NOVEL SULFONAMIDE CARBOXAMIDE COMPOUNDS

Abstract

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

##STR00001##

Claims

1. A compound of formula (I): ##STR00069## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is selected from O or S; R.sup.1 is a 5-membered heteroaryl group substituted with at least one group R.sup.X, wherein R.sup.X is any monovalent group comprising a heteroaryl group, and wherein the 5-membered heteroaryl group of R.sup.1 may optionally be further substituted; and R.sup.2 is a cyclic group substituted at the -position, wherein R.sup.2 may optionally be further substituted; provided that the compound is not: ##STR00070##

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

3. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein the 5-membered heteroaryl group of R.sup.1 contains at least one nitrogen atom in the 5-membered ring structure, and optionally wherein the 5-membered heteroaryl group of R.sup.1 contains only carbon and nitrogen atoms in the 5-membered ring structure.

4. (canceled)

5. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein R.sup.X is an optionally substituted heteroarylalkyl group.

6. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein: (i) R.sup.X contains only atoms selected from the group consisting of carbon, hydrogen, nitrogen, oxygen and halogen atoms; and/or (ii) R.sup.X contains from 5 to 11 atoms other than hydrogen or halogen.

7. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein R.sup.X does not contain an amide group.

8. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 7, wherein R.sup.X does not contain a carbonyl group.

9. (canceled)

10. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein: (i) Q is O; and/or (ii) the 5-membered heteroaryl group of R.sup.1 is further substituted with one, two or three substituents independently selected from halo; CN; NO.sub.2; N.sub.3; R.sup.; 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(RP).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(RP).sub.2; NH.sub.2; NHR.sup.; N(RR).sub.2; R.sup.NH.sub.2; R.sup.NHR.sup.; R.sup.N(RR).sub.2; CHO; CORP; 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 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.

11. 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.

12. (canceled)

13. (canceled)

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 -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.

15. 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.

16. (canceled)

17. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in claim 1, wherein Q is O; R.sup.1 is ##STR00071## wherein: V is independently selected from C and N, and W, X, Y and Z are each independently selected from N, O, S, NH and CH, provided that at least one of V, W, X, Y and Z is N or NH, and at least two of V, W, X, Y and Z are C or CH; m is 1; n is 0, 1 or 2; R.sup.X is R.sup.10-L-, wherein L is a bond or an alkylene or an alkenylene group, wherein the alkylene or alkenylene group may optionally include one or more heteroatoms N or O in its carbon skeleton, wherein the alkylene or alkenylene group may be optionally substituted with one or more substituents independently selected from halo, CN, OH, NH.sub.2, oxo (O) and NH, and wherein R.sup.10 is a monocyclic heteroaryl group, wherein the monocyclic heteroaryl group may optionally be substituted with one or more groups independently selected from halo, OH, NH.sub.2, CN, R.sup.2, OR.sup.2, NHR.sup.2O or N(R.sup.2).sub.2, wherein each R.sup.20 is independently selected from a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkenyl or C.sub.1-C.sub.4 alkynyl group, any of which may optionally be halo-substituted, provided that R.sup.X contains from 5 to 14 atoms other than hydrogen or halogen; each R.sup.Y is independently selected from a C.sub.1-C.sub.6 saturated hydrocarbyl group, wherein the saturated hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the saturated hydrocarbyl group may optionally be substituted with one or more groups independently selected from halo, CN, OH, NH.sub.2 and oxo (O), and wherein the saturated hydrocarbyl group may optionally include one or two heteroatoms N or O in its carbon skeleton; and 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 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 the phenyl or 5- or 6-membered heteroaryl group is further substituted at the position with a substituent selected from R.sup.14, OR.sup.14 and COR.sup.14, wherein R.sup.14 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.14 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, two or three substituents independently selected from halo, NO.sub.2, CN, COOR.sup.15, CONH.sub.2, CONHR.sup.15 or CON(R.sup.15).sub.2, wherein each R.sup.15 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 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.15, CONH.sub.2, CONHR.sup.15 or CON(R.sup.15).sub.2, wherein each R.sup.15 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 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.15, CONH.sub.2, CONHR.sup.15 or CON(R.sup.15).sub.2, wherein each R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group; or (iv) 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.12OR.sup.13, R.sup.12N(R.sup.13).sub.2, R.sup.12CN or R.sup.12CCR.sup.13, 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 R.sup.12 is independently selected from a bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 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 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, two or three substituents independently selected from halo, NO.sub.2, CN, COOR.sup.15, CONH.sub.2, CONHR.sup.15 or CON(R.sup.15).sub.2, wherein each R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group; or (v) 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.12OR.sup.13, R.sup.12N(R.sup.13).sub.2, R.sup.12CN or R.sup.12CCR.sup.13, 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 R.sup.12 is independently selected from a bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 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.15, CONH.sub.2, CONHR.sup.15 or CON(R.sup.15).sub.2, wherein each R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group.

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: ##STR00072## ##STR00073##

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 inhibitor.

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 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).

25. 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.

25. 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.

26. 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

[0427] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0428] 2-MeTHF 2-methyltetrahydrofuran [0429] Ac.sub.2O acetic anhydride [0430] AcOH acetic acid [0431] aq aqueous [0432] Boc tert-butyloxycarbonyl [0433] br broad [0434] Cbz carboxybenzyl [0435] CDI 1,1-carbonyl-diimidazole [0436] conc concentrated [0437] d doublet [0438] DABCO 1,4-diazabicyclo[2.2.2]octane [0439] DCE 1,2-dichloroethane, also called ethylene dichloride [0440] DCM dichloromethane [0441] DIPEA N,N-diisopropylethylamine, also called Hnig's base [0442] DMA dimethylacetamide [0443] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0444] DME dimethoxyethane [0445] DMF N,N-dimethylformamide [0446] DMSO dimethyl sulfoxide [0447] eq or equiv equivalent [0448] (ES+) electrospray ionization, positive mode [0449] Et ethyl [0450] EtOAc ethyl acetate [0451] EtOH ethanol [0452] h hour(s) [0453] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0454] HPLC high performance liquid chromatography [0455] LC liquid chromatography [0456] m multiplet [0457] m-CPBA 3-chloroperoxybenzoic acid [0458] Me methyl [0459] MeCN acetonitrile [0460] MeOH methanol [0461] (M+H)+ protonated molecular ion [0462] MHz megahertz [0463] min minute(s) [0464] MS mass spectrometry [0465] Ms mesyl, also called methanesulfonyl [0466] MsCl mesyl chloride, also called methanesulfonyl chloride [0467] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0468] m/z mass-to-charge ratio [0469] NaOtBu sodium tert-butoxide [0470] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0471] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0472] NMP N-methylpyrrolidine [0473] NMR nuclear magnetic resonance (spectroscopy) [0474] Pd(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o) [0475] Pd(dppf)C.sub.2 [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [0476] PE petroleum ether [0477] Ph phenyl [0478] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0479] prep-HPLC preparative high performance liquid chromatography [0480] prep-TLC preparative thin layer chromatography [0481] PTSA p-toluenesulfonic acid [0482] q quartet [0483] RP reversed phase [0484] RT room temperature [0485] s singlet [0486] Sept septuplet [0487] sat saturated [0488] SCX solid supported cation exchange (resin) [0489] t triplet [0490] T3P propylphosphonic anhydride [0491] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0492] TEA triethylamine [0493] TFA 2,2,2-trifluoroacetic acid [0494] THF tetrahydrofuran [0495] TLC thin layer chromatography [0496] wt % weight percent or percent by weight

EXPERIMENTAL METHODS

Nuclear Magnetic Resonance

[0497] 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: [0498] a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe, [0499] a Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control, [0500] a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe, [0501] 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 [0502] an Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

LC-MS

[0503] LC-MS Methods: Using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC & Agilent 6110 MSD. Mobile Phase: A: 0.025% NH.sub.3.H.sub.2O in water (v/v); B: acetonitrile. Column: Kinetex EVO C18 2.130 mm, 5 m.

Reversed Phase HPLC Conditions for the LCMS Analytical Methods

Methods 1a and 1b:

[0504] Waters Xselect CSH C18 XP column (4.630 mm, 2.5 m) at 40 C.; flow rate 2.5-4.5 mL min.sup.1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 1a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 1b) over 4 min employing UV detection at 254 nm. Gradient information: 0-3.00 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 3.00-3.01 min, held at 5% water-95% acetonitrile, flow rate increased to 4.5 mL min.sup.1; 3.01-3.50 min, held at 5% water-95% acetonitrile; 3.50-3.60 min, returned to 95% water-5% acetonitrile, flow rate reduced to 3.50 mL min.sup.1; 3.60-3.90 min, held at 95% water-5% acetonitrile; 3.90-4.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 2.5 mL min.sup.1.

Method 1c:

[0505] Agilent 1290 series with UV detector and HP 6130 MSD mass detector using Waters XBridge BEH C18 XP column (2.150 mm, 2.5 m) at 35 C.; flow rate 0.6 mL/min; mobile phase A: ammonium acetate (10 mM); water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM); water/MeOH/acetonitrile (100:540:360); over 4 min employing UV detection at 215 and 238 nm. Gradient information: 0-0.5 min, held at 80% A-20% B; 0.5-2.0 min, ramped from 80% A-20% B to 100% B.

Reversed Phase HPLC Conditions for the UPLC Analytical Methods

Methods 2a and 2b:

[0506] Waters BEH C18 (2.130 mm, 1.7 m) at 40 C.; flow rate 0.77 mL min.sup.1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 2a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 2b) over 3 min employing UV detection at 254 nm. Gradient information: 0-0.11 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

Method 1 (Acidic Preparation):

[0507] Waters X-Select CSH column C18, 5 m (1950 mm), flow rate 28 mL min.sup.1 eluting with a H.sub.2O-MeCN gradient containing 0.1% v/v formic acid over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 20% MeCN; 0.2-5.5 min, ramped from 20% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

Method 2 (Basic Preparation):

[0508] Waters X-Bridge Prep column C18.5 m (1950 mm), flow rate 28 mL min.sup.1 eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 10% MeCN; 0.2-5.5 min, ramped from 10% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

Method 3:

[0509] 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.

Method 4:

[0510] 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-(Pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide

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

[0511] ##STR00041##

[0512] 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%).

[0513] .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).

[0514] 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

[0515] ##STR00042##

[0516] 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.

[0517] LCMS; m/z 494.2 (M+Na).sup.+ (ES.sup.+).

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

[0518] ##STR00043##

[0519] 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.

[0520] .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.

[0521] LCMS; m/z 388 (M+H).sup.+ (ES.sup.+); 386 (MH).sup. (ES.sup.).

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

[0522] ##STR00044##

[0523] K.sub.2CO.sub.3 (0.535 g, 3.87 mmol) was added to a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.5 g, 1.290 mmol) and 2-(chloromethyl)pyrimidine hydrochloride (0.213 g, 1.290 mmol) in DMF (8 mL). The reaction mixture was heated to 70 C. and stirred for 16 hours. Then the reaction mixture was washed with saturated brine (320 mL), the washings were combined and extracted with DCM (320 mL). The organic extracts were combined, dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-100% EtOAc/isohexane), then purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane and 0-10% MeOH/DCM) to afford the title compound (62 mg, 6%) as a yellow oil.

[0524] .sup.1H NMR (DMSO-d6) 8.83 (d, J=4.9 Hz, 2H), 8.11 (d, J=2.3 Hz, 1H), 7.50 (t, J=4.9 Hz, 1H), 7.02-6.95 (m, 4H), 6.80-6.74 (m, 5H), 5.72 (s, 2H), 4.16 (s, 4H), 3.72 (s, 6H).

[0525] LCMS; m/z 502.4 (M+Na).sup.+ (ES.sup.+).

Step E: 1-(Pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide

[0526] ##STR00045##

[0527] N,N-Bis(4-methoxybenzyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (60 mg, 0.079 mmol) was dissolved in DCM (1 mL) and TFA (1 mL) was added. The solution was stirred for 16 hours. The reaction mixture was concentrated in vacuo, suspended in toluene (5 mL) and concentrated again. The crude product was purified by chromatography on silica gel (12 g column, 0-5% MeOH/DCM) to afford the title compound (16 mg, 84%) as a brown solid.

[0528] .sup.1H NMR (DMSO-d6) 8.81 (d, J=4.9 Hz, 2H), 7.98 (d, J=2.3 Hz, 1H), 7.48 (t, J=4.9 Hz, 1H), 7.15 (s, 2H), 6.61 (d, J=2.3 Hz, 1H), 5.63 (s, 2H).

[0529] LCMS; m/z 240.2 (M+H).sup.+ (ES.sup.+).

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

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

[0530] ##STR00046##

[0531] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(pyrimidin-2-ylmethyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-(chloromethyl)oxazole to afford the title compound (523 mg, 83%) as a colourless crystalline solid.

[0532] .sup.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).

[0533] LCMS; m/z 491 (M+Na).sup.+ (ES.sup.+).

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

[0534] ##STR00047##

[0535] Prepared according to the general procedure of 1-(pyrimidin-2-ylmethyl)-H-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.

[0536] .sup.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 P3: 1-((1-Methyl-1H-imidazol-2-yl)methyl)-1H-pyrazole-3-sulfonamide

Step A: N,N-bis(4-Methoxybenzyl)-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazole-3-sulfonamide

[0537] ##STR00048##

[0538] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(pyrimidin-2-ylmethyl)-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)-1-methyl-1H-imidazole, HCl salt to afford the title compound (270 mg, 37%) as a yellow oil.

[0539] .sup.1H NMR (DMSO-d6) 7.98 (d, J=2.4 Hz, 1H), 7.18 (d, J=1.2 Hz, 1H), 6.99-6.95 (m, 4H), 6.90 (d, J=1.2 Hz, 1H), 6.81-6.75 (m, 4H), 6.72 (d, J=2.4 Hz, 1H), 5.56 (s, 2H), 4.18 (s, 4H), 3.72 (s, 6H), 3.68 (s, 3H).

[0540] LCMS; m/z 482.8 (M+H).sup.+ (ES.sup.+).

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

[0541] ##STR00049##

[0542] Prepared according to the general procedure of 1-(pyrimidin-2-ylmethyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazole-3-sulfonamide to afford the title compound (105 mg, 85%) as a yellow oil.

[0543] .sup.1H NMR (DMSO-d6) 7.90 (d, J=2.4 Hz, 1H), 7.42 (s, 2H), 7.15 (d, J=1.2 Hz, 1H), 6.85 (d, J=1.2 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 5.50 (s, 2H), 3.68 (s, 3H).

[0544] LCMS; m/z 242.3 (M+H).sup.+ (ES.sup.+).

Intermediate P4: 1-(Pyridin-2-yl)-1H-pyrazole-3-sulfonamide

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

[0545] ##STR00050##

[0546] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(pyrimidin-2-ylmethyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-bromopyridine to afford the title compound (210 mg, 83%) as an oil.

[0547] LCMS; m/z 465 (M+H).sup.+ (ES.sup.+).

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

[0548] ##STR00051##

[0549] Prepared according to the general procedure of 1-(pyrimidin-2-ylmethyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(pyridin-2-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (82 mg, 67%) as a white solid.

[0550] LCMS; m/z 225 (M+H).sup.+ (ES.sup.+).

Intermediate P5: 1-(Thiazol-2-yl)-1H-pyrazole-3-sulfonamide

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

[0551] ##STR00052##

[0552] Prepared according to the general procedure of N,N-bis(4-methoxybenzyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step D) from N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step C) and 2-bromothiazole to afford the title compound (169 mg, 84%) as an oil.

[0553] .sup.1H NMR (CDCl.sub.3) 8.38 (d, J=2.6 Hz, 1H), 7.62 (d, J=3.5 Hz, 1H), 7.23 (d, J=3.4 Hz, 1H), 7.19-7.14 (m, 4H), 6.85-6.77 (m, 5H), 4.40 (s, 4H), 3.79 (s, 6H).

[0554] LCMS; m/z 471 (M+H).sup.+ (ES.sup.+).

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

[0555] ##STR00053##

[0556] Prepared according to the general procedure of 1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(thiazol-2-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (45 mg, 34%) as a white solid.

[0557] LCMS; m/z 231 (M+H).sup.+ (ES.sup.+).

Intermediate P6: 1-(Pyridin-3-yl)-1H-pyrazole-3-sulfonamide

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

[0558] ##STR00054##

[0559] 3-Bromopyridine (130 L, 1.349 mmol) and N1,N2-dimethylethane-1,2-diamine (15 L, 0.139 mmol) were added to a suspension of N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P1, Step C) (495 mg, 1.278 mmol), K.sub.2CO.sub.3 (350 mg, 2.53 mmol) and CuI (15 mg, 0.079 mmol) in dry DMF (8 mL). The resulting mixture was heated to 140 C. (bath temperature) for 3 days. The mixture was cooled to room temperature, diluted with EtOAc (50 mL) and filtered through Celite. The solution was concentrated in vacuo to give a brown oil, which was purified by chromatography on silica gel (40 g column 0-50% EtOAc/isohexane) to afford the title compound as a colourless oil (127 mg, 20%).

[0560] .sup.1H NMR (CDCl.sub.3) 9.05 (d, J=2.6 Hz, 1H), 8.67 (dd, J=4.9, 1.4 Hz, 1H), 8.17 (ddd, J=8.4, 2.6, 1.4 Hz, 1H), 8.06 (d, J=2.6 Hz, 1H), 7.60 (dd, J=8.4, 4.9 Hz, 1H), 7.16-7.11 (m, 4H), 6.90 (d, J=2.6 Hz, 1H), 6.80-6.75 (m, 4H), 4.40 (s, 4H), 3.76 (s, 6H).

[0561] LCMS; m/z 465 (M+H).sup.+ (ES.sup.+).

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

[0562] ##STR00055##

[0563] Prepared according to the general procedure of 1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P1, Step E) from N,N-bis(4-methoxybenzyl)-1-(pyridin-3-yl)-1H-pyrazole-3-sulfonamide to afford the title compound (51 mg, 86%) as a white solid.

[0564] .sup.1H NMR (MeOH-d4) 9.12 (dd, J=2.7, 0.8 Hz, 1H), 8.59 (dd, J=4.9, 1.4 Hz, 1H), 8.49 (d, J=2.6 Hz, 1H), 8.33 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.62 (ddd, J=8.4, 4.8, 0.8 Hz, 1H), 6.95 (d, J=2.6 Hz, 1H). NH.sub.2 not observed.

Intermediate P7: 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

[0565] ##STR00056##

[0566] 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.

[0567] .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).

[0568] 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

[0569] ##STR00057##

[0570] 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.

[0571] .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).

[0572] LCMS; m/z 405.4 (M+H).sup.+ (ES.sup.+).

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

[0573] ##STR00058##

[0574] 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.

[0575] .sup.1H NMR (CDCl.sub.3) 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m, 4H).

PREPARATION OF EXAMPLES

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

[0576] ##STR00059##

[0577] Sodium tert-butoxide (2M in THF) (0.033 mL, 0.066 mmol) was added to a solution of 1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P1) (15 mg, 0.063 mmol) in THF (2 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (14 mg, 0.070 mmol) was added and the reaction mixture was stirred at room temperature overnight. Volatiles were evaporated and the crude product was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (3.5 mg, 13%) as a white solid.

[0578] .sup.1H NMR (DMSO-d6) 10.81 (br s, 1H), 8.79 (d, J=4.9 Hz, 2H), 8.04 (d, J=2.4 Hz, 1H), 7.94 (s, 1H), 7.48 (t, J=4.9 Hz, 1H), 6.92 (s, 1H), 6.77 (d, J=2.4 Hz, 1H), 5.66 (s, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 1.92 (p, J=7.4 Hz, 4H).

[0579] LCMS; m/z 439.4 (M+H).sup.+ (ES.sup.+).

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

[0580] ##STR00060##

[0581] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(oxazol-2-ylmethyl)-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 (27 mg, 25%) as a white solid.

[0582] .sup.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.

[0583] LCMS; m/z 428 (M+H).sup.+ (ES.sup.+); 426 (MH).sup. (ES.sup.).

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

[0584] ##STR00061##

[0585] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-((1-methyl-1H-imidazol-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 (34 mg, 21%) as a white solid.

[0586] .sup.1H NMR (DMSO-d6) 10.85 (br s, 1H), 7.97 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.14 (d, J=1.1 Hz, 1H), 6.93 (s, 1H), 6.85 (d, J=1.2 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 5.53 (s, 2H), 3.63 (s, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 1.95 (p, J=7.5 Hz, 4H).

[0587] LCMS; m/z 441.4 (M+H).sup.+ (ES.sup.+).

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

[0588] ##STR00062##

[0589] Sodium tert-butoxide (2 M in THF) (0.103 mL, 0.206 mmol) was added to a solution of 1-(pyridin-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate P4) (44 mg, 0.196 mmol) in THF (2 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (41 mg, 0.206 mmol) was added and the reaction mixture was stirred at room temperature for 15 hours. EtOAc (6 mL) was added and the suspension stirred for 1 hour, filtered, and washed with EtOAc (1 mL). The collected solid was dried under reduced pressure to afford the title compound (15 mg, 16%) as a white solid.

[0590] .sup.1H NMR (DMSO-d6) 8.52 (d, J=2.6 Hz, 1H), 8.47 (ddd, J=4.9, 1.9, 0.9 Hz, 1H), 8.05-7.98 (m, 1H), 7.92-7.86 (m, 1H), 7.48 (s, 1H), 7.37 (ddd, J=7.3, 4.9, 1.0 Hz, 1H), 6.75 (s, 1H), 6.67 (d, J=2.6 Hz, 1H), 2.73 (t, J=7.4 Hz, 4H), 2.67 (t, J=7.3 Hz, 4H), 1.87 (p, J=7.5 Hz, 4H).

[0591] LCMS; m/z 424 (M+H).sup.+ (ES.sup.+).

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

[0592] ##STR00063##

[0593] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyridin-2-yl)-H-pyrazole-3-sulfonamide, sodium salt (Example 4) from 1-(thiazol-2-yl)-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 (16 mg, 24%) as a white solid.

[0594] .sup.1H NMR (DMSO-d6) 8.40 (d, J=2.6 Hz, 1H), 7.64 (d, J=3.5 Hz, 1H), 7.57 (d, J=3.5 Hz, 1H), 7.48 (s, 1H), 6.77 (s, 1H), 6.70 (d, J=2.6 Hz, 1H), 2.81-2.70 (m, 8H), 1.93-1.87 (m, 4H).

[0595] LCMS; m/z 430 (M+H).sup.+ (ES.sup.+).

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

[0596] ##STR00064##

[0597] Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-sulfonamide (Example 1) from 1-(pyridin-3-yl)-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 (16 mg, 17%) as a white solid.

[0598] .sup.1H NMR (DMSO-d6) 11.12 (br s, 1H), 9.11 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.6 Hz, 1H), 8.62 (dd, J=4.7, 1.4 Hz, 1H), 8.25 (ddd, J=8.4, 2.7, 1.5 Hz, 1H), 7.95 (s, 1H), 7.62 (ddd, J=8.3, 4.7, 0.7 Hz, 1H), 6.98 (d, J=2.6 Hz, 1H), 6.88 (s, 1H), 2.76 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.88 (p, J=7.4 Hz, 4H).

[0599] LCMS; m/z 424 (M+H).sup.+ (ES.sup.+); 422 (MH).sup. (ES.sup.).

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

[0600] ##STR00065##

[0601] HATU (58 mg, 0.151 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 P7) (65 mg, 0.145 mmol) and N-methyl-1-(thiazol-2-yl)methanamine (19 mg, 0.151 mmol) in DMF (1 mL) and stirred 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 (18 mg, 26%) as a white solid.

[0602] .sup.1H NMR (DMSO-d6), rotamers; 10.95 (br s, 1H), 8.09-8.07 (2s, 1H), 7.89-7.65 (m, 2H), 7.11-7.08 (2s, 1H), 6.94 (s, 1H), 4.97-4.92 (2s, 2H), 3.97-3.95 (2s, 3H), 3.12-3.01 (2s, 3H), 2.78 (t, J=7.6 Hz, 4H), 2.64-2.53 (m, 4H), 1.94-1.92 (m, 4H).

[0603] LCMS; m/z 515 (M+H).sup.+ (ES.sup.+).

Example 8: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazole-5-carboxamide

[0604] ##STR00066##

[0605] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-N-(thiazol-2-ylmethyl)-1H-pyrazole-5-carboxamide (Example 7) 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 P7) and N-methyl-1-(1-methyl-H-imidazol-2-yl)methanamine to afford the title compound (11 mg, 13%) as a white solid.

[0606] .sup.1H NMR (DMSO-d6), rotamers; 7.71 (s, 1H), 7.20 (s, 0.4H), 7.14 (s, 0.6H), 7.05 (s, 0.6H), 6.93 (s, 0.4H), 6.85-6.83 (m, 2H), 4.73-4.17 (m, 2H), 3.89 (s, 3H), 3.64-3.45 (2s, 3H), 2.98-2.94 (2s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.63-2.59 (m, 4H), 1.94-1.87 (m, 4H). NH not observed.

[0607] LCMS; m/z 512 (M+H).sup.+ (ES.sup.+).

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

[0608] ##STR00067##

[0609] Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-N-(thiazol-2-ylmethyl)-1H-pyrazole-5-carboxamide (Example 7) 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 P7) and N-methylthiazol-2-amine to afford the title compound (4 mg, 7%) as a white solid.

[0610] .sup.1H NMR (DMSO-d6) 11.03 (br s, 1H), 8.11 (br s, 1H), 7.66 (d, J=3.6 Hz, 1H), 7.45 (d, J=3.6 Hz, 1H), 7.38 (s, 1H), 6.95 (s, 1H), 4.05 (s, 3H), 3.72 (s, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.3 Hz, 4H), 1.99-1.92 (m, 4H).

[0611] LCMS; m/z 501 (M+H).sup.+ (ES.sup.+).

Example 10: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazole-5-carboxamide, Partial Ammonium Salt

[0612] ##STR00068##

[0613] N-Methyl-1-(1-methyl-1H-pyrazol-5-yl)methanamine (23.45 mg, 0.187 mmol), NaHCO.sub.3 (16 mg, 0.10 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 P7) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 2 days. The reaction was quenched with water (1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (14 mg, 17%) as a white solid.

[0614] .sup.1H NMR (DMSO-d6), rotamers; 7.65 & 7.58 (2s, 1H), 7.50-7.00 (br s, 1H), 7.36 (d, J=1.9 Hz, 1H), 6.81 (s, 1H), 6.81 & 6.60 (2s, 1H), 6.27 & 6.14 (2s, 1H), 4.76 & 4.70 (2s, 2H), 3.87 & 3.80 (2s, 3H), 3.80 & 3.58 (2s, 3H), 2.99 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.5 Hz, 4H), 1.89 (p, J=7.5 Hz, 4H).

[0615] LCMS; m/z 512.4 (M+H).sup.+ (ES.sup.+); 510.3 (MH).sup. (ES.sup.).

EXAMPLESBIOLOGICAL STUDIES

NLRP3 and Pyroptosis

[0616] 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

[0617] 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

[0618] The following method step-by-step assay was followed for compound screening. [0619] 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) [0620] 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 [0621] 3. Incubate for 3 hrs at 37 C. and 5% CO.sub.2 [0622] 4. Add 5 l nigericin (Sigma #N7143) (FAC 5 M) to all wells [0623] 5. Incubate for 1 hr at 37 C. and 5% CO.sub.2 [0624] 6. At the end of the incubation period, spin plates at 300g for 3 mins and remove supernatant [0625] 7. Then add 50 l of resazurin (Sigma #R7017) (FAC 100 M resazurin in RPMI medium without FBS) and incubate plates for a further 1-1.5 h at 37 C. and 5% CO.sub.2 [0626] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [0627] 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

[0628]

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

[0629] The results of the pyroptosis assay performed are summarised in Table 1 below as THP IC.sub.50.

Human Whole Blood IL1 Release Assay

[0630] 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.

[0631] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [0632] 1. Plate out 80 l of whole blood containing 1 g/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [0633] 2. Add 10 l compound (8 points half-log dilution with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [0634] 3. Incubate for 3 hrs at 37 C., 5% CO.sub.2 [0635] 4. Add 10 l nigericin (Sigma #N7143) (10 M FAC) to all wells [0636] 5. Incubate for 1 hr at 37 C., 5% CO.sub.2 [0637] 6. At the end of the incubation period, spin plates at 300g for 5 mins to pellet cells and remove 20 l of supernatant and add to 96-well v-bottom plates for IL-1 analysis (note: these plates containing the supernatants can be stored at 80 C. to be analysed at a later date) [0638] 7. IL-1 was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [0639] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[0640] The results of the human whole blood assay are summarised in Table 1 below as HWB IC.sub.50.

TABLE-US-00002 TABLE 1 NLRP.sub.3 inhibitory activity Example No THP IC.sub.50 HWB IC.sub.50 1 ++ ND 2 ++++ * 3 +++++ **** 4 ++ ND 5 ++ ND 6 ++ ND 7 +++ ** 8 ++++ *** 9 +++ ND 10 ++ ND [THP IC.sub.50 (0.04 M = +++++, 0.16 M = ++++, 0.64 M = +++, 2.56 M = ++, 10 M = +, not determined = ND)] [HWB IC.sub.50 (0.4 M = *****, (0.8 M = ****, 1.6 M = ***, 3.2 M = **, 10 M = *, not determined = ND)]

[0641] As is evident from the results presented in Table 1, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and in the human whole blood assay.

[0642] 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.