=21.3, 8.1, 1.3 Hz, 2H), 4.34 (s, 4H), 3.83 (d, J=1.5 Hz, 3H), 3.78 (s, 6H).

[0972] LCMS; m/z 498 (M+Na).sup.+ (ES.sup.+).

Step B: 5-(3-Fluorooxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[0973] ##STR00173##

[0974] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 5-(3-fluorooxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (48 mg, 96%) as a yellow solid.

[0975] 1H NMR (DMSO-d6) 7.51 (s, 2H), 7.03 (d, J=2.6 Hz, 1H), 5.20-4.96 (m, 4H), 3.81 (d, J=1.3 Hz, 3H).

[0976] LCMS m/z 236.4 (M+H).sup.+ (ES.sup.+); 234 (MH).sup. (ES.sup.).

Intermediate P40: 5-(2-Hydroxy-2-methylpropyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: 5-(2-Hydroxy-2-methylpropyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0977] ##STR00174##

[0978] Prepared according to the general procedure of 5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step B) from N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide and isobutylene oxide to afford the title compound (152 mg, 12%) as a colourless solid.

[0979] 1H NMR (CDCl.sub.3) 7.12-7.08 (m, 4H), 6.81-6.77 (m, 4H), 6.48 (s, 1H), 4.34 (s, 4H), 3.93 (s, 3H), 3.80 (s, 6H), 2.82 (s, 2H), 1.31 (s, 6H). Exchangeable proton not visible.

Step B: 5-(2-Hydroxy-2-methylpropyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0980] ##STR00175##

[0981] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from 5-(2-hydroxy-2-methylpropyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (51 mg, 55%) as a colourless solid.

[0982] 1H NMR (DMSO-d6) 7.30 (s, 2H), 6.41 (s, 1H), 4.57 (s, 1H), 3.83 (s, 3H), 2.75 (s, 2H), 1.15 (s, 6H).

[0983] LCMS m/z 234 (M+H).sup.+ (ES.sup.+).

Intermediate P41: 5-(4-Hydroxytetrahydro-2H-pyran-4-yl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: 5-(4-Hydroxytetrahydro-2H-pyran-4-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0984] ##STR00176##

[0985] Prepared according to the general procedure of 5-(3-hydroxyoxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step B) from N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide and dihydro-2H-pyran-4(3H)-one to afford the title compound (483 mg, 48%) as a colourless solid. 1H NMR (DMSO-d6) 7.20-6.96 (m, 4H), 6.93-6.70 (m, 4H), 6.46 (s, 1H), 5.56 (br s, 1H), 4.21 (s, 4H), 4.03 (s, 3H), 3.81-3.60 (m, 10H), 1.97-1.75 (m, 4H).

[0986] LCMS m/z 502.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-(4-Hydroxytetrahydro-2H-pyran-4-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[0987] ##STR00177##

[0988] Prepared according to the general procedure of 5-(3-hydroxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step C) from 5-(4-hydroxytetrahydro-2H-pyran-4-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (197 mg, 85%) as a colourless solid.

[0989] 1H NMR (DMSO-d6) 7.36 (s, 2H), 6.46 (s, 1H), 5.56 (s, 1H), 4.02 (s, 3H), 3.87-3.51 (m, 4H), 2.02-1.71 (m, 4H).

[0990] LCMS m/z 262.1 (M+H).sup.+ (ES.sup.+); 260.1 (MH).sup. (ES.sup.).

Intermediate P42: 1-(Oxazol-2-ylmethyl)-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-(oxazol-2-ylmethyl)-1H-pyrazole-3-sulfonamide

[0991] ##STR00178##

[0992] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-(chloromethyl)oxazole to afford the title compound (523 mg, 83%) as a colourless crystalline solid.

[0993] 1H NMR (CDCl.sub.3) 7.68 (d, J=0.9 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.17 (d, J=1.0 Hz, 1H), 7.06-6.99 (m, 4H), 6.79-6.72 (m, 4H), 6.69 (d, J=2.4 Hz, 1H), 5.50 (s, 2H), 4.30 (s, 4H), 3.78 (s, 6H).

[0994] LCMS; m/z 491 (M+Na).sup.+ (ES.sup.+).

Step B: 1-(Oxazol-2-ylmethyl)-1H-pyrazole-3-sulfonamide

[0995] ##STR00179##

[0996] Prepared according to the general procedure of 1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(oxazol-2-ylmethyl)-1H-pyrazole-3-sulfonamide to afford the title compound (146 mg, 59%) as a colourless crystalline solid.

[0997] 1H NMR (DMSO-d6) 8.14 (d, J=0.9 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.45 (s, 2H), 7.25 (d, J=0.8 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 5.64 (s, 2H).

Intermediate P43: 2-Methyl-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazole-4-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-2-methyl-1H-imidazole-4-sulfonamide

[0998] ##STR00180##

[0999] 2-Methyl-1H-imidazole-4-sulfonylchloride (1 g, 5.5 mmol) was suspended in DCM (30 mL) at room temperature. To this suspension was added bis(4-methoxybenzyl)amine (1.5 g, 6 mmol) and potassium tert-butoxide (0.25 g, 2 mmol) and the mixture was stirred for 18 hours at room temperature. The DCM layer was washed with water and brine, dried (sodium sulfate), filtered and evaporated. The residue was further purified by column chromatography on silica gel (0-5% MeOH/DCM) to afford the title compound (2.4 g, 100%) as a brown oil.

[1000] .sup.1H NMR (CDCl.sub.3): 7.37 (s, 1H), 7.07 (d, 4H), 6.76 (d, 4H), 4.30 (s, 4H), 3.80 (s, 6H), 2.43 (s, 3H).

Step B: 2-Methyl-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazole-4-sulfonamide

[1001] ##STR00181##

[1002] N,N-Bis(4-methoxybenzyl)-2-methyl-1H-imidazole-4-sulfonamide (280 mg, 0.64 mmol) was dissolved in DMF (1 mL). Potassium carbonate (500 mg, 3.6 mmol) was added, followed by 3-bromomethylfuran (400 mg, 2.5 mmol). The reaction mixture was stirred for 48 hours at room temperature. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried (sodium sulphate), filtered and evaporated. The residue was purified by chromatography over silica gel to afford the title compound (242 mg, 78%) as a solid.

[1003] .sup.1H NMR (CDCl.sub.3) 7.45 (s, 1H), 7.10 (d, 4H), 6.76 (d, 4H), 4.32 (s, 4H), 3.97 (dd, 1H), 3.82 (m, 2H), 3.78 (s, 6H), 2.44 (s, 3H), 2.07 (m, 1H), 1.89 (m, 2H), 1.61 (m, 1H).

Step C: 2-Methyl-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazole-4-sulfonamide

[1004] ##STR00182##

[1005] N,N-Bis(4-methoxybenzyl)-2-methyl-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazole-4-sulfonamide (0.2 g, 0.42 mmol) was dissolved in DCM (10 mL). Trifluoroacetic acid (10 mL) was added and the mixture was stirred for 18 hours at room temperature. The solvents were evaporated and a 7N solution of ammonia in methanol was added to the residue. The solvents were evaporated and the residue was triturated with water, filtered and lyophilized. The residue was further purified by chromatography over silica gel (3.5 M ammonia in methanol/DCM) to afford the title compound (45 mg, 45%) as a white solid.

[1006] .sup.1H NMR (CD.sub.3OD) 7.56 (s, 1H), 4.11 (m, 2H), 3.96 (dd, 1H), 3.80 (m, 2H), 2.40 (s, 3H), 2.07 (m, 1H), 1.89 (m, 2H), 1.61 (m, 1H).

Intermediate P44: 1-(2-Hydroxyethyl)-2-methyl-1H-imidazole-4-sulfonamide

Step A: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-N,N-bis(4-methoxybenzyl)-2-methyl-1H-imidazole-4-sulfonamide

[1007] ##STR00183##

[1008] N,N-Bis(4-methoxybenzyl)-2-methyl-1H-imidazole-4-sulfonamide (Intermediate P43, Step A) (280 mg, 0.64 mmol) was dissolved in DMF (10 mL). Potassium carbonate (500 mg, 3.6 mmol) was added, followed by (2-bromoethoxy)(tert-butyl)dimethylsilane (600 mg, 2.5 mmol). The reaction mixture was stirred for 48 hours at room temperature. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried (sodium sulphate), filtered and evaporated. The residue was purified over silica to afford the title compound (350 mg, 100%).

[1009] .sup.1H NMR (CDCl.sub.3) 7.40 (s, 1H), 7.10 (d, 4H), 6.76 (d, 4H), 4.29 (s, 4H), 3.97 (t, 2H), 3.86 (t, 2H), 3.78 (s, 6H), 2.45 (s, 3H), 0.84 (s, 9H), 0.03 (s, 6H).

Step B: 1-(2-Hydroxyethyl)-N,N-bis(4-methoxybenzyl)-2-methyl-1H-imidazole-4-sulfonamide

[1010] ##STR00184##

[1011] 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-N,N-bis(4-methoxybenzyl)-2-methyl-1H-imidazole-4-sulfonamide (350 mg, 0.63 mmol) was dissolved in DCM (10 mL). Tetrabutylammonium fluoride (0.60 g, 1.90 mmol) was added and the mixture was stirred overnight at room temperature. The DCM layer was washed with brine, dried, filtered and evaporated to afford the title compound, which was used as such for the next step.

Step C: 1-(2-Hydroxyethyl)-2-methyl-1H-imidazole-4-sulfonamide

[1012] ##STR00185##

[1013] 1-(2-Hydroxyethyl)-N,N-bis(4-methoxybenzyl)-2-methyl-1H-imidazole-4-sulfonamide (0.28 g, 0.64 mmol) was dissolved in DCM (10 mL). Trifluoroacetic acid (10 mL) was added and the mixture was stirred for 18 hours at room temperature. The solvents were evaporated and a 7N solution of ammonia in methanol was added to the residue. The solvents were evaporated and the residue was triturated with water, filtered and lyophilized. The residue was further purified by chromatography over silica gel (3.5 M ammonia in methanol/DCM) to afford the title compound (340 mg, 100%) as a solid, still containing inorganic salts.

[1014] .sup.1H NMR (CD.sub.3OD) 7.59 (s, 1H), 4.07 (t, 2H), 3.81 (t, 2H), 2.42 (s, 3H).

Intermediate P45: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt

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

[1015] ##STR00186##

[1016] 2 M Sodium tert-butoxide in THF (1.005 mL, 2.009 mmol) was added to a solution of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (0.5 g, 1-914 mmol) in THF (15 mL) and stirred at room temperature for 1 hour to give a white suspension. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.419 g, 2.105 mmol) in THF (5 mL) was added and stirred at room temperature overnight. The resultant colourless precipitate was collected by filtration, washing with THF (4 mL), and dried in vacuo to afford the title compound (930 mg, 91%) as a colourless solid. .sup.1H NMR (DMSO-d.sub.6) 7.51 (s, 1H), 6.96 (s, 1H), 6.77 (s, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 2.74 (t, J=7.4 Hz, 4H), 2.66 (t, J=7.3 Hz, 4H), 1.90 (p, J=7.4 Hz, 4H), 1.30 (t, J=7.1 Hz, 3H).

[1017] LCMS; m/z 433.4 (M+H).sup.+ (ES.sup.+).

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

[1018] ##STR00187##

[1019] Ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt (3.15 g, 6.24 mmol) was dissolved in MeOH (20 mL), 2 M aqueous NaOH (3.12 mL, 6.24 mmol) was added and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (2.80 g, 99%) as a colourless solid.

[1020] .sup.1H NMR (DMSO-d.sub.6) 7.57 (s, 1H), 6.76 (s, 1H), 6.44 (s, 1H), 4.02 (s, 3H), 2.74 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.89 (p, J=7.4 Hz, 4H).

[1021] LCMS; m/z 405.4 (M+H).sup.+ (ES.sup.+).

Intermediate P46: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-1-carboxylic acid, disodium salt

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

[1022] ##STR00188##

[1023] Prepared according to the general procedure of ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt (Intermediate P45, Step A) from ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate and 2-isocyanato-1,3-diisopropylbenzene (Intermediate A6) to afford the title compound as a colourless solid (2.16 g, 60%)

[1024] 1H NMR (DMSO-d6) 7.35 (s, 1H), 7.15-7.05 (m, 1H), 7.05-6.95 (m, 2H), 6.93 (s, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 3.20-3.02 (m, 2H), 1.28 (t, J=7.1 Hz, 3H), 1.03 (d, J=6.9 Hz, 12H).

[1025] LCMS; m/z 437.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-s-carboxylic acid, disodium salt

[1026] ##STR00189##

[1027] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P45, Step B) from ethyl 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt to afford the title compound (2.0 g, 99%) as a colourless solid.

[1028] 1H NMR (DMSO-d6) 7.44 (s, 1H), 7.13-7.05 (m, 1H), 7.05-6.94 (m, 2H), 6.42 (s, 1H), 4.00 (s, 3H), 3.16-3.03 (m, 2H), 1.01 (d, J=6.8 Hz, 12H).

[1029] LCMS; m/z 409.4 (M+H).sup.+ (ES.sup.+).

Intermediate P47: 5-(3-(Dimethylamino)oxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

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

[1030] ##STR00190##

[1031] A solution of n-BuLi (2.5 M in hexanes; 0.70 mL, 1.750 mmol) was added dropwise to a stirred solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step A) (0.70 g, 1.74 mmol) in THF (15 mL) at 78 C. The reaction was stirred for 1 hour, then a solution of 2-methyl-N-(oxetan-3-ylidene) propane-2-sulfinamide (0.40 g, 2.28 mmol) in THF (5 mL) was added. The reaction mixture was left at 78 C. for 5 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with DCM (320 mL). The organic extracts were dried (MgSO.sub.4), filtered and concentrated in vacuo. The resultant orange gum was dissolved in MeOH (18 mL) and HCl (3.7 M in 1,4-dioxane, 1.7 mL, 6.29 mmol) was added. The solution was stirred for 16 hours and then concentrated in vacuo. The crude product was loaded onto a column (SCX; 5 g) in MeOH and the column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (0.25 g, 41%) as a thick brown gum.

[1032] .sup.1H NMR (DMSO-d.sub.6) 7.09-7.04 (m, 4H), 6.86-6.8 (m, 4H), 6.79 (s, 1H), 4.87 (d, J=6.4 Hz, 2H), 4.65 (d, J=6.4 Hz, 2H), 4.22 (s, 4H), 3.84 (s, 3H), 3.71 (s, 6H), 3.16 (s, 2H).

[1033] LCMS; m/z 473.5 (M+H).sup.+ (ES.sup.+).

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

[1034] ##STR00191##

[1035] A solution of 5-(3-aminooxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.25 g, 0.41 mmol), formaldehyde (37% in H.sub.2O, 10% MeOH) (0.31 mL, 4.16 mmol) and formic acid (0.16 mL, 4.17 mmol) was stirred at 60 C. for 18 hours. The mixture was concentrated in vacuo and the crude product was loaded onto a column (SCX; 1 g) in MeOH and the column was washed with MeOH and then the product was eluted with 0.7 M ammonia in DCM:MeOH (9:1.50 mL). The resultant mixture was concentrated in vacuo to afford the title compound (0.17 g, 61%) as an orange oil.

[1036] .sup.1H NMR (DMSO-d6) 7.11-7.03 (m, 4H), 6.86-6.78 (m, 4H), 6.77 (s, 1H), 4.93 (d, J=7.2 Hz, 2H), 4.74 (d, J=7.2 Hz, 2H), 4.23 (s, 4H), 3.75 (s, 3H), 3.72 (s, 6H), 2.19 (s, 6H).

[1037] LCMS m/z 501.4 (M+H).sup.+ (ES.sup.+).

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

[1038] ##STR00192##

[1039] 5-(3-(Dimethylamino)oxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.17 g, 0.25 mmol) was dissolved in TFA (3 mL) and stirred at room temperature for 23 hours. Additional TFA (3 mL) was added and the mixture was stirred for a further 3 hours at room temperature. The mixture was then evaporated to dryness and purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford an orange solid. The product was further purified by precipitation on addition of isohexane to a solution of the product in 19:1 DCM:MeOH. The product was collected by filtration to afford the title compound (65 mg, 84%) as an orange solid.

[1040] .sup.1H NMR (DMSO-d.sub.6) 7.46 (s, 2H), 6.79 (s, 1H), 5.00 (d, J=7.6 Hz, 2H), 4.85 (d, J=7.6 Hz, 2H), 3.76 (s, 3H), 2.38 (br s, 6H).

[1041] LCMS; m/z 261.1 (M+H).sup.+ (ES.sup.+).

Intermediate P48: 5-(((2-Hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

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

[1042] ##STR00193##

[1043] A solution of n-BuLi (2.5M in hexanes; 4.0 ml, 10 mmol) was added dropwise to a stirred solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28, Step A) (4.00 g, 9.96 mmol) in THF (40 mL) at 78 C. The reaction was stirred for 1 hour. Then DMF (0.85 ml, 11.0 mmol) in THF (15 mL) were added dropwise, whilst maintaining the temperature below 65 C. The reaction mixture was stirred for a further 1 hour at 78 C. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc (350 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g column, 0-60% EtOAc/isohexane) to afford the title compound (4.0 g, 93%) as a white solid.

[1044] .sup.1H NMR (DMSO-d6) 9.90 (s, 1H), 7.41 (s, 1H), 7.11-7.02 (m, 4H), 6.87-6.78 (m, 4H), 4.25 (s, 4H), 4.17 (s, 3H), 3.72 (s, 6H).

[1045] LCMS m/z 448.1 (M+H.sub.3O)+(ES.sup.+).

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

[1046] ##STR00194##

[1047] 2-(Methylamino)ethanol (112 L, 1.40 mmol) was added to a solution of 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.40 g, 0.93 mmol) in dry THF (20 mL) containing 4 molecular sieves and stirred for 1 hour. Sodium triacetoxyborohydride (0.30 g, 1.42 mmol) and acetic acid (6 L, 0.1 mmol) were added and the reaction was stirred at room temperature for 3 days. An additional portion of acetic acid (54 L, 0.94 mmol) was added and the reaction mixture stirred for 20 hours at 60 C. Then 2-(methylamino)ethanol (112 L, 1.39 mmol) and more sodium triacetoxyborohydride (0.30 g, 1.42 mmol) were added and the reaction was heated at 60 C. for another 20 hours. The reaction was quenched with water (1 mL) and loaded onto a column (SCX). The column was washed with 20% MeOH in DCM and then the crude product was eluted with 0.7M ammonia in DCM:MeOH (9:1, 50 mL). The resultant mixture was concentrated in vacuo and the crude product was further purified by chromatography on silica gel (12 g column, 0-20% (0.7M ammonia in MeOH)/DCM) to afford the title compound (0.19 g, 41%) as a colourless gum.

[1048] .sup.1H NMR (DMSO-d.sub.6) 7.07-6.99 (m, 4H), 6.86-6.77 (m, 4H), 6.61 (s, 1H), 4.49 (t, J=5.3 Hz, 1H), 4.20 (s, 4H), 3.91 (s, 3H), 3.72 (s, 6H), 3.60 (s, 2H), 3.54 (td, J=5.2, 6.1 Hz, 2H), 2.47 (t, J=6.1 Hz, 2H), 2.17 (s, 3H).

[1049] LCMS; m/z 489.2 (M+H).sup.+ (ES.sup.+).

Step C: 5-(((2-Hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1050] ##STR00195##

[1051] 5-(((2-Hydroxyethyl)(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.19 g, 0.39 mmol) was dissolved in TFA (5.0 mL, 65 mmol) and stirred for 4 hours. The solution was diluted with toluene (20 mL) and concentrated in vacuo. The crude product was loaded onto a column (SCX) in THF and the column was washed with MeOH and then the product was eluted with 0.7M ammonia in 10% MeOH/DCM. The resultant mixture was concentrated in vacuo to afford the title compound (95 mg, 95%) as a colourless gum.

[1052] .sup.1H NMR (DMSO-d6) 7.34 (s, 2H), 6.49 (s, 1H), 4.47 (t, J=5.3 Hz, 1H), 3.87 (s, 3H), 3.58 (s, 2H), 3.56-3.48 (m, 2H), 2.45 (t, J=6.1 Hz, 2H), 2.17 (s, 3H).

[1053] LCMS m/z 249.1 (M+H).sup.+ (ES.sup.+).

Intermediate P49: 5-(((2-Methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-5-(((2-methoxyethyl)(methyl)amino) methyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1054] ##STR00196##

[1055] Prepared according to the general procedure of 5-(((2-hydroxyethyl)(methyl)amino) methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P48, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P48, Step A) and 2-methoxy-N-methylethanamine to afford the title compound (0.41 g, 86%) as a pale colourless oil.

[1056] .sup.1H NMR (DMSO-d6) 7.08-6.99 (m, 4H), 6.86-6.77 (m, 4H), 6.59 (s, 1H), 4.20 (s, 4H), 3.90 (s, 3H), 3.72 (s, 6H), 3.60 (s, 2H), 3.46 (t, J=5.7 Hz, 2H), 3.24 (s, 3H), 2.55 (t, J=5.7 Hz, 2H), 2.17 (s, 3H).

[1057] LCMS; m/z 503.4 (M+H).sup.+ (ES.sup.+).

Step B: 5-(((2-Methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1058] ##STR00197##

[1059] Prepared according to the general procedure of 5-(((2-hydroxyethyl)(methyl)amino) methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P48, Step C) from N,N-bis(4-methoxybenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.20 g, 91%) as a white solid. 15 .sup.1H NMR (DMSO-d6) 7.34 (s, 2H), 6.49 (s, 1H), 3.86 (s, 3H), 3.58 (s, 2H), 3.45 (t, J=5.8 Hz, 2H), 3.24 (s, 3H), 2.54 (t, J=5.8 Hz, 2H), 2.18 (s, 3H).

[1060] LCMS m/z 263.1 (M+H).sup.+ (ES.sup.+).

Intermediate P50: 1-Methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide

Step A: 5-(Hydroxymethyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1061] ##STR00198##

[1062] A solution of LiBH.sub.4 (2 M in THF; 4.3 mL, 8.6 mmol) was added dropwise over 5 minutes to a stirred solution of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (1.00 g, 4.29 mmol) in THF (10 mL) at 0 C. The reaction was allowed to warm to room temperature, stirred for 3 hours and then heated at 40 C. for 20 hours. The reaction was cooled to 0 C. LiAlH.sub.4 (2 M in THF; 0.55 mL, 1.10 mmol) was added and the reaction was stirred for a further 2 days at 40 C. The reaction was cooled to 0 C. and aqueous saturated ammonium chloride (10 mL) was cautiously added dropwise over 10 minutes. The mixture was allowed to warm to room temperature and EtOAc (30 mL) was added. The reaction mixture was stirred vigorously for 10 minutes and then filtered through a pad of Celite. The layers were separated and the aqueous layer was saturated with NaCl and extracted further with EtOAc (520 mL). The combined organic extracts were dried (MgSO.sub.4), filtered and evaporated in vacuo to afford the title compound (0.67 g, 78%) as a white solid.

[1063] .sup.1H NMR (DMSO-d.sub.6) 5.70 (s, 1H), 3.73 (s, 2H), 3.02 (s, 3H). Three exchangeable protons not observed.

[1064] LCMS; m/z 192.0 (M+H).sup.+ (ES.sup.+).

Step B: 5-Formyl-1-methyl-1H-pyrazole-3-sulfonamide

[1065] ##STR00199##

[1066] Manganese(IV) oxide (1.00 g, 11.5 mmol) was added to a solution of 5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.55 g, 2.88 mmol) in 1,2-dimethoxyethane (30 mL). The reaction mixture was stirred for 20 hours at room temperature and then at 40 C. for a further 6 hours. Further manganese(IV) oxide (0.50 g, 5.75 mmol) was added and the reaction was heated at 40 C. for 2 days. The mixture was cooled to room temperature and filtered through a pad of Celite, washing with 1,2-dimethoxyethane. The filtrate was concentrated in vacuo to afford the title compound (0.29 g, 52%), as a yellow gum.

[1067] .sup.1H NMR (DMSO-d.sub.6) 9.92 (s, 1H), 7.64 (s, 2H), 7.31 (s, 1H), 4.16 (s, 3H).

[1068] LCMS; m/z 189.9 (M+H).sup.+ (ES.sup.+).

Step C: 1-Methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide

[1069] ##STR00200##

[1070] Prepared according to the general procedure of 5-(((2-hydroxyethyl)(methyl)amino) methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P48, Step B) from 5-formyl-1-methyl-1H-pyrazole-3-sulfonamide and morpholine to afford the title (73 mg, 25%) as a colourless gum.

[1071] .sup.1H NMR (DMSO-d6) 7.36 (s, 2H), 6.50 (s, 1H), 3.87 (s, 3H), 3.57 (m, 4H), 3.56 (s, 2H), 2.37 (m, 4H).

[1072] LCMS m/z 261.0 (M+H).sup.+ (ES.sup.+).

Intermediate P51: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt

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

[1073] ##STR00201##

[1074] Prepared according to the general procedure of ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt (Intermediate P45, Step A) from ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate and 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A9) to afford the title compound (1.32 g, 92%) as a colourless solid.

[1075] 1H NMR (DMSO-d6), rotamers; 7.41 (s, 1H), 7.01 (s, 2H), 6.92 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 3.13 (br s, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.04 (d, J=6.8 Hz, 12H).

[1076] LCMS; m/z 471.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt

[1077] ##STR00202##

[1078] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P45, Step B) from ethyl 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt to afford the title compound (1.0 g, 77%) as a colourless solid.

[1079] 1H NMR (DMSO-d6) 7.49 (s, 1H), 7.00 (s, 2H), 6.42 (s, 1H), 4.01 (s, 3H), 3.09 (br s, 2H), 1.02 (d, J=6.8 Hz, 12H).

[1080] LCMS; m/z 443.4 (M+H).sup.+ (ES.sup.+).

Intermediate P52: N,N-Bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

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

[1081] ##STR00203##

[1082] A solution of 1-methyl-1H-pyrazol-3-amine (25 g, 257.42 mmol, 1 eq) in MeCN (600 mL) at 0 C. was treated with concentrated HCl (60 mL) and H.sub.2O (60 mL). Then an aqueous solution of NaNO.sub.2 (21.31 g, 308.90 mmol, 1.2 eq) in H.sub.2O (60 mL) was added slowly. The resulting mixture was stirred at 0 C. for 40 minutes. AcOH (6 mL), CuCl.sub.2 (17.31 g, 128.71 mmol, 0.5 eq) and CuCl (1.27 g, 12.87 mmol, 307.78 L, 0.05 eq) were added, then SO.sub.2 gas (15 psi) was bubbled into the mixture for 15 minutes at 0 C. The reaction mixture was concentrated in vacuo to remove most of the MeCN. Then the reaction mixture was treated with H.sub.2O (2.5 L) and extracted with EtOAc (21.2 L). The combined organic layers were washed with brine (32 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=15:1 to 5:1) to give the title compound (19 g, 41%) as a yellow oil.

[1083] .sup.1H NMR (CDCl.sub.3): 7.52 (d, 1H), 6.89 (d, 1H) and 4.07 (s, 3H).

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

[1084] ##STR00204##

[1085] To a solution of bis(4-methoxybenzyl)amine (99.83 g, 387.96 mmol, 0.91 eq) in THF (1 L) was added TEA (86.28 g, 852.65 mmol, 118.68 mL, 2 eq), followed by 1-methyl-1H-pyrazole-3-sulfonyl chloride (77 g, 426.33 mmol, 1 eq). Then the reaction mixture was stirred at 25 C. for 12 hours. The reaction mixture was concentrated in vacuo to remove most of the THF. The reaction mixture was quenched by addition of aqueous HCl (1 M, 500 mL) and then extracted with EtOAc (2500 mL). The combined organic layers were washed with brine (2600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of petroleum ether and ethyl acetate (70 mL, v:v=5:1) to give the title compound (138 g, 81%) as a white solid.

[1086] .sup.1H NMR (CDCl.sub.3): 7.40 (d, 1H), 7.08 (d, 4H), 6.78 (d, 4H), 6.65-6.63 (m, 1H), 4.32 (s, 4H), 3.98 (s, 3H) and 3.79 (s, 6H).

[1087] LCMS: m/z 402.2 (M+H).sup.+ (ES.sup.+).

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

[1088] ##STR00205##

[1089] A solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (100 g, 249.08 mmol, 1 eq) in THF (1.35 L) was cooled to 70 C. Then n-BuLi (2.5 M, 104.61 mL, 1.05 eq) was added dropwise. The reaction mixture was stirred at 70 C. for 1 hour, then CO.sub.2 (15 psi) was bubbled into the mixture for 15 minutes. The reaction mixture was stirred at 70 C. for another 1 hour. The reaction mixture was quenched with H.sub.2O (1.2 L) and adjusted with aqueous HCl (1 M) to pH=3. Then the mixture was extracted with EtOAc (21). The combined organic layers were washed with brine (21 L), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (300 mL, v:v=1:1) to give the title compound (94 g, 84% yield, 99% purity on LCMS) as a white solid.

[1090] .sup.1H NMR (DMSO-d.sub.6): 6.98-7.16 (m, 5H), 6.82 (d, 4H), 4.25 (s, 4H), 4.15 (s, 3H) and 3.72 (s, 6H).

[1091] LCMS: m/z 468.2 (M+Na).sup.+ (ES.sup.+).

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

[1092] ##STR00206##

[1093] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (8 g, 17.96 mmol, 1 eq) in DMF (100 mL) was added with HATU (10.24 g, 26.94 mmol, 1.5 eq), DIPEA (6.96 g, 53.87 mmol, 3 eq) and bis(2-methoxyethyl)amine (2.87 g, 21.55 mmol, 1.2 eq). The reaction mixture was stirred at 25 C. for 1 hour. Then the reaction mixture was diluted with EtOAc (50 mL), washed with saturated aqueous NH.sub.4C solution (350 mL) and brine (350 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.05% NH.sub.3.H.sub.2O-MeCN) to give the title compound (8 g, 79%) as a red oil.

[1094] .sup.1H NMR (CD.sub.3OD): 7.05 (d, 4H), 6.81-6.77 (m, 5H), 4.29 (s, 4H), 3.90 (s, 3H), 3.79-3.72 (m, 8H), 3.68-3.57 (m, 4H), 3.48-3.46 (m, 2H), 3.38 (s, 3H) and 3.27 (s, 3H).

[1095] LCMS: m/z 561.3 (M+H).sup.+ (ES.sup.+).

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

[1096] ##STR00207##

[1097] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (8 g, 14.27 mmol, 1 eq) in DCM (50 mL) was added TFA (56 g, 491.13 mmol, 34.42 eq). The reaction mixture was stirred at 25 C. for 12 hours and then concentrated in vacuo. The residue was triturated with a mixture of EtOAc and PE (50 mL, v:v=3:2) to give the title compound (4.0 g, 88%) as a white solid.

[1098] .sup.1H NMR (DMSO-d.sub.6): 7.50 (s, 2H), 6.74 (s, 1H), 3.84 (s, 3H), 3.63 (t, 4H), 3.43-340 (m, 4H), 3.28 (s, 3H) and 3.18 (s, 3H).

Intermediate P53: 1-(2-Hydroxy-2-methylpropyl)-1H-pyrazole-4-sulfonamide

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

[1099] ##STR00208##

[1100] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (500 mg, 1.29 mmol, 1 eq) in MeCN (10 mL) was added K.sub.2CO.sub.3 (356 mg, 2.58 mmol, 2 eq) and 2,2-dimethyloxirane (279 mg, 3.87 mmol, 343.78 L, 3 eq). The mixture was stirred at 80 C. for 12 hours under nitrogen. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The residue was triturated with a mixture of MTBE and EtOAc (20 mL, v:v=10:1) to give the title compound (550 mg, 1.08 mmol, 83% yield, 90% purity) as a white solid.

[1101] .sup.1H NMR (DMSO-d.sub.6): 8.24 (s, 1H), 7.78 (s, 1H), 7.08-7.04 (m, 4H), 6.82-6.79 (m, 4H), 4.15 (d, 4H), 4.08 (s, 2H), 3.71 (s, 6H) and 1.07 (s, 6H).

[1102] LCMS: m/z 460.0 (M+H).sup.+ (ES.sup.+).

Step B: 1-(2-Hydroxy-2-methylpropyl)-1H-pyrazole-4-sulfonamide

[1103] ##STR00209##

[1104] To a solution of 1-(2-hydroxy-2-methylpropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (500 mg, 979.20 mol, 1 eq) in DCM (4 mL) was added TFA (12.32 g, 108.05 mmol, 8 mL, 110.34 eq). The reaction mixture was stirred at 25 C. for 12 hours and then concentrated under reduced pressure. The residue was treated with resin (Amberlyst A-21, ion exchange resin) to give the title compound (150 mg, 615.70 mol, 63% yield, 90% purity) as a pale yellow oil, which was used into the next step without further purification.

[1105] .sup.1H NMR (DMSO-d.sub.6): 8.05 (s, 1H), 7.73 (s, 1H), 7.07-7.5 (br s, 2H), 4.06 (s, 2H) and 1.05 (d, 6H).

[1106] LCMS: m/z 219.9 (M+H).sup.+ (ES.sup.+).

Intermediate P54: (R)-1-(2-Hydroxypropyl)-1H-pyrazole-4-sulfonamide

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

[1107] ##STR00210##

[1108] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (400 mg, 1.03 mmol, 1 eq) in CH.sub.3CN (10 mL) was added K.sub.2CO.sub.3 (285 mg, 2.06 mmol, 2 eq) and (2R)-2-methyloxirane (120 mg, 2.06 mmol, 144.66 L, 2 eq). The mixture was stirred at 70 C. for 12 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to give the title compound (450 mg, crude) as a white solid, which was used directly in the next step.

[1109] LCMS: m/z 446.2 (M+H).sup.+ (ES.sup.+).

Step B: (R)-1-(2-Hydroxypropyl)-1H-pyrazole-4-sulfonamide

[1110] ##STR00211##

[1111] To a solution of (R)-1-(2-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (450 mg, 898.93 mol, 1 eq) in DCM (3 mL) was added TFA (9.24 g, 81.04 mmol, 6 mL, 90.15 eq). The reaction mixture was stirred at 25 C. for 12 hours and then concentrated under reduced pressure. The residue was treated with resin (Amberlyst A-21, ion exchange resin) to give the title compound (200 mg, crude) as a brown oil. .sup.1H NMR (DMSO-d.sub.6): 8.10 (s, 1H), 7.71 (s, 1H), 7.25 (s, 1H), 4.97 (d, 1H), 4.12-4.10 (m, 2H), 3.96-4.00 (m, 1H) and 1.05 (d, 3H).

[1112] LCMS: m/z 206.2 (M+H).sup.+ (ES.sup.+).

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

[1113] ##STR00212##

[1114] To a solution of phosgene (4.45 mL, 20% weight in toluene, 8.4 mmol) in EtOAc (90 mL) was added dropwise a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in EtOAc (45 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 3 hours and upon cooling was filtered and concentrated in vacuo to afford the title compound as a brown oil (756 mg, 100%). The crude product was used directly in the next step without further purification.

[1115] .sup.1H NMR (CDCl.sub.3) 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m, 4H).

Intermediate A2: 5-Fluoro-2-isocyanato-1,3-diisopropylbenzene

[1116] ##STR00213##

[1117] 4-Fluoro-2,6-diisopropylaniline (1 g, 5.12 mmol) and triethylamine (0.785 mL, 5.63 mmol) were dissolved in THF (10 mL) and cooled to 0 C. Triphosgene (0.760 g, 2.56 mmol) was added to the mixture portionwise and the reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated in vacuo. Isohexane (50 mL) was added and the suspension filtered through silica (3 g). The filtrate was dried under reduced pressure to afford the title compound (900 mg, 75%) as a colourless oil.

[1118] .sup.1H NMR (DMSO-d6) 6.80 (d, J=9.4 Hz, 2H), 3.27-3.12 (m, 2H), 1.23 (d, J=6.8 Hz, 12H).

Intermediate A3: 7-Fluoro-5-(pyridin-3-yl)-2,3-dihydro-1H-inden-4-amine

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

[1119] ##STR00214##

[1120] To an ice-cooled solution of N-(2,3-dihydro-1H-inden-4-yl)pivalamide (2.5 g, 11.50 mmol) in dry DCM (50 mL) was added pyridine hydrofluoride (9 mL, 69.9 mmol). The pale yellow mixture was stirred for 30 minuted at 0 C. A solution of bis(tert-butylcarbonyloxy)iodobenzene (7.5 g, 17.91 mmol) in DCM (10 mL) was then slowly added over 10 minutes. The reaction was slowly allowed to reach room temperature and stirred overnight. It was then quenched with triethylamine (0.5 mL, 3.58 mmol) and the mixture was absorbed onto silica gel and purified by chromatography on silica gel (120 g column, 0-30% EtOAc/isohexane) to afford the title compound (0.64 g, 22%) as a yellow crystalline solid.

[1121] .sup.1H NMR (CDCl.sub.3) 7.68 (dd, J=8.8, 4.5 Hz, 1H), 7.14 (s, 1H), 6.87 (t, J=8.6 Hz, 1H), 3.01 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.18 (p, J=7.5 Hz, 2H), 1.34 (s, 9H).

[1122] LCMS; m/z 236.3 (M+H).sup.+ (ES.sup.+); 234.2 (MH).sup. (ES.sup.).

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

[1123] ##STR00215##

[1124] N-(7-Fluoro-2,3-dihydro-1H-inden-4-yl)pivalamide (0.632 g, 2.69 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature. H.sub.2SO.sub.4 (95% aqueous) (5 mL, 89 mmol) was slowly added to water (5 mL) and this mixture was then added to the reaction mixture. The slurry was heated to 100 C. (bath temperature) over the weekend. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and then basified with 2 M aqueous NaOH. The mixture was extracted with DCM (3100 mL). The combined organic phases were washed, dried by passing through a hydrophobic frit and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-30% EtOAc/isohexane) to afford the title compound (350 mg, 82%) as a pale pink oil that solidified on standing.

[1125] .sup.1H NMR (CDCl.sub.3) 6.71 (dd, J=9.0, 8.2 Hz, 1H), 6.46 (dd, J=8.5, 3.9 Hz, 1H), 3.45 (s, 2H), 2.96 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.16 (p, J=7.6 Hz, 2H).

[1126] LCMS; m/z 152.3 (M+H).sup.+ (ES.sup.+).

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

[1127] ##STR00216##

[1128] 7-Fluoro-2,3-dihydro-1H-inden-4-amine (345 mg, 2.282 mmol) was dissolved in DCM (1 mL). NBS (450 mg, 2.53 mmol) was added at room temperature in a single portion. The mixture turned dark brown immediately and was stirred for 15 minutes at room temperature. The reaction mixture was partitioned between DCM (20 mL) and 1 M aqueous NaOH (20 mL) and stirred for 15 minutes. The organic phase was separated and washed with brine (1 mL), and then dried by passing through a hydrophobic frit. The solvent was removed in vacuo to give a dark brown oil. The crude product was purified by chromatography on silica gel (24 g column, 0-20% EtOAc/isohexane) to afford the title compound (323 mg, 55%) as a dark purple oil.

[1129] .sup.1H NMR (CDCl.sub.3) 7.08 (d, J=7.8 Hz, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.95 (t, J=7.5 Hz, 2H), 2.20 (p, J=7.6 Hz, 2H). NH.sub.2 not observed.

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

[1130] ##STR00217##

[1131] 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (0.45 g, 1-956 mmol) was dissolved in dioxane (5 mL). A solution of potassium carbonate (0.8 g, 5.79 mmol) in water (1 mL) was added along with pyridin-3-ylboronic acid (0.27 g, 2.197 mmol). The mixture was degassed with nitrogen for 15 minutes and then Pd(dppf)Cl.sub.2.DCM (0.080 g, 0.098 mmol) was added. The reaction mixture was heated to 80 C. (bath temperature) for 18 hours. The mixture was cooled to room temperature and partitioned between DCM (30 mL) and water (1 mL). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to give a brown solid. The crude product was purified by chromatography on silica gel (12 g column, 0-100% EtOAc/isohexane) to afford the title compound (0.32 g, 68%) as a green crystalline solid.

[1132] .sup.1H NMR (CDCl.sub.3) 8.79 (s, 1H), 8.65 (s, 1H), 8.00 (d, J=7.1 Hz, 1H), 7.56 (s, 1H), 6.71 (d, J=8.9 Hz, 1H), 3.04 (t, J=7.6 Hz, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.24 (p, J=7.5 Hz, 2H). NH.sub.2 not observed.

[1133] LCMS; m/z 229.3 (M+H).sup.+ (ES.sup.+).

Intermediate A4: 4-Fluoro-2-isopropyl-6-(pyridin-3-yl)aniline

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

[1134] ##STR00218##

[1135] N-Bromosuccinimide (5.64 g, 31.7 mmol) was added portionwise to 4-fluoro-2-isopropylaniline (4.62 g, 30.2 mmol) in DCM (72 mL) at 0 C. The resulting mixture was stirred at 0 C. for 1 hour and then left to warm to room temperature over 21 hours. The reaction mixture was washed with a solution of aqueous sodium hydroxide (2 M, 250 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give a brown residue. The crude product was then filtered through a plug of silica (50 g) and washed through with 50% DCM in iso-hexane (500 mL). The red filtrate was concentrated to dryness and the crude product was purified by chromatography on silica gel (120 g column, 0-10% DCM/iso-hexane) to afford the title compound (4.99 g, 70%) as a red oil.

[1136] .sup.1H NMR (CDCl.sub.3) 7.07 (dd, 1H), 6.86 (dd, 1H), 4.14 (s, 2H), 2.93 (sept, 1H) and 1.25 (d, 6H). NH.sub.2 not observed.

[1137] LCMS; m/z 232.2/234.3 (M+H).sup.+ (ES.sup.+).

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

[1138] ##STR00219##

[1139] To a stirred, nitrogen-degassed mixture of 2-bromo-4-fluoro-6-isopropylaniline (1.00 g, 4.27 mmol) was added pyridin-3-ylboronic acid (0.577 g, 4.69 mmol), Pd(dppf)Cl.sub.2 (0.156 g, 0.213 mmol) and potassium carbonate (1.769 g, 12.80 mmol) in a 10:1 mixture of 1,4-dioxane:water (33 mL). The reaction mixture was then heated to 80 C. under a nitrogen atmosphere for 2 days, left to cool to room temperature, filtered through a pad of Celite (10 g) and the filter cake washed with EtOAc (230 mL). The filtrate was poured onto water (50 mL) and the organic layer collected. The aqueous layer was extracted with EtOAc (220 mL). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to dryness. The crude product was purified by chromatography on silica gel (80 g column, 0-60% EtOAc/iso-hexane) to afford the title compound (273 mg, 27%) as a brown gum.

[1140] .sup.1H NMR (CDCl.sub.3) 8.70 (dd, 1H), 8.63 (dd, 1H), 7.82 (ddd, 1H), 7.48-7.34 (m, 1H), 6.94 (dd, 1H), 6.70 (dd, 1H), 2.93 (sept, 1H), 3.98-2.44 (br s, 2H) and 1.29 (d, 6H).

[1141] LCMS; m/z 231.1 (M+H).sup.+ (ES.sup.+).

[1142] The following intermediate was synthesised following the general procedure for Intermediate A4:

TABLE-US-00001 Intermediate Structure Analytical data A5 [00220] .sup.1H NMR (CDCl.sub.3) 8.25 (d, 1H), 7.00 (dd, 1H), 6.93 (dd, 1H), 6.85 (s, 1H), 6.71 (dd, 1H), 4.01 (s, 3H), 2.92 (sept, 1H) and 1.28 (d, 6H). Exchangeable NH.sub.2 observed as broad signal from 4.5-0.5 ppm. LCMS m/z 261.1 (M + H).sup.+ (ES.sup.+). (174 mg, 78%)

Intermediate A6: 2-Isocyanato-1,3-diisopropylbenzene

[1143] ##STR00221##

[1144] 2,6-Diisopropylaniline (3.07 g, 17-14 mmol) was dissolved in dry THF (40 mL) and Et.sub.3N (3 mL, 21.52 mmol) was added. A solution of triphosgene (4.26 g, 14.35 mmol) in dry THF (12 mL) was added over 5 minutes, resulting in the formation of a thick colourless precipitate. The reaction mixture was stirred at room temperature overnight. The THF was removed in vacuo and toluene (50 mL) was added. The mixture was filtered through a short silica plug eluting with toluene (150 mL). The filtrate was concentrated in vacuo to afford the title compound (2.76 g, 92%) as a colourless oil.

[1145] .sup.1H NMR (CDCl.sub.3) 7.20-7.10 (m, 3H), 3.22 (hept, J=6.9 Hz, 2H), 1.26 (d, J=6.8 Hz, 12H).

Intermediate A7: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine

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

[1146] ##STR00222##

[1147] To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (36.21 g, 215.51 mmol, 1.05 eq) and K.sub.2CO.sub.3 (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H.sub.2O (40 mL) was added Pd(dppf)Cl.sub.2 (7.51 g, 10.26 mmol, 0.05 eq) under N.sub.2 atmosphere. Then the reaction mixture was stirred at 80 C. for 5 hours. The reaction mixture was quenched by addition of H.sub.2O (600 mL) and extracted with EtOAc (2500 mL). The combined organic layers were washed with brine (2600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 100:1) to give the title compound (27 g, 77% yield, 89% purity on LCMS) as a yellow oil.

[1148] .sup.1H NMR (CDCl.sub.3): 6.81-6.76 (m, 2H), 6.66-6.62 (m, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 3.69 (br s, 2H) and 1.25 (s, 3H).

[1149] LCMS: m/z 152.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Fluoro-2-isopropylaniline

[1150] ##STR00223##

[1151] To a solution of 4-fluoro-2-(prop-1-en-2-yl)aniline (21 g, 138.91 mmol, 1 eq) in MeOH (300 mL) was added Pd/C (2.1 g, 178.59 mmol, 10 wt % loading on activated carbon) under N.sub.2 atmosphere. The reaction mixture was degassed in vacuo and purged with H.sub.2 several times. The reaction mixture was stirred at 25 C. for 12 hours under H.sub.2 (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (20 g, crude) as a yellow oil.

[1152] .sup.1H NMR (CDCl.sub.3): 6.86 (dd, 1H), 6.75-6.72 (m, 1H), 6.63-6.61 (m, 1H), 3.50 (br s, 2H), 2.95-2.84 (m, 1H) and 1.25 (d, 6H).

[1153] LCMS: m/z 154.2 (M+H).sup.+ (ES.sup.+).

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

[1154] ##STR00224##

[1155] To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 mL) was added NBS (23.24 g, 130-55 mmol, 1 eq) at 25 C. The reaction mixture was stirred at 25 C. for 10 minutes. Then the reaction mixture was poured into H.sub.2O (300 mL) and extracted with EtOAc (2250 mL). The organic phases were washed with brine (2400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting only by using petroleum ether) to give the title compound (30 g, 99%) as a black brown oil.

[1156] .sup.1H NMR (CDCl.sub.3): 6.99 (dd, 1H), 6.78 (dd, 1H), 3.91 (br s, 2H), 2.88-2.71 (m, 1H) and 1.17 (d, 6H).

[1157] LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

Step D: 4-Bromo-2-isopropoxypyridine

[1158] ##STR00225##

[1159] To a solution of 4-bromo-2-chloropyridine (20 g, 103.93 mmol, 1 eq) in THF (400 mL) was added NaH (6.24 g, 155.89 mmol, 60% purity, 1.5 eq) at 0 C. Then the mixture was stirred for 0.5 hour. Propan-2-ol (6.87 g, 114.32 mmol, 8.75 mL, 1.1 eq) was added and the resulting mixture was warmed to 50 C. and stirred for 12 hours. The reaction mixture was quenched with H.sub.2O (1 L) at 25 C. and extracted with EtOAc (2200 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=50:1 to 40:1) to give the title compound (22 g, 98%) as a light yellow oil.

[1160] .sup.1H NMR (CDCl.sub.3): 7.96 (d, 1H), 6.98 (dd, 1H), 6.89 (d, 1H), 5.44-5.24 (m, 1H) and 1.34 (d, 6H).

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

[1161] ##STR00226##

[1162] To a solution of 4-bromo-2-isopropoxypyridine (19 g, 87.93 mmol, 1 eq) and 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (22.33 g, 87.93 mmol, 1 eq) in 1,4-dioxane (300 mL) was added KOAc (25.89 g, 263.80 mmol, 3 eq) followed by Pd(dppf)Cl.sub.2 (1.93 g, 2.64 mmol, 0.03 eq) under nitrogen. Then the reaction mixture was heated to 80 C. and stirred for 12 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=50:1 to 20:1) to give the title compound (22 g, 95%) as a light yellow oil.

[1163] .sup.1H NMR (CDCl.sub.3): 8.16 (d, 1H), 7.13 (d, 1H), 7.08 (s, 1H), 5.32-5.24 (m, 1H), 1.34 (s, 12H) and 1.27 (s, 6H).

[1164] LCMS: m/z 264.2 (M+H).sup.+ (ES.sup.+).

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

[1165] ##STR00227##

[1166] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (10.94 g, 47.12 mmol, 1 eq) and 2-isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (12.4 g, 47.12 mmol, 1 eq) in 1,4-dioxane (200 mL) and H.sub.2O (20 mL) was added Pd(dppf)Cl.sub.2 (1.72 g, 2.36 mmol, 0.05 eq) followed by K.sub.2CO.sub.3 (19.54 g, 141-37 mmol, 3 eq) at 25 C. Then the reaction mixture was heated to 80 C. and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=50:1 to 20:1) to give the title compound (10.3 g, 69% yield, 91% purity on LCMS) as a brown oil.

[1167] .sup.1H NMR (CDCl.sub.3): 8.21 (d, 1H), 6.94-6.91 (m, 2H), 6.76 (s, 1H), 6.72 (dd, 1H), 5.38-5.29 (m, 1H), 3.64 (br s, 2H), 2.98-2.89 (m, 1H), 1.38 (d, 6H) and 1.30-1.27 (m, 6H).

[1168] LCMS: m/z 289.2 (M+H).sup.+ (ES.sup.+).

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

[1169] ##STR00228##

[1170] To a solution of 4-fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylaniline (4 g, 13.87 mmol, 1 eq) in THF (80 mL) was added TEA (2.81 g, 27.74 mmol, 3.86 mL, 2 eq). The mixture was cooled to 0 C. and then triphosgene (1.65 g, 5.55 mmol, 0.4 eq) was added to the mixture. The resulting mixture was heated to 70 C. and stirred for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=100:1 to 30:1) to give the title compound (1.9 g, 44% yield) as a yellow oil, which was used directly in the next step.

Intermediate A8: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

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

[1171] ##STR00229##

[1172] To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol, 62.50 mL, 1 eq) in concentrated H.sub.2SO.sub.4 (30 mL) was added a mixture of HNO.sub.3 (50 mL, 69 wt % in water) and concentrated H.sub.2SO.sub.4 (50 mL) dropwise at 0 C. over a period of 3.5 hours. The reaction mixture was stirred at 0 C. for 0.5 hour. Then the reaction mixture was poured into ice water (600 mL) and extracted with ethyl acetate (2400 mL). The combined organic layers were washed with water (500 mL), saturated aqueous NaHCO.sub.3 solution (500 mL) and brine (2500 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (55 g, 66%) as a colourless oil.

[1173] .sup.1H NMR (CDCl.sub.3): 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

[1174] ##STR00230##

[1175] To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g, contained another regio-isomer) in MeOH (500 mL) was added Pd/C (5 g, 10 wt % loading on activated carbon) under N.sub.2 atmosphere. The suspension was degassed under vacuum and purged with H.sub.2 several times. The reaction mixture was stirred under H.sub.2 (50 psi) at 20 C. for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:4) to give the title compound (19.82 g, 43% yield, 96.39% purity on LCMS) as a brown oil.

[1176] .sup.1H NMR (CDCl.sub.3): 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).

[1177] LCMS: m/z 134.2 (M+H).sup.+ (ES.sup.+).

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

[1178] ##STR00231##

[1179] To a solution of 2,3-dihydro-1H-inden-4-amine (19.8 g, 148.66 mmol, 1 eq) and TEA (19.56 g, 193.26 mmol, 1.3 eq) in DCM (300 mL) was added dropwise Ac.sub.2O (17.45 g, 170.96 mmol, 1.15 eq) over 6 minutes at 0 C. Then the reaction mixture was warmed to 16 C. and stirred for 1.4 hours. The mixture was poured into water (500 mL) and extracted with DCM (2300 mL). The combined organic phases were washed with brine (2500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (25.74 g, 96% yield, 96.69% purity on LCMS) as a white solid.

[1180] .sup.1H NMR (CDCl.sub.3): 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).

[1181] LCMS: m/z 176.2 (M+H).sup.+ (ES.sup.+).

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

[1182] ##STR00232##

[1183] N-(2,3-dihydro-1H-inden-4-yl)acetamide (34.6 g, 197.46 mmol, 1 eq), p-toluenesulfonic acid (18.70 g, 108.60 mmol, 0.55 eq) and Pd(OAc).sub.2 (2.22 g, 9.87 mmol, 0.05 eq) were suspended in toluene (400 mL) and stirred at 20 C. for 0.5 hour under air atmosphere. NBS (38.66 g, 217.20 mmol, 1.1 eq) was added. Then the reaction mixture was stirred at 20 C. for 2 hours. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (2500 mL). The combined organic phases were washed with brine (2500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10: 1 to 2:1) to give the title compound (13.9 g, 27% yield, 98.1% purity on LCMS) as a white solid.

[1184] .sup.1H NMR (CDCl.sub.3): 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).

[1185] LCMS: m/z 254.1 (M+H).sup.+ (ES.sup.+).

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

[1186] ##STR00233##

[1187] A mixture of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide (45.68 g, 179.76 mmol, 1 eq) in EtOH (200 mL) and concentrated HCl (300 mL, 36 wt % in water) was stirred at 80 C. for 36 hours. The reaction mixture was cooled to 0 C. in an ice bath and some solid precipitated. The suspension was filtered. The filter cake was washed with ice water (50 mL) and dried in vacuo to give the title compound (34.1 g, 72% yield, 94.08% purity on LCMS, HCl salt) as a grey solid.

[1188] .sup.1H NMR (DMSO-d.sub.6): 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).

[1189] LCMS: m/z 212.0 (M+H).sup.+ (ES.sup.+).

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

[1190] ##STR00234##

[1191] A solution of (2-methoxypyridin-4-yl)boronic acid (25.11 g, 164.15 mmol, 1.2 eq), 5-bromo-2,3-dihydro-1H-inden-4-amine (34 g, 136.80 mmol, 1 eq, HCl salt) and K.sub.2CO.sub.3 (60.50 g, 437-74 mmol, 3.2 eq) in dioxane (500 mL) and H.sub.2O (100 mL) was degassed with nitrogen for 15 minutes before Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (6 g, 7.35 mmol, 0.053 eq) was added. The reaction mixture was heated to 80 C. for 12 hours. The mixture was poured into water (500 mL) and extracted with ethyl acetate (2500 mL). The combined organic phases were washed with brine (2700 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 10:1) to give the title compound (27.4 g, 79% yield, 95% purity on LCMS) as a white solid.

[1192] .sup.1H NMR (CDCl.sub.3): 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).

[1193] LCMS: m/z 241.2 (M+H).sup.+ (ES.sup.+).

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

[1194] ##STR00235##

[1195] To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50-35 mmol, 1.1 eq) in THF (275 mL) was added bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) in portions at 0 C. Then the reaction mixture was stirred at 16 C. for 0.5 hour. The reaction mixture was filtered and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacuo to give the title compound (9.04 g, 74%) as a light yellow solid.

[1196] .sup.1H NMR (CDCl.sub.3): 8.28 (d, 1H), 7.20-7.16 (m, 3H), 7.02 (s, 1H), 4.16 (s, 3H), 3.04-2.99 (m 4H) and 2.23-2.15 (m, 2H).

Intermediate A9: 5-Chloro-2-isocyanato-1,3-diisopropylbenzene

[1197] ##STR00236##

[1198] To a solution of 4-chloro-2,6-diisopropylaniline (0.105 g, 0.496 mmol) in toluene (1 mL) was added a phosgene solution (0.65 mL, 20 wt % in toluene, 1.22 mmol) and the reaction mixture was refluxed for 1 hour. Upon cooling, the mixture was concentrated in vacuo to afford the title compound as an orange oil (0.111 g, 94%).

[1199] .sup.1H NMR (CDCl.sub.3) 7.07 (d, 2H), 3.17 (h, 2H), 1.24 (d, 12H).

Preparation of Examples

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

[1200] ##STR00237##

[1201] 1-(Tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate PI) (47 mg, 0.216 mmol) was dissolved in dry THF (2 mL) and sodium tert-butoxide (2M in THF) (108 l, 0.216 mmol) was added. After stirring for 30 minutes, a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (43.1 mg, 0.216 mmol) in THF (1 mL) was added. The cloudy reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in DMSO (2 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (37.1 mg, 39%) as a colourless powder.

[1202] .sup.1H NMR (DMSO-d6) 7.88 (d, J=2.4 Hz, 1H), 7.83 (s, 1H), 6.87 (s, 1H), 6.63 (d, J=2.4 Hz, 1H), 5.13-5.05 (m, 1H), 4.01-3.93 (m, 2H), 3.89 (dd, J=9.5, 3.6 Hz, 1H), 3.81 (td, J=8.3, 5.6 Hz, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.46-235 (m, 1H), 2.29-2.20 (m, 1H), 1.93 (p, J=7.4 Hz, 4H). One exchangeable proton not visible.

[1203] LCMS; m/z 417 (M+H).sup.+ (ES.sup.+); 415 (MH).sup. (ES.sup.).

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

[1204] ##STR00238##

[1205] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(2-methoxyethyl)-1H-pyrazole-3-sulfonamide (Intermediate P2) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (6 mg, 4%) as a white solid.

[1206] .sup.1H NMR (DMSO-d6) 10.81 (br s, 1H), 7.95-7.75 (m, 2H), 6.89 (s, 1H), 6.63 (s, 1H), 4.32 (t, J=5.3 Hz, 2H), 3.69 (t, J=5.3 Hz, 2H), 3.22 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.64-2.60 (m, 4H), 1.98-1.90 (m, 4H).

[1207] LCMS; m/z 405 (M+H).sup.+ (ES.sup.+).

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

[1208] ##STR00239##

[1209] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-((tetrahydrofuran-2-yl)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P3) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (44.8 mg, 44%) as a white solid.

[1210] .sup.1H NMR (DMSO-d6) 7.81 (s, 1H), 7.76 (s, 1H), 6.87 (s, 1H), 6.59 (s, 1H), 4.26-4.11 (m, 3H), 3.76-3.69 (m, 1H), 3.66-3.59 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H), 1.97-1.86 (m, 1H), 1.81-1.67 (m, 2H), 1.63-1.53 (m, 1H).

[1211] One exchangeable proton not visible.

[1212] LCMS; m/z 431 (M+H).sup.+ (ES.sup.+); 429 (MH).sup. (ES.sup.).

[1213] Enantiomers were separated using chiral preparative scale SFC purification (Amy-C column; isocratic elution using 35:65 MeOH:CO.sub.2 (0.2% v/v NH.sub.3), 4 minute run)

Example 4: Enantiomer 1 (Elutes at 1.9 Minutes)

[1214] .sup.1H NMR (DMSO-d6) 7.89 (s, 1H), 7.80 (d, J=2.3 Hz, 1H), 6.89 (s, 1H), 6.63 (d, J=2.4 Hz, 1H), 4.30-4.07 (m, 3H), 3.79-3.65 (m, 1H), 3.67-3.56 (m, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.3 Hz, 4H), 2.00-1.83 (m, 5H), 1.82-1.65 (m, 2H), 1.64-1.51 (m, 1H). One exchangeable proton not visible.

[1215] LCMS; m/z 431.4 (M+H).sup.+ (ES.sup.+); 429.4 (MH).sup. (ES.sup.).

Example 5: Enantiomer 2 (Elutes at 2.8 Minutes)

[1216] .sup.1H NMR (DMSO-d6) 10.81 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=2.4 Hz, 1H), 6.92 (s, 1H), 6.71 (d, J=2.4 Hz, 1H), 4.31-4.10 (m, 3H), 3.82-3.67 (m, 1H), 3.66-3.58 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 2.00-1.86 (m, 5H), 1.83-1.65 (m, 2H), 1.64-1.50 (m, 1H).

[1217] LCMS; m/z 431.4 (M+H).sup.+ (ES.sup.+); 429.3 (MH).sup. (ES.sup.).

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

[1218] ##STR00240##

[1219] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P4) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (7.2 mg, 7%) as a colourless powder.

[1220] .sup.1H NMR (DMSO-d6) 10.81 (br s, 1H), 7.93 (s, 2H), 6.91 (s, 1H), 6.69 (s, 1H), 4.19 (d, J=7.6 Hz, 2H), 3.75 (td, J=8.1, 5.6 Hz, 1H), 3.66-3.58 (m, 2H), 3.45 (dd, J=8.7, 5.5 Hz, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.75-2.66 (m, 1H), 2.60 (t, J=7.3 Hz, 4H), 1.94 (pent, J=7.4 Hz, 4H), 1.93-1.84 (m, 1H), 1.66-1.53 (m, 1H).

[1221] LCMS; m/z 431 (M+H).sup.+ (ES.sup.+); 429 (MH).sup. (ES.sup.).

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

[1222] ##STR00241##

[1223] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(3-hydroxypropyl)-1H-pyrazole-3-sulfonamide (Intermediate P5) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (31 mg, 30%) as a white solid.

[1224] .sup.1H NMR (DMSO-d6) 10.81 (s, 1H), 8.02 (s, 1H), 7.94 (d, J=2.3 Hz, 1H), 6.94 (s, 1H), 6.74 (d, J=2.4 Hz, 1H), 4.64 (t, J=5.1 Hz, 1H), 4.26 (t, J=7.1 Hz, 2H), 3.39 (td, J=6.1, 5.0 Hz, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.5 Hz, 4H), 1.97-1.90 (m, 6H).

[1225] LCMS; m/z 405 (M+H).sup.+ (ES.sup.+).

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

[1226] ##STR00242##

[1227] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(2-hydroxyethyl)-1H-pyrazole-3-sulfonamide (Intermediate P6) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (11 mg, 9%) as a white solid.

[1228] .sup.1H NMR (DMSO-d6) 7.81-7.64 (m, 2H), 6.84 (s, 1H), 6.52 (s, 1H), 4.95 (t, J=5.2 Hz, 1H), 4.16 (t, J=5.7 Hz, 2H), 3.75-3.71 (m, 2H), 2.77 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 1.95-1.89 (m 4H). One exchangeable proton not visible.

[1229] LCMS; m/z 391 (M+H).sup.+ (ES.sup.+).

Example 9: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1230] ##STR00243##

[1231] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P7) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (2.6 mg, 7%) as a white solid.

[1232] .sup.1H NMR (DMSO-d6) 8.38 (d, J=2.9 Hz, 1H), 7.90 (br s, 1H), 6.93 (d, J=2.8 Hz, 1H), 6.81 (s, 1H), 5.12 (br s, 1H), 4.69 (d, J=12.5 Hz, 1H), 4.49 (d, J=11.8 Hz, 1H), 4.42 (d, J=12.5 Hz, 1H), 4.28 (d, J=11.8 Hz, 1H), 3.49-3.40 (m, 2H), 2.75 (t, J=7.3 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 1.94-1.86 (m, 4H), 1.24 (s, 3H).

[1233] LCMS; m/z 431 (M+H).sup.+ (ES.sup.+).

Example 10:N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide

[1234] ##STR00244##

[1235] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide (Intermediate P8) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (10.6 mg, 8%) as a colourless solid.

[1236] .sup.1H NMR (DMSO-d6) 10.74, (br s, 1H), 7.89 (s, 1H), 7.76 (d, J=2.4 Hz, 1H), 6.90 (s, 1H), 6.66 (d, J=2.3 Hz, 1H), 4.77 (s, 1H), 4.08 (s, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.5 Hz, 4H), 1.05 (s, 6H).

[1237] LCMS; m/z 419 (M+H).sup.+ (ES.sup.+); 417 (MH).sup. (ES.sup.).

Example 11: (S)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide

[1238] ##STR00245##

[1239] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from (S)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide (Intermediate P9) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (15.4 mg, 30%) as a white solid.

[1240] .sup.1H NMR (DMSO-d6) 7.98 (s, 1H), 7.84 (d, J=2.4 Hz, 1H), 6.93 (s, 1H), 6.70 (d, J=2.4 Hz, 1H), 5.01 (d, J=5.0 Hz, 1H), 4.09 (dd, J=5.9, 2.0 Hz, 2H), 3.98-3.96 (m, 1H), 2.79 (t, J=7.4 Hz, 4H), 2.63-2.57 (m, 4H), 1.98-1.91 (m, 4H), 1.03 (d, J=6.2 Hz, 3H).

[1241] One exchangeable proton not visible.

[1242] LCMS; m/z 405 (M+H).sup.+ (ES.sup.+).

Example 12: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(oxetan-3-yl)-1H-pyrazole-3-sulfonamide

[1243] ##STR00246##

[1244] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(oxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P10) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (26 mg, 19%) as a white solid.

[1245] .sup.1H NMR (DMSO-d6) 7.84 (br s, J=2.3 Hz, 1H), 7.51 (s, 1H), 6.77 (s, 1H), 6.45 (d, J=2.3 Hz, 1H), 5.58-5.55 (m, 1H), 4.95-4.81 (m, 4H), 2.75 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.3 Hz, 4H), 1.92-1.89 (m, 4H). One exchangeable proton not visible.

[1246] LCMS; m/z 403 (M+H).sup.+ (ES.sup.+).

Example 13: (R)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

[1247] ##STR00247##

[1248] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from (R)-1-(1-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate P11) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (34 mg, 13%) as a white solid.

[1249] .sup.1H NMR (DMSO-d6) 10.82 (br s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 6.92 (s, 1H), 6.69 (s, 1H), 5.00 (d, J=5.0 Hz, 1H), 4.09 (dd, J=5.0, 1.8 Hz, 2H), 4.05-395 (m, 1H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.98-1.91 (m, 4H), 1.03 (d, J=6.2 Hz, 3H).

[1250] LCMS; m/z 405 (M+H).sup.+ (ES.sup.+).

Example 14: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-methoxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide

[1251] ##STR00248##

[1252] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(2-methoxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide (Intermediate P12) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (42.2 mg, 38%) as a colourless powder.

[1253] .sup.1H NMR (DMSO-d6) 10.81 (s, 1H), 8.00 (s, 1H), 7.78 (d, J=2.4 Hz, 1H), 6.94 (s, 1H), 6.75 (d, J=2.4 Hz, 1H), 4.23 (s, 2H), 3.16 (s, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 1.95 (p, J=7.4 Hz, 4H), 1.07 (s, 6H).

[1254] LCMS; m/z 433 (M+H).sup.+ (ES.sup.+); 431 (MH).sup. (ES.sup.).

Example 15: (S)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

[1255] ##STR00249##

[1256] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from (S)-1-(1-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate P13) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (16 mg, 14%) as a white solid.

[1257] .sup.1H NMR (DMSO-d6) 7.90-7.76 (m, 1H), 7.70 (s, 1H), 6.83 (s, 1H), 6.54-6.48 (m, 1H), 5.02-4.93 (m, 1H), 4.06-3.92 (m, 3H), 2.76 (t, J=7.2 Hz, 4H), 2.63 (t, J=7.1 Hz, 4H), 1.95-1.91 (m, 4H), 1.03 (d, J=6.1 Hz, 3H). One exchangeable proton not visible.

[1258] LCMS; m/z 405 (M+H).sup.+ (ES.sup.+).

Example 16: (R)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide

[1259] ##STR00250##

[1260] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from (R)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide (Intermediate P14) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (42 mg, 38%) as a white solid.

[1261] .sup.1H NMR (DMSO-d6) 7.62 (d, J=2.3 Hz, 1H), 7.55 (s, 1H), 6.77 (s, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.99 (br s, 1H), 4.05-3.90 (m, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.93-1.86 (m, 4H), 1.01 (d, J=5.9 Hz, 3H). One exchangeable proton not visible.

[1262] LCMS; m/z 405 (M+H).sup.+ (ES.sup.+).

Example 17: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-1-(2-methoxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide

[1263] ##STR00251##

[1264] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(2-methoxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide (Intermediate P12) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (17.9 mg, 23%) as a colourless solid.

[1265] .sup.1H NMR (DMSO-d6) 11.02 (s, 1H), 7.75 (s, 1H), 7.75 (s, 1H), 6.91 (d, J=9.9 Hz, 2H), 6.70 (s, 1H), 4.21 (s, 2H), 3.17 (s, 3H), 2.94 (sept, J=7.4 Hz, 2H), 1.08 (s, 6H), 1.05 (br S, 12H).

[1266] LCMS; m/z 455 (M+H).sup.+ (ES.sup.+); 453 (MH).sup. (ES.sup.).

Example 8: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide

[1267] ##STR00252##

[1268] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide (Intermediate P8) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (87 mg, 62%) as a clear colourless crystalline solid.

[1269] .sup.1H NMR (DMSO-d6) 7.69 (s, 1H), 7.60 (s, 1H), 6.86 (s, 1H), 6.83 (s, 1H), 6.55 (s, 1H), 4.75 (s, 1H), 4.03 (s, 2H), 3.08-2.96 (m, 2H), 1.05 (s, 6H), 1.03 (d, J=6.8 Hz, 12H).

[1270] One exchangeable proton not visible.

[1271] LCMS; m/z 441.2 (M+H).sup.+ (ES.sup.+).

Example 19: N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide

[1272] ##STR00253##

[1273] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-sulfonamide (Intermediate P8) and 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A9) to afford the title compound (19.1 mg, 13%) as a light yellow crystalline solid.

[1274] .sup.1H NMR (DMSO-d6) 7.71 (s, 2H), 7.08 (s, 2H), 6.58 (s, 1H), 4.76 (s, 1H), 4.04 (s, 2H), 3.05-2.93 (m, 2H), 1.05 (s, 6H), 1.04 (d, J=6.6 Hz, 12H). One exchangeable proton not visible.

[1275] LCMS; m/z 457.5 (M+H).sup.+ (ES.sup.+).

Example 20: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide

[1276] ##STR00254##

[1277] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate P15) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (13 mg, 16%) as a white solid.

[1278] .sup.1H NMR (DMSO-d6) 10.75 (br s, 1H), 7.93 (s, 2H), 6.91 (s, 1H), 6.67 (s, 1H), 5.11 (t, J=5.5 Hz, 1H), 3.57 (d, J=5.6 Hz, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.3 Hz, 4H), 1.93 (p, J=7.5 Hz, 4H), 1.47 (s, 6H).

[1279] LCMS; m/z 419.2 (M+H).sup.+ (ES.sup.+); 417.4 (MH).sup. (ES.sup.).

Example 21: (S)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxybutyl)-1H-pyrazole-3-sulfonamide

[1280] ##STR00255##

[1281] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from (S)-1-(2-hydroxybutyl)-1H-pyrazole-3-sulfonamide (Intermediate P16) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (19.7 mg, 20%) as a clear colourless solid.

[1282] .sup.1H NMR (DMSO-d6) 10.78 (s, 1H), 7.94 (s, 1H), 7.82 (d, J=2.3 Hz, 1H), 6.91 (s, 1H), 6.67 (d, J=2.3 Hz, 1H), 4.96 (d, J=5.6 Hz, 1H), 4.14 (dd, J=13.7, 4.7 Hz, 1H), 4.06 (dd, J=13.7, 7.2 Hz, 1H), 3.75-3.66 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.94 (p, J=7.4 Hz, 4H), 1.43-1.33 (m, 1H), 1.33-1.22 (m, 1H), 0.87 (t, J=7.4 Hz, 3H).

[1283] LCMS; m/z 419.8 (M+H).sup.+ (ES.sup.+).

Example 22: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxycyclopentyl)-1H-pyrazole-1-sulfonamide (racemic anti)

[1284] ##STR00256##

[1285] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(2-hydroxycyclopentyl)-1H-pyrazole-3-sulfonamide (racemic anti) (Intermediate P17) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (9.7 mg, 16%) as a clear colourless solid.

[1286] .sup.1H NMR (DMSO-d6) 10.82 (s, 1H), 7.98 (s, 1H), 7.94 (d, J=2.4 Hz, 1H), 6.92 (s, 1H), 6.71 (d, J=2.4 Hz, 1H), 5.17 (d, J=5.1 Hz, 1H), 4.49-4.41 (m, 1H), 4.32-3.96 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 2.23-2.11 (m, 1H), 2.01-1.88 (m, 6H), 1.81-1.70 (m, 2H), 1.62-1.51 (m, 1H).

[1287] LCMS; m/z 431.3 (M+H).sup.+ (ES.sup.+).

Example 23: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(3-hydroxybutan-2-yl)-1H-pyrazole-3-sulfonamide, partial ammonium salt (racemicR,R and S,S enantiomers)

[1288] ##STR00257##

[1289] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(3-hydroxybutan-2-yl)-1H-pyrazole-3-sulfonamide (racemicR,R and S,S enantiomers) (Intermediate P8) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (80.7 mg, 50%) as a clear colourless solid.

[1290] .sup.1H NMR (DMSO-d6) 7.90 (s, 1H), 7.86 (d, J=2.4 Hz, 1H), 6.90 (s, 1H), 6.66 (d, J=2.4 Hz, 1H), 5.04 (d, J=5.3 Hz, 1H), 4.25-413 (m, 1H), 3.86-3.75 (m, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 2.00-1.86 (m, 4H), 1.44 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.3 Hz, 3H). One exchangeable proton not visible.

[1291] LCMS; m/z 419.4 (M+H).sup.+ (ES.sup.+).

Example 24: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(1-(hydroxymethyl)cyclobutyl)-1H-pyrazole-3-sulfonamide

[1292] ##STR00258##

[1293] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(1-(hydroxymethyl)cyclobutyl)-1H-pyrazole-3-sulfonamide (Intermediate P19) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (16.4 mg, 28%) as a clear colourless solid.

[1294] .sup.1H NMR (DMSO-d6) 7.78 (s, 1H), 7.74 (d, J=2.4 Hz, 1H), 6.85 (s, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.15 (t, J=5.5 Hz, 1H), 3.72 (d, J=5.5 Hz, 2H), 2.77 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 2.48-2.41 (m, 2H), 2.34-2.24 (m, 2H), 1.97-1.78 (m, 6H). One exchangeable proton not visible.

[1295] LCMS; m/z 431.3 (M+H).sup.+ (ES.sup.+).

Example 25: (R)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxybutyl)-1H-pyrazole-3-sulfonamide

[1296] ##STR00259##

[1297] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from (R)-1-(2-hydroxybutyl)-1H-pyrazole-3-sulfonamide (Intermediate P20) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (112 mg, 50%) as a clear colourless solid.

[1298] .sup.1H NMR (DMSO-d6) 8.01 (s, 1H), 7.84 (d, J=2.4 Hz, 1H), 6.92 (s, 1H), 6.70 (d, J=2.4 Hz, 1H), 4.99 (d, J=5.6 Hz, 1H), 4.15 (dd, J=13.7, 4.5 Hz, 1H), 4.07 (dd, J=13.7, 7.2 Hz, 1H), 3.76-3.66 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.98-1.89 (m, 4H), 1.44-132 (m, 1H), 1.32-1.21 (m, 1H), 0.87 (t, J=7.4 Hz, 3H). One exchangeable proton not visible.

[1299] LCMS; m/z 419.1 (M+H).sup.+ (ES.sup.+).

Example 26: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(3-hydroxybutan-2-yl)-1H-pyrazole-3-sulfonamide (racemicR,S and S,R enantiomers)

[1300] ##STR00260##

[1301] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(3-hydroxybutan-2-yl)-1H-pyrazole-3-sulfonamide (racemicR,S and S,R enantiomers) (Intermediate P21) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (35 mg, 16%) as a clear colourless solid.

[1302] .sup.1H NMR (DMSO-d6) 10.77 (s, 1H), 8.00 (s, 1H), 7.86 (d, J=2.4 Hz, 1H), 6.92 (s, 1H), 6.71 (d, J=2.4 Hz, 1H), 4.96 (d, J=5.0 Hz, 1H), 4.35-4.24 (m, 1H), 3.90-379 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.00-1.88 (m, 4H), 1.39 (d, J=7.0 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H).

[1303] LCMS; m/z 419.4 (M+H).sup.+ (ES.sup.+).

Example 27: (R)N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide

[1304] ##STR00261##

[1305] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from (R)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide (Intermediate P14) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (62 mg, 49%) as a colourless solid.

[1306] .sup.1H NMR (DMSO-d6) 11.00 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.83 (s, 1H), 6.93 (d, J=9.9 Hz, 2H), 6.73 (d, J=2.3 Hz, 1H), 5.03 (d, J=4.9 Hz, 1H), 4.11 (d, J=5.8 Hz, 2H), 4.06-3.91 (m, 1H), 3.05-2.83 (m, 2H), 1.26-0.88 (m, 15H).

[1307] LCMS; m/z 427.3 (M+H).sup.+ (ES.sup.+).

Example 28: (R)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxypropyl)-1H-imidazole-4-sulfonamide

[1308] ##STR00262##

[1309] To a solution of (R)-1-(2-hydroxypropyl)-1H-imidazole-4-sulfonamide (Intermediate P22) (120 mg, 0.573 mmol) in THF (2 mL) was added sodium tert-butoxide (2M in THF) (0.3 mL, 0.600 mmol) and the mixture was stirred at room temperature for 1 hour. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (120 mg, 0.602 mmol) in THF (2 mL) was added and the mixture was stirred at room temperature overnight. The volatiles were evaporated, the residue dissolved in DMSO and purified by prep-HPLC to afford the title compound (29 mg, 12%) as a white solid.

[1310] .sup.1H NMR (DMSO-d6) 8.02 (s, 1H), 7.79 (d, J=1.3 Hz, 1H), 7.76 (d, J=1.3 Hz, 1H), 6.90 (s, 1H), 5.01 (d, J=4.1 Hz, 1H), 4.05-3.96 (m, 1H), 3.92-3.82 (m, 2H), 2.77 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H), 1.01 (d, J=5.8 Hz, 3H).

[1311] One exchangeable proton not visible.

[1312] LCMS; m/z 405.3 (M+H).sup.+ (ES.sup.+).

Example 29: (S)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxypropyl)-1H-imidazole-4-sulfonamide

[1313] ##STR00263##

[1314] Prepared according to the general procedure of (R)N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxypropyl)-1H-imidazole-4-sulfonamide (Example 28) from (S)-1-(2-hydroxypropyl)-1H-imidazole-4-sulfonamide (Intermediate P23) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (13 mg, 13%) as a white solid.

[1315] .sup.1H NMR (DMSO-d6) 8.75 (br s, 1H), 7.98 (s, 1H), 7.73 (s, 2H), 6.88 (s, 1H), 5.01 (d, J=4.1 Hz, 1H), 4.08-3.93 (m, 1H), 3.92-3.79 (m, 2H), 2.77 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H), 1.01 (d, J=5.8 Hz, 3H).

[1316] LCMS; m/z 405.3 (M+H).sup.+ (ES.sup.+).

Example 30: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazole-3-sulfonamide

[1317] ##STR00264##

[1318] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazole-3-sulfonamide (Intermediate P24) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (66 mg, 50%) as a white solid.

[1319] .sup.1H NMR (DMSO-d6) 7.92-7.79 (m, 2H), 6.87 (s, 1H), 6.80 (d, J=6.3 Hz, 1H), 6.67-6.59 (m, 1H), 4.48-4.25 (m, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H). One exchangeable proton not visible.

[1320] LCMS; m/z 459.3 (M+H).sup.+ (ES.sup.+).

Example 31: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-sulfonamide, sodium salt

[1321] ##STR00265##

[1322] 1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-sulfonamide (Intermediate P25) (30 mg, 0.130 mmol) was dissolved in THF (5 mL) and 60% sodium hydride (7.78 mg, 0.195 mmol) added. After 1 hour, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (25.8 mg, 0.130 mmol) was added and the mixture stirred at room temperature for 15 hours. The suspension was filtered and washed with THF (1 mL). The collected solid was triturated with ethyl acetate (10 mL) for 10 hours and filtered. The collected solid was dried under reduced pressure to afford the title compound (47 mg, 74%) as a white solid.

[1323] .sup.1H NMR (DMSO-d6) 7.74 (d, J=2.2 Hz, 1H), 7.53 (s, 1H), 6.77 (s, 1H), 6.40 (d, J=2.3 Hz, 1H), 4.40-4.38 (m, 1H), 3.96 (dt, J=11.5, 3.4 Hz, 2H), 3.50-3.37 (m, 2H), 2.75 (t, J=7.3 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 2.02-1.83 (m, 8H). One exchangeable proton not visible.

[1324] LCMS; m/z 431 (M+H).sup.+ (ES.sup.+).

Example 32: N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-sulfonamide, sodium salt

[1325] ##STR00266##

[1326] Sodium tert-butoxide (0.114 mL, 0.227 mmol) was added to a solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-sulfonamide (Intermediate P25) (50 mg, 0.216 mmol) in THF (1 mL) and stirred at room temperature for 1 hour to give a white suspension. Then 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A9) (56.5 mg, 0.238 mmol) in THF (1 mL) was added and stirred at room temperature overnight. The resultant colourless precipitate was collected by filtration, washed with THF (10 mL) and EtOAc (10 mL), and dried in vacuo to afford a colourless solid. The residue was triturated with TBME (310 mL). The resultant solid was filtered, rinsed with TBME (10 mL), and dried in vacuo to afford the title compound (25 mg, 22%) as a colourless solid.

[1327] .sup.1H NMR (DMSO-d6) 7.73 (d, J=2.3 Hz, 1H), 7.45 (br. s, 1H), 7.01 (s, 2H), 6.38 (br. s, 1H), 4.44-4.30 (m, 1H), 3.96 (dt, J=3.3, 11.1 Hz, 2H), 3.50-339 (m, 2H), 3.22-307 (m, 2H), 1.98-1.88 (m, 4H), 1.03 (d, J=6.8 Hz, 12H). One exchangeable proton not visible.

[1328] LCMS; m/z 469.4 (M+H).sup.+ (ES.sup.+).

Example 33: (R)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropyl)-2H-1,2,3-triazole-4-sulfonamide, partial ammonium salt

[1329] ##STR00267##

[1330] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from (R)-2-(2-hydroxypropyl)-2H-1,2,3-triazole-4-sulfonamide (Intermediate P26) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (39 mg, 25%) as a white solid.

[1331] 1H NMR (DMSO-d6) 8.05 (s, 1H), 7.87 (s, 1H), 7.08 (br s, 1H), 6.87 (s, 1H), 5.04 (d, J=5.4 Hz, 1H), 4.39-4.30 (m, 2H), 4.11 (app sept, J=6.3 Hz, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.92 (p, J=7.4 Hz, 4H), 1.07 (d, J=6.3 Hz, 3H).

[1332] LCMS; m/z 406.4 (M+H).sup.+ (ES.sup.+).

Example 34: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(3-hydroxycyclobutyl)-1H-pyrazole-3-sulfonamide

[1333] ##STR00268##

[1334] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(3-hydroxycyclobutyl)-1H-pyrazole-3-sulfonamide (Intermediate P27) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (27 mg, 20%) as a white solid.

[1335] 1H NMR (DMSO-d6) 7.95 (d, J=2.3 Hz, 1H), 7.92 (s, 1H), 6.90 (s, 1H), 6.67 (d, J=2.3 Hz, 1H), 5.26 (d, J=5.0 Hz, 1H), 5.07-4.98 (m, 1H), 4.47-4.37 (m, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.66-2.56 (m, 6H), 2.40-2.33 (m, 2H), 1.93 (p, J=7.4 Hz, 4H). NH not resolved.

[1336] LCMS; m/z 417.4 (M+H).sup.+ (ES.sup.+).

Example 35: N-((7-Fluoro-5-(pyridin-3-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[1337] ##STR00269##

[1338] 7-Fluoro-5-(pyridin-3-yl)-2,3-dihydro-1H-inden-4-amine (150 mg, 0.657 mmol) (Intermediate A3) was dissolved in dry THF (2 mL). Triethylamine (101 l, 0.723 mmol) and a solution of bis(trichloromethyl) carbonate (195 mg, 0.657 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 2 hours and then concentrated in vacuo. The residue was suspended in toluene (10 mL) and filtered through a phase separation cartridge washing with toluene (10 mL). The combined filtrates were concentrated in vacuo and then dissolved in dry THF (4 mL) to give a stock solution of 3-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (0.165 M in THF). 5-(3-Methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P29) (40 mg, 0.162 mmol) was dissolved in dry THF (2 mL). Sodium tert-butoxide (2 M in THF) (80 l, 0.160 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then a solution of 3-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (1 mL, 0.165M in THF) was added and the mixture was stirred overnight. The THF was removed in vacuo and the residue was dissolved in DMSO (2 mL) and then purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (3 mg, 3.6%) as a colourless powder.

[1339] 1H NMR (DMSO-d6) 10.94 (s, 1H), 8.56 (dd, J=4.8, 1.7 Hz, 1H), 8.48 (s, 1H), 7.84 (s, 1H), 7.75-7.70 (m, 1H), 7.43 (dd, J=7.9, 4.9 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H), 6.96 (s, 1H), 4.89 (d, J=7.3 Hz, 2H), 4.80 (d, J=7.4 Hz, 2H), 3.76 (s, 3H), 2.98 (s, 3H), 2.95 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.04 (p, J=7.6 Hz, 2H).

[1340] LCMS; m/z 502.4 (M+H).sup.+ (ES.sup.+); 500.3 (MH) (ES).

Example 36: (R)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxypropyl)-1H-1,2,4-triazole-3-sulfonamide

[1341] ##STR00270##

[1342] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from (R)-1-(2-hydroxypropyl)-1H-1,2,4-triazole-3-sulfonamide (Intermediate P30) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (18 mg, 14%) as a colourless solid.

[1343] 1H NMR (DMSO-d6) 11.23 (bs, 1H), 8.56 (s, 1H), 7.92 (s, 1H), 6.87 (s, 1H), 5.08 (d, J=5.0 Hz, 1H), 4.25-4.03 (m, 2H), 4.03-3.92 (m, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.5 Hz, 4H), 1.07 (d, J=6.2 Hz, 3H).

[1344] LCMS; m/z 406.4 (M+H).sup.+ (ES.sup.+).

Example 37: (R)N-((4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl) carbamoyl)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide

[1345] ##STR00271##

[1346] To a solution of 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A4) (4 g, 17.37 mmol) in THF (20 mL) was added TEA (3.52 g, 34.74 mmol) and triphosgene (2.06 g, 6.95 mmol) at 5C. The mixture was stirred at 70 C. for 20 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (30:1 PE/EtOAc) to give 3-(5-fluoro-2-isocyanato-3-isopropylphenyl)pyridine (1.9 g, 43%) as a yellow oil.

[1347] To a solution of (R)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide (Intermediate P14) (300 mg, 1.46 mmol) in THF (5 mL) was added CH.sub.3ONa (87 mg, 1.61 mmol) and the mixture was stirred at 30 C. for 30 minutes. 3-(5-Fluoro-2-isocyanato-3-isopropylphenyl)pyridine (412 mg, 1.61 mmol) was added and the reaction was stirred at 30 C. for 15.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (62 mg, 9%) as a white solid.

[1348] 1H NMR (DMSO-d6) 8.52-8.48 (m, 2H), 7.75-7.70 (m, 3H), 7.34-7.32 (m, 1H), 7.18-7.15 (m, 1H), 7.03-7.02 (m, 1H), 6.43 (s, 1H), 5.05 (s, 1H), 4.11-3.96 (m, 3H), 3.07-3.05 (m, 1H), 1.09 (d, J=6.4 Hz, 6H), 1.04 (d, J=6.4 Hz, 3H).

[1349] LCMS; m/z 462.2 (M+H).sup.+ (ES.sup.+).

[1350] EE analysis by SFC: retention time 1.134 min, 100% ee value.

Example 38: 1-Cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[1351] ##STR00272##

[1352] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-cyclopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P31) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (46 mg, 34%) as a colourless solid.

[1353] 1H NMR (DMSO-d6) 7.97 (s, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 4.92 (d, J=7.4 Hz, 2H), 4.80 (d, J=7.3 Hz, 2H), 3.61-3.51 (m, 1H), 3.00 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.3 Hz, 4H), 1.92 (p, J=7.4 Hz, 4H), 1.14-1.05 (m, 2H), 0.99-0.92 (m, 2H). NH missing.

[1354] LCMS; m/z 473.4 (M+H).sup.+ (ES.sup.+).

Example 39: 1-(tert-Butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[1355] ##STR00273##

[1356] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(tert-butyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P32) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (32 mg, 29%) as a colourless solid.

[1357] 1H NMR (DMSO-d6) 7.96 (s, 1H), 6.98 (s, 1H), 6.89 (s, 1H), 4.91 (d, J=7.4 Hz, 2H), 4.74 (d, J=7.4 Hz, 2H), 2.97 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 1.91 (p, J=7.4 Hz, 4H), 1.50 (s, 9H). NH missing.

[1358] LCMS; m/z 511.4 (M+H).sup.+ (ES.sup.+).

Example 40: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[1359] ##STR00274##

[1360] 4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (Intermediate A5) (50 mg, 0.192 mmol) was dissolved in dry THF (1 mL). Triethylamine (35 l, 0.251 mmol) was added, followed by a solution of bis(trichloromethyl) carbonate (55 mg, 0.185 mmol) in THF (1 mL). The cloudy reaction mixture was stirred for 1 hour at room temperature and then the mixture was diluted with toluene (5 mL), filtered through a hydrophobic frit and concentrated in vacuo to give the crude isocyanate.

[1361] 5-(3-Methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P29) (48 mg, 0.194 mmol) was dissolved in dry THF (2 mL). Sodium tert-butoxide (2 M in THF) (110 l, 0.220 mmol) was added and the mixture was stirred for 1 hour at room temperature. A solution of the previously prepared isocyanate in dry THF (2 mL) was added via syringe and the mixture was stirred overnight. The THF was removed in vacuo and the residue was dissolved in DMSO (2 mL) and then purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (23 mg, 22%) as a colourless solid.

[1362] 1H NMR (DMSO-d6) 11.08 (s, 1H), 8.12 (d, J=5.3 Hz, 1H), 7.89 (s, 1H), 7.23 (dd, J=10.1, 2.9 Hz, 1H), 7.05 (dd, J=8.8, 2.9 Hz, 1H), 6.99 (s, 1H), 6.92 (dd, J=5.4, 1.5 Hz, 1H), 6.79 (s, 1H), 4.86 (d, J=7.4 Hz, 2H), 4.79 (d, J=7.3 Hz, 2H), 3.75 (s, 3H), 3.34 (s, 3H), 3.04 (sept, J=7.0 Hz, 1H), 2.95 (s, 3H), 1.09 (br s, 6H).

[1363] LCMS; m/z 534.4 (M+H).sup.+ (ES.sup.+); 532.2 (MH) (ES).

Example 41: 5-(3-Ethoxyoxetan-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1364] ##STR00275##

[1365] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 5-(3-ethoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P33) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (47 mg, 33%) as a colourless solid.

[1366] 1H NMR (DMSO-d6) =7.89 (s, 1H), 6.95 (s, 1H), 6.88 (s, 1H), 4.86 (d, J=7.2 Hz, 2H), 4.79 (d, J=7.2 Hz, 2H), 3.72 (s, 3H), 3.10 (q, J=7.0 Hz, 2H), 2.77 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 1.91 (p, J=7.4 Hz, 4H), 1.08 (t, J=7.0 Hz, 3H). NH missing.

[1367] LCMS; m/z 461.5 (M+H).sup.+ (ES.sup.+).

Example 42:N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[1368] ##STR00276##

[1369] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P35) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (42 mg, 40%) as a colourless solid.

[1370] 1H NMR (DMSO-d6) 7.90 (s, 1H), 6.94 (s, 1H), 6.88 (s, 1H), 4.89-4.73 (m, 4H), 4.24 (sept, J=6.7 Hz, 1H), 2.99 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 1.97-1.84 (m, 4H), 1.36 (d, J=6.5 Hz, 6H). NH not observed.

[1371] LCMS; m/z 475.3 (M+H).sup.+ (ES.sup.+).

Example 43: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-5-(3-hydroxyoxetan-3-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1372] ##STR00277##

[1373] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 5-(3-hydroxyoxetan-3-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P34) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (58 mg, 52%) as a colourless solid.

[1374] 1H NMR (DMSO-d6) 7.73 (s, 1H), 6.90 (s, 1H), 6.87 (s, 1H), 6.75 (d, J=3.2 Hz, 2H), 4.82 (d, J=6.8 Hz, 2H), 4.76 (d, J=6.8 Hz, 2H), 4.52-4.28 (m, 1H), 3.13-2.95 (m, 2H), 1.37 (d, J=6.5 Hz, 6H), 1.06 (d, J=6.8 Hz, 12H). NH not observed.

[1375] LCMS; m/z 483.3 (M+H).sup.+ (ES.sup.+).

Example 44: 1-Ethyl-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-5-(3-hydroxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[1376] ##STR00278##

[1377] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-ethyl-5-(3-hydroxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P36) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (49 mg, 40%) as a colourless solid.

[1378] 1H NMR (DMSO-d6) 7.74 (s, 1H), 6.87 (d, J=10.0 Hz, 2H), 6.76 (s, 1H), 6.74 (s, 1H), 4.80 (d, J=6.8 Hz, 2H), 4.75 (d, J=6.8 Hz, 2H), 4.03 (q, J=7.2 Hz, 2H), 3.12-2.96 (m, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.05 (d, J=6.8 Hz, 12H). OH missing.

[1379] LCMS; m/z 469.5 (M+H).sup.+ (ES.sup.+).

Example 45: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[1380] ##STR00279##

[1381] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-ethyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P37) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (44 mg, 42%) as a colourless solid.

[1382] 1H NMR (DMSO-d6) 7.91 (s, 1H), 6.95 (s, 1H), 6.88 (s, 1H), 4.89-4.73 (m, 4H), 3.94 (q, J=7.2 Hz, 2H), 2.98 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 1.91 (p, J=7.4 Hz, 4H), 1.32 (t, J=7.2 Hz, 3H). NH missing.

[1383] LCMS; m/z 461.5 (M+H).sup.+ (ES.sup.+).

Example 46: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-hydroxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[1384] ##STR00280##

[1385] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-ethyl-5-(3-hydroxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P36) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (29 mg, 27%) as a colourless solid.

[1386] 1H NMR (DMSO-d6) 7.76 (s, 1H), 6.84 (s, 1H), 6.71 (s, 1H), 6.70 (s, 1H), 4.82 (d, J=6.8 Hz, 2H), 4.74 (d, J=6.8 Hz, 2H), 4.01 (q, J=7.2 Hz, 2H), 2.76 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 1.91 (p, J=8.3, 6.4 Hz, 4H), 1.33 (t, J=7.2 Hz, 3H). NH missing.

[1387] LCMS; m/z 447.5 (M+H).sup.+ (ES.sup.+).

Example 47:N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-hydroxyoxetan-3-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide

[1388] ##STR00281##

[1389] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 5-(3-hydroxyoxetan-3-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P34) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (26 mg, 24%) as a colourless solid.

[1390] 1H NMR (DMSO-d6) 10.90 (s, 1H), 7.95 (s, 1H), 6.91 (s, 1H), 6.85 (s, 1H), 6.77 (s, 1H), 4.85 (d, J=6.9 Hz, 2H), 4.77 (d, J=6.9 Hz, 2H), 4.53-4.31 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.00-1.85 (m, 4H), 1.38 (d, J=6.5 Hz, 6H).

[1391] LCMS; m/z 461.3 (M+H).sup.+ (ES.sup.+).

Example 48: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxytetrahydrofuran-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[1392] ##STR00282##

[1393] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 5-(3-methoxytetrahydrofuran-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (36 mg, 50%) as a colourless solid.

[1394] 1H NMR (DMSO-d6) 7.93 (s, 1H), 6.88 (s, 1H), 6.76 (s, 1H), 4.14 (dd, J=9.7, 1.0 Hz, 1H), 3.90 (s, 3H), 3.88-3.80 (m, 3H), 2.95 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.48-2.43 (m, 1H), 2.31-2.22 (m, 1H), 1.91 (p, J=7.5 Hz, 4H). NH missing.

[1395] LCMS; m/z 461.3 (M+H).sup.+ (ES.sup.+).

Example 49: 5-(3-Fluorooxetan-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1396] ##STR00283##

[1397] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 5-(3-fluorooxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P39) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (4 mg, 9%) as a colourless solid.

[1398] 1H NMR (DMSO-d6) 10.95 (s, 1H), 7.91 (s, 1H), 7.11 (s, 1H), 6.87 (s, 1H), 5.16-4.94 (m, 4H), 3.78 (d, J=1.2 Hz, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 1.91 (p, J=7.5 Hz, 4H).

[1399] LCMS; m/z 435 (M+H).sup.+ (ES.sup.+); 433 (MH).sup. (ES.sup.).

Example 50: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxy-2-methylpropyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt

[1400] ##STR00284##

[1401] Prepared according to the general procedure of N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-sulfonamide, sodium salt (Example 31) from 5-(2-hydroxy-2-methylpropyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P40) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (77 mg, 74%) as a colourless solid.

[1402] 1H NMR (DMSO-d6) 7.53 (s, 1H), 6.76 (s, 1H), 6.23 (s, 1H), 4.50 (s, 1H), 3.75 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.71-2.61 (m, 6H), 1.93-1.86 (m, 4H), 1.13 (s, 6H).

[1403] LCMS; m/z 433 (M+H).sup.+ (ES.sup.+).

Example 51: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-hydroxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[1404] ##STR00285##

[1405] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 5-(3-hydroxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P28) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (15 mg, 20%) as a colourless solid.

[1406] 1H NMR (DMSO-d6) 10.84 (br s, 1H), 8.00 (s, 1H), 6.93 (s, 2H), 6.75 (s, 1H), 4.91-4.84 (m, 2H), 4.75 (d, J=7.1 Hz, 2H), 3.81 (s, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 1.99-1.92 (m, 4H).

[1407] LCMS; m/z 433 (M+H).sup.+ (ES.sup.+).

Example 52: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1408] ##STR00286##

[1409] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P29) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (48 mg, 58%) as a colourless solid.

[1410] 1H NMR (DMSO-d6) 7.55 (s, 1H), 6.96-6.67 (m, 3H), 4.85-4.59 (m, 4H), 3.67 (s, 3H), 3.24-2.99 (m, 2H), 2.95 (s, 3H), 1.04 (d, J=6.8 Hz, 12H). NH not observed.

[1411] LCMS; m/z 469.5 (M+H).sup.+ (ES.sup.+); 467.3 (MH) (ES).

Example 53: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[1412] ##STR00287##

[1413] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 5-(3-methoxyoxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P29) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (44 mg, 57%) as a colourless solid.

[1414] 1H NMR (DMSO-d6) 7.74 (s, 1H), 6.88-6.80 (m, 2H), 4.84 (d, J=7.5 Hz, 2H), 4.78 (d, J=7.3 Hz, 2H), 3.68 (s, 3H), 2.97 (s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.90 (p, J=7.4 Hz, 4H). NH not observed.

[1415] LCMS; m/z 447.5 (M+H).sup.+ (ES.sup.+); 445.3 (MH) (ES).

Example 54: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-5-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-methyl-1H-pyrazole-3-sulfonamide

[1416] ##STR00288##

[1417] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 5-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P41) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (43 mg, 46%) as a colourless solid.

[1418] 1H NMR (DMSO-d6) 7.72 (s, 1H), 6.88 (d, J=9.9 Hz, 2H), 6.49 (s, 1H), 5.53 (s, 1H), 4.00 (s, 3H), 3.84-3.51 (m, 2H), 3.70-3.62 (m, 2H), 3.12-3.00 (m, 2H), 1.95-1.73 (m, 4H), 1.06 (d, J=6.8 Hz, 12H). One exchangeable proton not seen.

[1419] LCMS; m/z 483.5 (M+H).sup.+ (ES.sup.+); 481.3 (MH) (ES).

Example 55: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt

[1420] ##STR00289##

[1421] Prepared according to the general procedure of N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3-sulfonamide, sodium salt (Example 31) from 5-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P41) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (43 mg, 53%) as a colourless solid. 1H NMR (DMSO-d6) 7.55 (s, 1H), 6.77 (s, 1H), 6.29 (s, 1H), 5.45 (s, 1H), 3.94 (s, 3H), 3.81-3.62 (m, 4H), 2.75 (t, J=7.3 Hz, 4H), 2.67 (t, J=7.3 Hz, 4H), 1.96-1.76 (m, 8H).

[1422] LCMS; m/z 461.4 (M+H).sup.+ (ES.sup.+); 459.3 (MH) (ES).

Example 56: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(oxazol-2-ylmethyl)-1H-pyrazole-3-sulfonamide

[1423] ##STR00290##

[1424] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(oxazol-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P42) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (27 mg, 25%) as a white solid.

[1425] 1H NMR (DMSO-d6) 8.11 (d, J=0.9 Hz, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.24 (d, J=0.9 Hz, 1H), 6.89 (s, 1H), 6.70 (s, 1H), 5.62 (s, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H). NH not observed.

[1426] LCMS; m/z 428 (M+H).sup.+ (ES.sup.+); 426 (MH).sup. (ES.sup.).

Example 57: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-methyl-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazole-4-sulfonamide, potassium salt

[1427] ##STR00291##

[1428] To a solution of 2-methyl-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazole-4-sulfonamide (Intermediate P43) (45 mg, 0.18 mmol) in THF (3 mL) was added potassium tert-butoxide (21 mg, 0.18 mmol). The mixture was stirred for 40 minutes. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (37 mg, 0.18 mmol) in THF (1 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and DMSO (1 mL) was added. The solution (suspensions were filtered first over cotton wool) was submitted for purification by reversed phase column chromatography (see Experimental Methods) to afford the title compound (43 mg, 53%) as a white solid.

[1429] 1H NMR (Methanol-d4) 7.49 (s, 1H), 6.85 (s, 1H), 4.18-4.01 (m, 2H), 4.01-3.86 (m, 1H), 3.88-3.59 (m, 2H), 2.76 (m, 9H), 2.38 (s, 3H), 2.18-1.91 (m, 4H), 1.89-1.71 (m, 2H), 1.70-1.41 (m, 1H).

[1430] LCMS; m/z 445 (M+H).sup.+ (ES.sup.+); 443 (MH).sup. (ES.sup.).

Example 58:N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxyethyl)-2-methyl-1H-imidazole-4-sulfonamide, potassium salt

[1431] ##STR00292##

[1432] Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-methyl-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazole-4-sulfonamide, potassium salt (Example 57) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 1-(2-hydroxyethyl)-2-methyl-1H-imidazole-4-sulfonamide (Intermediate P44) to afford the title compound (5 mg, 14%) as a white solid.

[1433] .sup.1H NMR (Methanol-d4) 7.60 (s, 1H), 6.90 (s, 1H), 4.04 (d, 2H), 3.80 (t, 2H), 2.94-2.61 (m, 9H), 2.41 (s, 3H), 2.12-1.94 (m, 4H).

[1434] LCMS; m/z 405 (M+H).sup.+ (ES.sup.+).

Example 50: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt

[1435] ##STR00293##

[1436] 2-(Methylamino)ethanol (19.25 L, 0.240 mmol) and HATU (72 mg, 0.189 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P45) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 20 hours. The solution was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (39 mg, 54%) as a white solid.

[1437] 1H NMR (DMSO-d6), rotamers; 7.69 (s, 1H), 7.10 (s, 1H), 7.10 & 6.74 (2s, 1H), 6.82 (s, 1H), 4.96 & 4.84 (2t, J=5.5 Hz, 1H), 3.84 & 3.80 (2s, 3H), 3.59 (m, 1H), 3.55-3.41 (m, 3H), 3.06 & 2.97 (2s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.5 Hz, 4H), 1.92 (p, J=7.5 Hz, 4H).

[1438] LCMS; m/z 462.42 (M+H).sup.+ (ES.sup.+); 460.30 (MH) (ES).

Example 60: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide, sodium salt

[1439] ##STR00294##

[1440] HATU (49.3 mg, 0.130 mmol) was added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P45) (67.3 mg, 0.150 mmol) and N-methyltetrahydro-2H-pyran-4-amine (14.93 mg, 0.130 mmol) in DMF (1 mL) and the reaction mixture was stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide. The solid was dissolved in THF (2 mL) and 2 M sodium tert-butoxide in THF (54.0 L, 0.108 mmol) was added. The suspension was stirred at room temperature for 2 hours and filtered. The collected solid was washed with EtOAc (2 mL) and dried under reduced pressure for 6 hours to afford the title compound (46 mg, 80%) as a white solid.

[1441] .sup.1H NMR (DMSO-d6), rotamers; 7.47 (s, 1H), 6.77 (s, 1H), 6.58 (s, 1H), 4.53-4.49 (m, 0.6H), 3.94-3.90 (m, 2.4H), 3.80 (s, 3H), 3.43-3.41 (m, 1H), 3.16-3.12 (m, 1H), 2.89 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.66 (t, J=7.6 Hz, 4H), 1.93-1.80 (m, 6H), 1.59-1.55 (m, 2H).

[1442] LCMS; m/z 502 (M+H).sup.+ (ES.sup.+).

Example 61: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N-bis(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt

[1443] ##STR00295##

[1444] HATU (67.9 mg, 0.178 mmol) was added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P45) (66.7 mg, 0.149 mmol) and 2,2-azanediylbis(ethan-1-ol) (17.11 L, 0.178 mmol) in DMF (1 mL) and the reaction mixture was stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (32 mg, 42%) as a white solid.

[1445] .sup.1H NMR (DMSO-d6), rotamers; 7.60 (d, J=10.0 Hz, 1H), 7.24 (br s, 1H), 6.80 (s, 1H), 6.69 (s, 1H), 4.95-4.77 (m, 2H), 3.78 (s, 3H), 3.78-3.52 (m, 8H), 2.76 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.6 Hz, 4H), 1.95-1.88 (m, 4H).

[1446] LCMS; m/z 492 (M+H).sup.+ (ES.sup.+).

Example 62: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt

[1447] ##STR00296##

[1448] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,N-bis(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 61) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P45) and 2-((2-methoxyethyl)amino)ethan-1-ol to afford the title compound as a white solid (7 mg, 9%).

[1449] 1H NMR (DMSO-d6), rotamers; 7.61 (s, 1H), 7.11 (br s, 1H), 6.81 (s, 1H), 6.60 (s, 1H), 4.89-4.82 (m, 1H), 3.78 (s, 3H), 3.67-3.36 (m, 8H), 3.28-3.15 (22s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.95-1.88 (m, 4H).

[1450] LCMS; m/z 506 (M+H).sup.+ (ES.sup.+).

Example 63: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(oxetan-3-yl)-1H-pyrazole-5-carboxamide

[1451] ##STR00297##

[1452] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,N-bis(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 61) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P45) and N-methyloxetan-3-amine to afford the title compound (27 mg, 36%) as a white solid.

[1453] 1H NMR (DMSO-d6) rotamers: 10.95 (br s, 1H), 8.09 (s, 1H), 7.11 (s, 0.5H), 6.95 (s, 1H), 6.89 (s, 0.5H), 5.25-5.22 (m, 0.5H), 5.06-5.03 (m, 0.5H), 4.69-4.60 (m, 4H), 3.92 (s, 3H), 3.19-3.06 (m, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.5 Hz, 4H), 2.00-1.92 (m, 4H).

[1454] LCMS; m/z 474 (M+H).sup.+ (ES.sup.+).

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

[1455] ##STR00298##

[1456] 3-(Methylamino)propan-1-ol (19 L, 0.195 mmol), NaHCO.sub.3 (16 mg, 0.190 mmol) and HATU (72 mg, 0.189 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P45) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 2 days. The reaction was quenched with water (1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (37 mg, 48%) as a white solid.

[1457] .sup.1H NMR (DMSO-d6), rotamers; 7.81 (s, 1H), 7.61-6.99 (br s, 1H), 6.85 (s, 1H), 6.82-6.71 (m, 1H), 4.48 (br s, 1H), 3.94-3.78 (m, 3H), 3.59-3.13 (m, 4H), 3.07-2.90 (m, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 1.92 (p, J=7.4 Hz, 4H), 1.79-1.57 (m, 2H).

[1458] LCMS; m/z 476.4 (M+H).sup.+ (ES.sup.+); 474.4 (MH).sup. (ES.sup.).

Example 65: N-(2,3-Dihydroxypropyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt

[1459] ##STR00299##

[1460] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 64) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P45) and 3-(methylamino)propane-1,2-diol to afford the title compound (43 mg, 54%) as a white solid.

[1461] 1H NMR (DMSO-d6), rotamers; 7.83-7.64 (m, 1H), 7.61-7.01 (m, 1H), 6.87-6.80 (m, 1H), 6.78-6.71 (m, 1H), 5.13-4.99 (m, 1H), 4.96-4.84 (m, 1H), 4.62 (s, 1H), 3.90-3.73 (m, 3H), 3.71-3.09 (m, 5H), 3.07 (s, 1H), 2.98 (s, 1H), 2.76 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 2.07-1.79 (m, 4H).

[1462] LCMS; m/z 492.4 (M+H).sup.+ (ES.sup.+); 490.2 (MH) (ES).

Example 66: N-Ethyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt

[1463] ##STR00300##

[1464] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 64) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P45) and 2-(ethylamino)ethan-1-ol to afford the title compound (39 mg, 52%) as a white solid.

[1465] 1H NMR (DMSO-d6), rotamers; 8.16-6.99 (br s, 1H), 7.82 & 7.80 (2s, 1H), 6.86 (s, 1H), 6.79 & 6.74 (2s, 1H), 4.93 & 4.82 (2m, 1H), 3.82 (s, 3H), 3.65-3.33 (m, 6H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.3 Hz, 4H), 1.93 (quin, J=7.4 Hz, 4H), 1.15 & 1.08 (2t, J=7.1 Hz, 3H).

[1466] LCMS; m/z 476.5 (M+H).sup.+ (ES.sup.+); 474.3 (MH) (ES).

Example 67: N-((2,6-Diisopropylphenyl)carbamoyl)-1-methyl-5-(morpholine-4-carbonyl)-1H-pyrazole-3-sulfonamide

[1467] ##STR00301##

[1468] Morpholine (19 L, 0.220 mmol) and HATU (82 mg, 0.217 mmol) were successively added to a solution of 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P46) (70 mg, 0.155 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (41 mg, 53%) as a white solid.

[1469] .sup.1H NMR (DMSO-d6), rotamers; 11.11 (br s, 1H), 7.79 (s, 1H), 7.22 (t, J=7.7 Hz, 1H), 7.10 (d, J=7.7 Hz, 2H), 6.91 (s, 1H), 3.93 (s, 3H), 3.72-3.39 (m, 8H), 2.98 (sept, J=6.9 Hz, 2H), 1.05 (d, J=6.8 Hz, 12H).

[1470] LCMS; m/z 478.4 (M+H).sup.+ (ES.sup.+); 476.4 (MH).sup. (ES.sup.).

Example 68: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1471] ##STR00302##

[1472] HATU (66.5 mg, 0.175 mmol) was added to a solution of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P46) (65.9 mg, 0.146 mmol) and 2-methoxy-N-methylethanamine (19.00 L, 0.175 mmol) in DMF (1 mL) and the mixture stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred at room temperature for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (18 mg, 25%) as a white solid.

[1473] .sup.1H NMR (DMSO-d6), rotamers; 11.11 (s, 1H), 8.00-7.72 (m, 1H), 7.28-7.20 (m, 1H), 7.15-7.09 (m, 2H), 7.02-6.86 (m, 1H), 3.93 (s, 1H), 3.86 (s, 2H), 3.66-3.57 (m, 1H), 3.57-3.45 (m, 2H), 3.44-3.37 (m, 1H), 3.27 (s, 1H), 3.16 (s, 2H), 3.03-2.87 (m, 4H), 1.17-0.77 (m, 12H).

[1474] LCMS; m/z 480 (M+H).sup.+ (ES.sup.+).

Example 69: 3-(N-((2,6-Diisopropylphenyl)carbamoyl) sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1475] ##STR00303##

[1476] Prepared according to the general procedure of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 68) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P46) and bis(2-methoxyethyl)amine to afford the title compound (22 mg, 23%) as a white solid.

[1477] 1H NMR (DMSO-d6), rotamers; 11.11 (s, 1H), 7.91 (s, 1H), 7.31-7.18 (m, 1H), 7.13 (s, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 3.86 (s, 3H), 3.66-3.58 (m, 2H), 3.56-3.47 (m, 4H), 3.43-3.35 (m, 2H), 3.27 (s, 3H), 3.14 (s, 3H), 2.94 (sept, J=6.8 Hz, 2H), 1.18-0.87 (m, 12H).

[1478] LCMS; m/z 524 (M+H).sup.+ (ES.sup.+).

Example 70: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(4-hydroxypiperidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1479] ##STR00304##

[1480] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 64) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P45) and piperidin-4-ol to afford the title compound (44 mg, 57%) as a white solid.

[1481] 1H NMR (DMSO-d6), rotamers; 7.88 (s, 1H), 7.48-6.92 (m, 1H), 6.88 (s, 1H), 6.78 (s, 1H), 4.83 (d, J=3.9 Hz, 1H), 3.96 (m, 1H), 3.87 (s, 3H), 3.77 (m, 1H), 3.63 (m, 1H), 3.32 (m, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.94 (quin, J=7.5 Hz, 4H), 1.77 (m, 2H), 1.39 m, 2H).

[1482] LCMS; m/z 488.4 (M+H).sup.+ (ES.sup.+); 486.3 (MH) (ES).

Example 71: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxypyrrolidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, partial ammonium salt

[1483] ##STR00305##

[1484] 3-Methoxypyrrolidine (19 mg, 0.188 mmol) and HATU (72 mg, 0.189 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P45) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 20 hours. The solution was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (25 mg, 32%) as a white solid.

[1485] .sup.1H NMR (DMSO-d6), rotamers; 7.82 (s, 1H), 7.08 (s, 1H), 6.96 (d, J=2.6 Hz, 1H), 6.86 (s, 1H), 4.07-3.90 (m, 4H), 3.75-3.67 (m, 1H), 3.64-3.39 (m, 4H), 3.26 (s, 1H), 3.19 (s, 1H), 2.76 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.06-1.84 (m, 6H).

[1486] LCMS; m/z 488.43 (M+H).sup.+ (ES.sup.+); 48635 (MH).sup. (ES.sup.).

Example 72: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt

[1487] ##STR00306##

[1488] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxypyrrolidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, partial ammonium salt (Example 71) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P45) and bis(2-methoxyethyl)amine to afford the title compound (36 mg, 44%) as a white solid.

[1489] 1H NMR (DMSO), rotamers; 7.79 (s, 1H), 7.10 (br s, 1H), 6.85 (s, 1H), 6.73 (s, 1H), 3.80 (s, 3H), 3.63 (t, J=5.8 Hz, 2H), 3.58-3.49 (m, 4H), 3.39 (t, J=5.0 Hz, 2H), 3.28 (s, 3H), 3.14 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.3 Hz, 4H), 1.92 (quin, J=7.5 Hz, 4H).

[1490] LCMS; m/z 520.44 (M+H).sup.+ (ES.sup.+); 518.30 (MH).sup. (ES.sup.).

Example 73: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, sodium salt

[1491] ##STR00307##

[1492] 2-Methoxy-N-methylethanamine (19 L, 0.173 mmol), HATU (71 mg, 0.187 mmol) and Hunig's base (65 L, 0.372 mmol) were successively added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate P45) (50 mg, 0.124 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (1 mL) and purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford crude product. 18 mg of the crude product were partitioned between TBME (1 mL) and 0.1 M aqueous NaHCO.sub.3 (340 L, 0.034 mmol). The layers were separated and the aqueous layer washed with further TBME (21 mL). The aqueous layer was evaporated in vacuo and dried to afford the title compound (17 mg, 27%) as a white solid.

[1493] .sup.1H NMR (DMSO), rotamers; 7.52 (s, 1H), 6.77 (s, 1H), 6.6 & 6.55 (2s, 1H), 3.81 & 3.76 (2s, 3H), 3.61 (m, 1H), 3.56 (m, 2H), 3.4 (m, 1H), 3.28 & 3.16 (2s, 3H), 3.05 & 2.97 (2s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.5 Hz, 4H), 1.89 (quin, J=7.5 Hz, 4H).

[1494] LCMS; m/z 476.4 (M+H).sup.+ (ES.sup.+); 474.3 (MH).sup. (ES.sup.).

Example 74:N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-(morpholine-4-carbonyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1495] ##STR00308##

[1496] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 73) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P45) and morpholine to afford the title compound (12 mg, 16%) as a white solid.

[1497] 1H NMR (DMSO), rotamers; 7.54 (s, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 3.84 (s, 3H), 3.76-3.43 (m, 8H), 2.75 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.3 Hz, 4H), 1.90 (quin, J=7.5 Hz, 4H).

[1498] LCMS; m/z 474.4 (M+H).sup.+ (ES.sup.+); 472.3 (MH) (ES).

Example 75:5-(3-(Dimethylamino)oxetan-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1499] ##STR00309##

[1500] 5-(3-(Dimethylamino)oxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P47) (65 mg, 0.21 mmol) was dissolved in 4:1 THF:DMF (2.5 mL) and sodium tert-butoxide (2 M in THF; 0.117 mL, 0.233 mmol) was added. After 1 hour, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (46.5 mg, 0.233 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on reversed phase flash chromatography C18 (12 g column, 10-40% MeCN/10 mM ammonium bicarbonate) to afford the title compound (20 mg, 20%) as a white solid.

[1501] .sup.1H NMR (DMSO-d.sub.6) 10.82 (br s, 1H), 7.98 (s, 1H), 6.92 (s, 1H), 6.84 (s, 1H), 4.95 (d, J=7.2 Hz, 2H), 4.76 (d, J=7.2 Hz, 2H), 3.76 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.21 (s, 6H), 1.93 (p, J=7.4 Hz, 4H).

[1502] LCMS; m/z 460.3 (M+H).sup.+ (ES.sup.+); 458.2 (MH).sup. (ES.sup.).

Example 76: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-5-(((2-hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1503] ##STR00310##

[1504] Prepared according to the general procedure for 5-(3-(dimethylamino)oxetan-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 75) from 5-(((2-hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P48) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (28 mg, 32%) as a white solid.

[1505] .sup.1H NMR (DMSO-d6) 10.97 (br s, 1H), 7.82 (s, 1H), 6.93 (d, J=9.9 Hz, 2H), 6.64 (s, 1H), 4.48 (t, J=5.3 Hz, 1H), 3.90 (s, 3H), 3.59 (s, 2H), 3.52 (q, J=5.9 Hz, 2H), 2.97 (m, 2H), 2.46 (t, J=6.1 Hz, 2H), 2.15 (s, 3H), 1.06 (br s, 12H).

[1506] LCMS m/z 470.5 (M+H).sup.+ (ES.sup.+); 468.2 (MH).sup. (ES.sup.).

Example 77:N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(((2-hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

[1507] ##STR00311##

[1508] Prepared according to the general procedure for 5-(3-(dimethylamino)oxetan-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 75) from 5-(((2-hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P48) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (22 mg, 27%) as a white solid.

[1509] .sup.1H NMR (DMSO-d6) 10.71 (br s, 1H), 7.94 (s, 1H), 6.91 (s, 1H), 6.61 (s, 1H), 4.47 (t, J=5.3 Hz, 1H), 3.88 (s, 3H), 3.59 (s, 2H), 3.52 (q, J=5.9 Hz, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.46 (t, J=6.1 Hz, 2H), 2.15 (s, 3H), 1.94 (p, J=7.5 Hz, 4H).

[1510] LCMS m/z 448.5 (M+H).sup.+ (ES.sup.+); 446.1 (MH).sup. (ES.sup.).

Example 78: N-((4-fluoro-2,6-Diisopropylphenyl)carbamoyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt

[1511] ##STR00312##

[1512] 5-(((2-Methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P49) (35 mg, 0.13 mmol) was dissolved in THF (2 mL) and sodium tert-butoxide (2M in THF; 0.074 mL, 0.148 mmol) was added. After 1 hour, 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) (35 mg, 0.16 mmol) was added and the mixture stirred at room temperature for 18 hours. The resulting solid was filtered off, washed with EtOAc, and dried to afford the title compound (22 mg, 39%) as a white solid.

[1513] .sup.1H NMR (DMSO-d6) 7.37 (s, 1H), 6.79 (d, J=10.0 Hz, 2H), 6.27 (s, 1H), 3.76 (s, 3H), 3.50 (s, 2H), 3.45 (t, J=5.8 Hz, 2H), 3.23 (s, 3H), 3.14 (m, 2H), 2.51 (t, J=5.8 Hz, 2H), 2.15 (s, 3H), 1.03 (d, J=6.8 Hz, 12H).

[1514] LCMS m/z 484.5 (M+H).sup.+ (ES.sup.+); 482.3 (MH) (ES).

Example 79: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt

[1515] ##STR00313##

[1516] Prepared according to the general procedure for N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 78) from 5-(((2-methoxyethyl)(methyl)amino) methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P49) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (32 mg, 47%) as a white solid.

[1517] .sup.1H NMR (DMSO-d6) 7.59 (m, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 3.79 (s, 3H), 3.52 (s, 2H), 3.44 (t, J=5.8 Hz, 2H), 3.23 (s, 3H), 2.75 (t, J=7.3 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 2.51 (t, J=5.8 Hz, 2H), 2.16 (s, 3H), 1.90 (p, J=7.5 Hz, 4H).

[1518] LCMS m/z 462.4 (M+H).sup.+ (ES.sup.+); 460.4 (MH) (ES).

Example 80: N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide, sodium salt

[1519] ##STR00314##

[1520] Prepared according to the general procedure for N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 78) from 1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide (Intermediate P50) and 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A9) to afford the title compound (38 mg, 53%) as a white solid.

[1521] .sup.1H NMR (DMSO-d6) 7.45 (s, 1H), 7.01 (s, 2H), 6.28 (s, 1H), 3.77 (s, 3H), 3.56 (t, J=4.6 Hz, 4H), 3.48 (s, 2H), 3.13 (m, 2H), 2.36 (t, J=4.6 Hz, 4H), 1.03 (d, J=6.8 Hz, 12H).

[1522] LCMS m/z 498.4/500.5 (M+H).sup.+ (ES.sup.+); 496.3/498.4 (MH).sup. (ES.sup.).

Example 81: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide

[1523] ##STR00315##

[1524] Prepared according to the general procedure for 5-(3-(dimethylamino)oxetan-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 75) from 1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide (Intermediate P50) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (12 mg, 18%) as a white solid.

[1525] .sup.1H NMR (DMSO-d6) 10.81 (br s, 1H), 7.96 (s, 1H), 6.91 (s, 1H), 6.62 (s, 1H), 3.88 (s, 3H), 3.56 (s, 2H), 3.56 (m, 4H), 2.78 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 2.36 (m, 4H), 1.93 (p, J=7.5 Hz, 4H).

[1526] LCMS m/z 460.4 (M+H).sup.+ (ES.sup.+); 458.4 (MH).sup. (ES.sup.).

Example 82: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1527] ##STR00316##

[1528] HATU (51.4 mg, 0.135 mmol) was added to a solution of 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P51) (54.8 mg, 0.113 mmol) and 2-(methylamino)-ethanol (9.19 L, 0.124 mmol) in DMF (1 mL) and the mixture was stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (10 mg, 18%) as a white solid.

[1529] 1H NMR (DMSO-d6) rotamers: 11.18 (s, 1H), 7.95 (s, 1H), 7.14 (s, 2H), 6.98 (s, 1H), 4.96-4.79 (m, 1H), 3.93-3.86 (m, 3H), 3.64-3.41 (m, 4H), 3.06-2.88 (m, 5H), 1.08 (br s, 12H).

[1530] LCMS m/z 500.4/502.4 (M+H).sup.+ (ES.sup.+).

Example 83: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N-(2-hydroxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

[1531] ##STR00317##

[1532] 2-(Methylamino)ethanol (18 L, 0.224 mmol) and HATU (82 mg, 0.217 mmol) were successively added to a solution of 3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P46) (70 mg, 0.155 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford a white solid. The solid was dissolved in DMF (0.5 mL), diluted with water (1 mL) and stirred for 20 hours. The resulting precipitate was filtered off, washed with water and TBME, and dried to afford the title compound (8 mg, 11%), as a white solid.

[1533] 1H NMR (DMSO-d6), rotamers; 11.07 (s, 1H), 7.88 (s, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.12 (d, J=7.7 Hz, 2H), 7.02&7.0 (2s, 1H), 4.96&4.81 (t, J=5.0&57 Hz, 1H), 3.94 &3.89 (2s, 3H), 3.59&3.40 (2t, J=5.6&5.1 Hz, 2H), 3.50 (2t, J=5.6&5.2 Hz, 2H), 3.03 & 2.98 (2s, 3H), 2.95 (m, 2H), 1.06 (br s, 12H).

[1534] LCMS; m/z 466.5 (M+H).sup.+ (ES.sup.+); 464.4 (MH).sup. (ES.sup.).

Example 84:3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt

[1535] ##STR00318##

[1536] 2-Aminoethanol (14 L, 0.232 mmol) and HATU (83 mg, 0.219 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P45) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (18 mg, 25%) as a white solid.

[1537] 1H NMR (DMSO-d6) 8.61 (t, J=5.7 Hz, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 6.88 (s, 1H), 4.73 (t, J=5.7 Hz, 1H), 4.10 (s, 3H), 3.48 (app q, J=6.0 Hz, 2H), 3.27 (app q, J=6.0 Hz, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H). One exchangeable proton not seen.

[1538] LCMS; m/z 448.4 (M+H).sup.+ (ES.sup.+); 446.4 (MH).sup. (ES.sup.).

Example 85: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt

[1539] ##STR00319##

[1540] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 84) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P45) and 2-methoxyethan-1-amine to afford the title compound (37 mg, 51%) as a colourless solid.

[1541] 1H NMR (DMSO-d6) 10.93 (br s, 1H), 8.74 (t, J=5.5 Hz, 1H), 7.90 (s, 1H), 7.36 (s, 1H), 6.90 (s, 1H), 4.11 (s, 3H), 3.44 (t, J=5.5 Hz, 2H), 3.39 (t, J=5.5 Hz, 2H), 3.26 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.3 Hz, 4H), 1.94 (p, J=7.5 Hz, 4H).

[1542] LCMS; m/z 462.4 (M+H).sup.+ (ES.sup.+); 460.3 (MH) (ES).

Example 86: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropyl-phenyl)carbamoyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, sodium salt

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

[1543] ##STR00320##

[1544] A solution of N,N-bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P52) (2.2 g, 6.87 mmol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine (Intermediate A7) (2.16 g, 6.87 mmol, 1 eq) and t-BuONa (659 mg, 6.87 mmol, 1 eq) in THF (100 mL) was stirred at 25 C. for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (column: Welch Ultimate XB_C18, 41 mm*235 mm*20/40 m, mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 0%-30%, 35 min) to give the title compound (2.5 g, 56% yield, 98% purity on LCMS) as a white solid.

[1545] .sup.1H NMR (DMSO-d.sub.6): 11.10 (br s, 1H), 8.06 (d, 1H), 7.79 (br s, 1H), 7.18 (d, 1H), 7.02 (d, 1H), 6.83-6.72 (m, 2H), 6.70 (s, 1H), 5.29-5.23 (m, 1H), 3.83 (s, 3H), 3.64-3.61 (m, 2H), 3.55-3.50 (m, 4H), 3.45-3.40 (m, 2H), 3.28 (s, 3H), 3.14 (s, 3H), 3.03-300 (m, 1H), 1.30 (d, 6H) and 1.09-1.05 (m, 6H).

[1546] LCMS: m/z 635.4 (M+H).sup.+ (ES.sup.+).

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

[1547] ##STR00321##

[1548] To a solution of 3-(N-((4-fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl) carbamoyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (2.5 g, 3-94 mmol, 1 eq, free form) in THF (100 mL) was added with t-BuONa (378 mg, 3.94 mmol, 1 eq). The reaction mixture was stirred at 25 C. for 1 hour and then concentrated in vacuo. The residue was triturated with isopropyl ether (20 mL) to give the title compound (2.2 g, 85% yield, 99% purity on LCMS, sodium salt) as a white solid.

[1549] .sup.1H NMR (DMSO-d.sub.6): 7.99-7.88 (m, 1H), 7.53-7.40 (m, 1H), 7.15-7.08 (m, 1H), 6.94-6.82 (m, 2H), 6.68 (s, 1H), 6.51-6.44 (m, 1H), 5.28-5.22 (m, 1H), 3.75 (s, 3H), 3.74-3.56 (m, 6H), 3.45-3.38 (m, 2H), 3.29 (s, 3H), 3.17 (s, 3H), 3.12-307 (m, 1H), 1.29 (d, 6H) and 1.20-1.04 (m, 6H).

[1550] LCMS: m/z 635.1 (M+H).sup.+ (ES.sup.+).

Example 87: N,N-Bis(2-methoxyethyl)-3-(N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide, sodium salt

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

[1551] ##STR00322##

[1552] A solution of N,N-bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P52) (2.56 g, 7.99 mmol, 1 eq) and t-BuONa (768 mg, 7.99 mmol, 1 eq) in THF (200 mL) was stirred at 25 C. for 30 minutes. Then 4(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A8) (3.34 g, 8.79 mmol, 1.1 eq) was added. The reaction mixture was stirred at 70 C. for 2 hours and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (column: Welch Ultimate XB_C18, 41 mm*235 mm*20/40 m, mobile phase: [A: water (0.05% ammonium hydroxide); B: MeCN]; B %: 0%-30%, 35 min) to give the title compound (1.35 g, 29% yield, 99% purity on LCMS) as a white solid.

[1553] .sup.1H NMR (DMSO-d.sub.6): 8.08 (d, 1H), 7.14-7.11 (m, 1H), 7.07-7.05 (m, 1H), 6.91 (d, 1H), 6.74 (s, 1H), 6.60 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.64-3.62 (m, 2H), 3.56-3.54 (m, 4H), 3.39-3.37 (m, 2H), 3.28 (s, 3H), 3.14 (s, 3H), 2.89 (t, 2H), 2.71 (t, 2H) and 1.99-1.94 (m, 2H).

[1554] LCMS: m/z 587.3 (M+H).sup.+ (ES.sup.+).

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

[1555] ##STR00323##

[1556] To a solution of N,N-bis(2-methoxyethyl)-3-(N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide (1.35 g, 2.30 mmol, 1 eq, free form) in THF (20 mL) was added with t-BuONa (221 mg, 2.30 mmol, 1 eq). The reaction mixture was stirred at 25 C. for 1 hour and then concentrated in vacuo. The residue was triturated with isopropyl ether (20 mL) to give the title compound (1.2 g, 85% yield, 99% purity on HPLC) as a white solid.

[1557] .sup.1H NMR (DMSO-d.sub.6): 8.05 (d, 1H), 7.30 (br s, 1H), 7.04 (dd, 2H), 6.92 (d, 1H), 6.76 (s, 1H), 6.48 (d, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.64-3.62 (m, 2H), 3.56-3.53 (m, 4H), 3.39-3.37 (m, 2H), 3.29 (s, 3H), 3.15 (s, 3H), 2.87 (t, 2H), 2.73-2.70 (m, 2H) and 1.98-1.91 (m, 2H).

[1558] LCMS: m/z 587.1 (M+H).sup.+ (ES.sup.+).

Example 88: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-sulfonamide

[1559] ##STR00324##

[1560] To a solution of 1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-sulfonamide (Intermediate P53) (150 mg, 684.12 mol, 1 eq) in THF (5 mL) was added CH.sub.3ONa (37 mg, 684.12 mol, 1 eq) and the resulting mixture was stirred at 25 C. for 30 minutes. Then a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (136 mg, 684.12 mol, 1 eq) in THF (2 mL) was added under nitrogen. The mixture was stirred at 70 C. for 1 hour under nitrogen. Then the reaction mixture was filtered and the filter cake was washed with EtOAc (10 mL. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*5 m; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; B %: 0%-30%, 12 minutes) to give the title compound (79.1 mg, 179.55 mol, 26% yield, 95% purity) as a white solid.

[1561] .sup.1H NMR (DMSO-d.sub.6): 7.98 (s, 1H), 7.63 (s, 1H), 7.57 (br s, 1H), 6.82 (s, 1H), 4.75 (s, 2H), 4.00 (s, 2H), 2.76 (t, 4H), 2.64 (t, 4H), 1.94-1.86 (m, 4H) and 1.05 (s, 6H).

[1562] LCMS: m/z 419.2 (M+H).sup.+ (ES.sup.+).

Example 89: (R)N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-hydroxypropyl)-1H-pyrazole-4-sulfonamide

[1563] ##STR00325##

[1564] To a solution of (R)-1-(2-hydroxypropyl)-1H-pyrazole-4-sulfonamide (Intermediate P54) (180 mg, 877.05 mol, 1 eq) in THF (2 mL) was added CH.sub.3ONa (47 mg, 877.05 mol, 1 eq) and the resulting mixture was stirred at 25 C. for 30 minutes. Then a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (175 mg, 877.05 mol, 1 eq) in THF (2 mL) was added and the mixture was stirred at 60 C. for another 30 minutes. The reaction mixture was quenched with water (20 mL) at 25 C. and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 m; mobile phase: [water (0.04% NH.sub.3. H.sub.2O+10 mM NH.sub.4HCO.sub.3)-acetonitrile]; B %: 10%-40%, 10 minutes) to give the title compound (122.23 mg, 299.17 mol, 34% yield, 99% purity) as a white solid.

[1565] .sup.1H NMR (DMSO-d.sub.6): 8.19 (s, 1H), 7.85 (br s, 1H), 7.76-7.78 (d, 1H), 6.89 (s, 1H), 4.96 (d, 1H), 4.06-4.03 (m, 2H), 4.00-3.95 (m, 1H), 2.78 (t, 4H), 2.61 (t, 4H), 1.89-1.97 (m, 4H) and 1.02 (d, 3H).

[1566] LCMS: m/z 405.2 (M+H).sup.+ (ES.sup.+).

[1567] The compounds of examples 90-107 were synthesised by methods analogous to those outlined above.

TABLE-US-00002 TABLE 1 Ex Structure and Name .sup.1H NMR spectrum MS MW 90 [00326] 1H NMR (DMSO-d6) 10.87 (br s, 1H), 8.15 (d, J = 5.3 Hz, 1H), 7.95-7.86 (m, 2H), 7.21 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.91-6.87 (m, 1H), 6.73 (br s, 1H), 6.62 (br s, 1H), 3.89 (s, 3H), 3.75 (p, J = 5.8 Hz, 1H), 3.19 (t, J = 6.8 Hz, 2H), 3.09 (s, 3H), 2.91 (t, J = 7.3 Hz, 2H), 2.75 (s, 2H), 2.72-2.62 (m, 4H), 1.98 (p, J = 7.4 Hz, 2H), 1.49 (s, 6H). m/z 555.2 (M + H)+ (ES+) 554.66 91 [00327] 1H NMR (DMSO-d6) 8.57 (d, J = 5.1 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.63 (br s, 1H), 7.61 (dd, J = 5.1, 1.8 Hz, 1H), 7.12 (s, 2H), 6.25 (d, J = 2.4 Hz, 1H), 5.00 (ddt, J = 7.9, 6.1, 3.8 Hz, 1H), 3.99-3.91 (m, 2H), 3.86 (dd, J = 9.4, 3.7 Hz, 1H), 3.79 (td, J = 8.4, 5.6 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.39-2.33 (m, 1H), 2.22 (m, 1H), 1.97 (p, J = 7.5 Hz, 2H). m/z 479.3 (M + H)+ (ES+) 478.52 92 [00328] 1H NMR (DMSO-d6) 8.56 (d, J = 5.1 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.64 (br s, 1H), 7.60 (dd, J = 5.1, 1.7 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.11 (s, 2H), 6.23 (d, J = 2.2 Hz, 1H), 4.90 (s, 1H), 4.04-3.90 (m, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.78 (t, J = 7.5 Hz, 2H), 1.98 (p, J = 7.6 Hz, 2H), 1.01 (d, J = 5.9 Hz, 3H). m/z 467.3 (M + H)+ (ES+) 466.51 93 [00329] 1H NMR (DMSO-d6) 8.58 (d, J = 5.1 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 5.1, 1.7 Hz, 1H), 7.58 (br s, 1H), 7.55 (d, J = 2.3 Hz, 1H), 7.11 (s, 2H), 6.24 (d, J = 2.2 Hz, 1H), 4.68 (s, 1H), 3.99 (s, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 1.97 (p, J = 7.5 Hz, 2H), 1.03 (s, 6H). m/z 481.3 (M + H)+ (ES+) 480.53 94 [00330] 1H NMR (DMSO-d6) 8.11 (d, J = 5.3 Hz, 1H), 7.80-7.64 (m, 2H), 7.16 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 5.3 Hz, 1H), 6.73 (s, 1H), 6.55-6.43 (m, 1H), 4.99 (d, J = 5.0 Hz, 1H), 4.09- 4.01 (m, 2H), 3.97 (p, J = 5.9 Hz, 1H), 3.88 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 1.98 (p, J = 7.5 Hz, 2H), 1.04 (d, J = 6.2 Hz, 3H). One exchangeable proton not observed. m/z 472.3 (M + H)+ (ES+) 471.53 95 [00331] 1H NMR (DMSO-d6) 8.11 (d, J = 5.2 Hz, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (s, 1H), 6.53 (s, 1H), 4.17 (s, 2H), 3.88 (s, 3H), 3.16 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H), 1.06 (s, 6H). One exchangeable proton not observed. m/z 500.3 (M + H)+ (ES+) 499.58 96 [00332] 1H NMR (DMSO-d6) 8.11 (d, J = 5.3 Hz, 1H), 7.84-7.61 (m, 2H), 7.16 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (s, 1H), 6.51 (s, 1H), 4.76 (s, 1H), 4.06 (s, 2H), 3.88 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H), 1.05 (s, 6H). One exchangeable proton not observed. m/z 486.3 (M + H)+ (ES+) 485.56 97 [00333] 1H NMR (DMSO-d6) 8.10 (d, J = 5.3 Hz, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.73 (s, 1H), 6.55 (s, 1H), 5.13-5.06 (m, 1H), 4.00-3.95 (m, 2H), 3.91- 3.86 (m, 4H), 3.82 (td, J = 8.4, 5.6 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.66 (t, J = 7.4 Hz, 2H), 2.49- 2.35 (m, 1H), 2.29-2.19 (m, 1H), 1.97 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. m/z 484.2 (M + H)+ (ES+) 483.54 98 [00334] 1H NMR (DMSO-d6) 10.90 (s, 1H), 8.14 (d, J = 5.2 Hz, 1H), 7.82 (s, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.96 (s, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.74- 6.72 (m, 1H), 4.87 (d, J = 7.3 Hz, 2H), 4.80 (d, J = 7.3 Hz, 2H), 3.73 (s, 3H), 3.32 (s, 3H), 2.98 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H), 1.96 (p, J = 7.5 Hz, 2H). m/z 514.3 (M + H)+ (ES+) 513.57 99 [00335] 1H NM R (DMSO-d6) 7.96 (s, 1H), 7.56 (s, 1H), 7.35 (s, 1H), 6.76 (s, 1H), 4.38 (tt, J = 10.3, 5.2 Hz, 1H), 3.98-3.90 (m, 2H), 3.44 (td, J = 11.4, 3.3 Hz, 2H), 2.75 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.92-1.90 (m, 8H). LCMS; m/z 431 (M + H).sup.+ (ES.sup.+) 430.5 100 [00336] 1H NMR (DMSO-d6) 7.96 (s, 1H), 7.58 (s, 1H), 7-39 (s, 1H), 6.77 (s, 1H), 5.00 (ddt, J = 7.9, 6.4, 3.7 Hz, 1H), 4.09-3.76 (m, 4H), 2.75 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 2.43-2.29 (m, 1H), 2.24-2.18 (m, 1H), 1.92- 1.89 (m, 4H). LCMS; m/z 417 (M + H).sup.+ (ES.sup.+) 416.5 101 [00337] 1H NMR (DMSO-d6) 7.87 (d, J = 0.6 Hz, 1H), 7.55 (d, J = 0.6 Hz, 1H), 7.35 (br s, 1H), 6.76 (s, 1H), 4.21 (t, J = 5.3 Hz, 2H), 3.65 (t, J = 5.3 Hz, 2H), 3.23 (s, 3H), 2.75 (t, J = 7.4 Hz, 4H), 2.66 (t, J = 7.3 Hz, 4H), 1.94-1.88 (m, 4H). LCMS; m/z 405 (M + H).sup.+ (ES.sup.+) 404.5 102 [00338] 1H NMR (DMSO-d6) 10.78 (s, 1H), 8.32 (s, 1H), 7.90-7.71 (m, 2H), 6.91 (d, J = 9.9 Hz, 2H), 4.30 (t, J = 5.2 Hz, 2H), 3.68 (t, J = 5.2 Hz, 2H), 3.31 (s, 3H), 2.96-2.83 (m, 2H), 1.03 (s, 12H). LCMS; m/z 427.1 (M + H).sup.+ (ES.sup.+) 426.5 103 [00339] 1H NMR (DMSO-d6) 8.49 (s, 1H), 7.86 (s, 1H), 6.88 (s, 1H), 5.10 (d, J = 5.0 Hz, 1H), 4.38 (dd, J = 13.6, 4.3 Hz, 1H), 4.28 (dd, J = 13.7, 7.2 Hz, 1H), 4.06-3.95 (m, 1H), 2.77 (t, J = 7.4 Hz, 4H), 2.61 (t, J = 7.4 Hz, 4H), 1.92 (p, J = 7.4 Hz, 4H), 1.06 (d, J = 6.3 Hz, 3H). Acidic NH not observed. LCMS; m/z 406.4 (M + H).sup.+ (ES.sup.+) 405.5 104 [00340] 1H NMR (DMSO-d6) 7.84-7.73 (m, 1H), 7.74- 7.67 (m, 1H), 6.85 (s, 1H), 6.58-6.50 (m, 1H), 5.03 (d, J = 5.5 Hz, 1H), 4.77 (t, J = 5.6 Hz, 1H), 4.25 (dd, J = 13.7, 3.8 Hz, 1H), 4.03 (dd, J = 13.8, 7.8 Hz, 1H), 3.83-3.76 (m, 1H), 3.39-3.33 (m, 1H), 3.30- 3.25 (m, 1H), 2.77 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 1.93 (p, J = 7.5 Hz, 4H). Acidic NH not observed. LCMS; m/z 421.4 (M + H)+ (ES+) 420.5 105 [00341] 1H NMR (DMSO-d6) 10.85 (br s, 1H), 7.89 (s, 1H), 6.89 (s, 1H), 6.68 (s, 1H), 5.68 (d, J = 4.4 Hz, 1H), 4.79 (s, 1H), 4.46- 4.42 (m, 1H), 4.18 (dd, J = 9.8, 6.4 Hz, 1H), 4.02 (dd, J = 9.4, 5.3 Hz, 1H), 3.97 (dd, J = 9.8, 3.8 Hz, 1H), 3.61 (dd, J = 9.4, 3.3 Hz, 1H), 2.78 (t, J = 7.5 Hz, 4H), 2.61 (t, J = 7.4 Hz, 4H), 1.94 (p, J = 7.4 Hz, 4H). OH not observed. LCMS; m/z 433.7 (M + H).sup.+ (ES.sup.+) 432.5 106 [00342] 1H NMR (DMSO-d6) 7.61 (d, J = 2.3 Hz, 1H), 7.52 (s, 1H), 6.38 (d, J = 2.3 Hz, 1H), 4.70 (br s, 1H), 4.01 (s, 2H), 2.78 (t, J = 7.5 Hz, 4H), 2.67 (t, J = 7.5 Hz, 4H), 1.95 (p, J = 7.5 Hz, 4H), 1.04 (s, 6H). LCMS; m/z 437.3 (M + H)+ (ES+) 436.5 107 [00343] 1H NMR (DMSO-d6) 10.80 (br s, 1H), 7.98- 7.93 (m. 2H), 6.92 (br s, 1H), 6.72-6.69 (m, 1H), 3.71 (p, J = 5.8 Hz, 1H), 3.19-3.14 (m, 2H), 2.95 (s, 3H), 2.78 (t, J = 7.4 Hz, 4H), 2.74 (s, 2H), 2.70-2.65 (m, 2H), 2.62 (t, J = 7.4 Hz, 4H), 1.95 (p, J = 7.3 Hz, 4H), 1.49 (s, 6H). LCMS; m/z 488.3 (M + H)+ (ES+) 487.6 .sup.1H NMR and MS data

ExamplesBiological Studies

NLRP3 and Pyroptosis

[1568] It is well established that the activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-1) from the cell.

THP-1 Cells: Culture and Preparation

[1569] THP-1 cells (ATCC # TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma # S8636) and penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma # P4333) in 10% Fetal Bovine Serum (FBS) (Sigma # F0804). The cells were routinely passaged and grown to confluency (10.sup.6 cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma # T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma # L4524) to give a 1 g/ml Final Assay Concentration (FAC). 40 l of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

THP-1 Cells Pyroptosis Assay

[1570] The following method step-by-step assay was followed for compound screening. [1571] 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 g/ml LPS in 40 l of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) [1572] 2. Add 5 l compound (8 points half-log dilution, with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1573] 3. Incubate for 3 hrs at 37 C. and 5% CO.sub.2 [1574] 4. Add 5 l nigericin (Sigma # N7143) (FAC 5 M) to all wells [1575] 5. Incubate for 1 hr at 37 C. and 5% CO.sub.2 [1576] 6. At the end of the incubation period, spin plates at 300g for 3 mins and remove supernatant [1577] 7. Then add 50 l of resazurin (Sigma # R7017) (FAC 100 M resazurin in RPMI medium without FBS) and incubate plates for a further 1-2 hrs at 37 C. and 5% CO.sub.2 [1578] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [1579] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

96-Well Plate Map

[1580]

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

[1581] The results of the pyroptosis assay performed are summarised in Table 2 below as THP IC.sub.50.

Human Whole Blood IL1 Release Assay

[1582] 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.

[1583] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [1584] 1. Plate out 80 l of whole blood containing 1 g/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [1585] 2. Add iol compound (8 points half-log dilution with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1586] 3. Incubate for 3 hrs at 37 C., 5% CO.sub.2 [1587] 4. Add 10 l Nigericin (Sigma # N7143) (10 M FAC) to all wells [1588] 5. Incubate for 1 hr at 37 C., 5 CO.sub.2 [1589] 6. At the end of the incubation period, spin plates at 300g for 5 mins to pellet cells and remove 20 l of supernatant and add to 96-well v-bottom plates for IL-13 analysis (note: these plates containing the supernatants can be stored at 80 C. to be analysed at a later date) [1590] 7. IL-1 was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [1591] 8. IC.sub.50 data is fitted to anon-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[1592] The results of the human whole blood assay are summarised in Table 2 below as HWB IC.sub.50.

TABLE-US-00004 TABLE 2 NLRP3 inhibitory activity Example No THP IC.sub.50 HWB IC.sub.50 1 +++ *** 2 +++ *** 3 ++++ *** 4 ++++ * 5 ++++ *** 6 ++++ *** 7 ++++ **** 8 ++++ ***** 9 ++ * 10 ++++ **** 11 ++++ ***** 12 +++ *** 13 +++ ***** 14 +++++ **** 15 ++++ *** 16 ++++ **** 17 ++ * 18 ++ ** 19 ++ * 20 ++++ *** 21 ++++ *** 22 ++++ **** 23 ++++ ***** 24 ++++ ***** 25 +++ *** 26 ++++ ***** 27 ++ ND 28 +++ *** 29 +++ *** 30 ++++ *** 31 +++ ** 32 ++ * 33 +++ *** 34 +++ *** 35 +++ *** 36 +++ **** 37 +++ ***** 38 +++++ ***** 39 ++++ ** 40 +++ ***** 41 ++++ **** 42 +++++ ***** 43 ++ ND 44 +++ ND 45 +++++ ***** 46 +++++ ***** 47 ++++ **** 48 +++++ ***** 49 +++ *** 50 ++++ *** 51 ++++ ***** 52 +++ ND 53 +++++ ***** 54 ++ ND 55 +++ *** 56 ++++ * 57 +++ *** 58 ++ *** 59 ++++ ***** 60 + ND 61 +++ ***** 62 ++++ **** 63 ++ ND 64 +++ ** 65 ++ ND 66 +++ *** 67 ++ ND 68 + ND 69 + ND 70 + ND 71 + ND 72 ++++ **** 73 ++++ **** 74 ++ ND 75 +++ *** 76 +++ ***** 77 ++++ ***** 78 ++ ND 79 +++ ** 80 ++ ND 81 ++ ND 82 ++++ *** 83 ++ ND 84 + ND 85 + ND 86 + * 87 +++ ***** 88 ++ ND 89 ++ ND 90 +++++ ***** 91 +++++ ***** 92 +++++ ***** 93 +++++ ***** 94 +++++ ***** 95 +++++ ***** 96 +++++ ***** 97 ++++ ***** 98 +++++ ***** 99 + ND 100 ++ ND 101 ++ ND 102 ND ND 103 +++ *** 104 +++ *** 105 +++ ND 106 +++++ **** 107 ++++ *** [THP IC50 (0.04 M = +++++, 0.16 M = ++++, 0.64 M = +++, 2.56 M = ++, 10 M = +, not determined = ND)] [HWB IC50 (0.4 M = *****, 0.8 M = ****, 1.6 M = ***, 3.2 M = **, 10 M = *, not determined = ND)]

PK Protocol

[1593] Pharmacokinetic parameters were determined in male Sprague Dawley rats (Charles River, UK, 250-350 g; or Vital River Laboratory Animal Technology Co Ltd, Beijing, China, 7-9 weeks old). Animals were individually housed during the study and maintained under a 12 h light/dark cycle. Animals had free access to food and water except that some orally dosed animals were food deprived overnight prior to the study. For intravenous administration, compounds were formulated as a solution in water or DMSO:PBS [10:90] in 2 mL/kg dosing volume and administered via tail vein. For oral administration, compounds were formulated as a solution in water or DMSO:water [10:90] in 5 mL/kg dosing volume and administered orally.

[1594] Serial blood samples (about 120-300 L) were taken from each animal at each of 8 time-points post dose (0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h) or at each of 12 time-points post dose (0.03, 0.1, 0.17, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h) or pre-dose and at each of 9 time-points post dose (0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h). Samples were held on ice for no longer than 30 minutes before centrifugation (10,000 rpm (8,385 g) for 3 minutes; or 5,696 rpm (3,000 g) for 15 minutes) for plasma generation. Plasma was frozen on dry ice prior to bioanalysis. PK parameters were generated from LC-MS/MS data using Dotmatics or Phoenix WinNonlin 6.3 software.

[1595] The pharmacokinetic parameters determined are summarised in Tables 3 and 4 below. Also included for comparative purposes in Table 3 are the intravenous pharmacokinetic parameters determined using the above protocol for MCC950, an NLRP3 inhibitor described in Baldwin et al., J. Med. Chem., 59(5), 1691-1710, 2016.

TABLE-US-00005 TABLE 3 PK data (intravenous administration) Example Dose AUC T.sub.1/2 V.sub.dss Cl No (mg/kg) (ng .Math. hr/mL) (hr) (L/kg) (mL/min/kg) 1 1 8622.1 3.4 0.43 1.9 2 1 1027.4 0.3 0.3 16.2 3 1 3680.6 6.7 1.57 4.5 10 1 4289.9 2.9 0.61 3.9 11 1 7383.2 2.9 0.36 2.3 13 1 38678.1 3.6 0.09 0.4 16 1 10217.1 3.8 0.41 1.8 23 1 20093.7 2.6 0.12 0.8 24 1 7029.4 3.5 0.37 2.4 26 1.74 8057.9 3.6 0.6 4.2 37 1 300.2 1.0 1.22 56.3 38 1 3881.3 1.1 0.35 4.6 42 1 2960.7 0.7 0.24 5.6 45 2.99 2319.1 0.8 1.11 21.6 46 1.42 2382.0 1.6 0.56 10.0 48 1 947.9 2.9 1.74 17.6 51 1 1857.3 6.6 1.18 9.0 53 1 1276.0 11.5 3.48 13.3 59 2.41 786.6 0.3 2.37 114.1 72 2.88 329.7 0.2 1.84 149.3 73 1 1162.1 2.9 2.24 14.4 77 1 2067.0 14.2 1.9 8.1 MCC950 1 611.1 1.2 0.53 27.8

TABLE-US-00006 TABLE 4 PK data (oral administration) Example Dose C.sub.max AUC T.sub.max T.sub.1/2 Cl/F No (mg/kg) (ng/mL) (ng .Math. hr/mL) (hr) (hr) (mL/min/kg) Bioavailability 10 3 1772.4 9657.8 0.29 3.5 5.2 75 16 3 3958.1 19567.5 0.83 3.2 2.6 63.8 73 3 700.6 2415.2 0.08 4.9 21.5 67

[1596] As is evident from the results presented in Table 2, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and in the human whole blood assay.

[1597] As is evident from the results presented in Tables 3 and 4, the compounds of the invention show advantageous pharmacokinetic properties, for example half-life T.sub.1/2, area under the curve AUC, clearance Cl and/or bioavailability, compared to the prior art compounds.

[1598] 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.