NOVEL COMPOUNDS

Abstract

The present invention relates to compounds of formula (I): wherein Q is selected from O or S; R1 is a non-aromatic heterocyclic group comprising at least one ring nitrogen atom, wherein R1 may optionally be substituted; R2 is an ,-substituted cyclic group which may optionally be further substituted; R3 and R4 are each independently hydrogen, halogen, OH, NH.sub.2, CN, R.sup.5, OR.sup.5, NHRs or N(R.sup.5)2; or R.sup.3 and R.sup.4 together with the carbon atom to which they are attached may form a 3- to 7-membered saturated or unsaturated, optionally substituted cyclic group; and R5 is independently optionally substituted C.sub.1-C.sub.4 alkyl. 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): ##STR00075## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is selected from O or S; R.sup.1 is a non-aromatic heterocyclic group comprising at least one ring nitrogen atom, wherein R.sup.1 may optionally be substituted; R.sup.2 is a cyclic group substituted at the and positions, wherein R.sup.2 may optionally be further substituted; R.sup.3 is hydrogen, halogen, OH, NH.sub.2, CN, R.sup.5, OR.sup.5, NHR.sup.5 or N(R.sup.5).sub.2; R.sup.4 is hydrogen, halogen, OH, NH.sub.2, CN, R.sup.5, OR.sup.5, NHR.sup.5 or N(R.sup.5).sub.2; or R.sup.3 and R.sup.4 together with the carbon atom to which they are attached may form a 3- to 7-membered saturated or unsaturated cyclic group, wherein the cyclic group may optionally be substituted; and R.sup.5 is independently optionally substituted C.sub.1-C.sub.4 alkyl.

2. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is a monocyclic or bicyclic non-aromatic heterocyclic group, wherein R.sup.1 may optionally be substituted.

3. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 2, wherein R.sup.1 is a 4-, 5- or 6-membered monocyclic non-aromatic heterocyclic group or a 7-, 8-, 9- or 10-membered bicyclic non-aromatic heterocyclic group, wherein R.sup.1 may optionally be substituted.

4. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the non-aromatic heterocyclic group of R.sup.1 is fully saturated.

5. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 comprises one, two or three ring nitrogen, oxygen or sulfur atoms.

6. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 5, wherein R.sup.1 comprises one or two ring nitrogen or oxygen atoms.

7. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 6, wherein R.sup.1 comprises one or two ring nitrogen atoms.

8. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is selected from: ##STR00076## wherein R.sup.1 may optionally be substituted or further substituted.

9. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is substituted with one, two or three substituents independently selected from halo; CN; 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.; R.sup.SH; R.sup.SR.sup.; R.sup.SOR.sup.; R.sup.SO.sub.2H; R.sup.SO.sub.2R.sup.; NH.sub.2; NHR.sup.; N(R.sup.).sub.2; R.sup.NH.sub.2; R.sup.NHR.sup.; R.sup.N(R.sup.).sub.2; CHO; COR.sup.; COOR.sup.; OCOR.sup.; R.sup.CHO; R.sup.COR.sup.; R.sup.COOR.sup.; R.sup.OCOR.sup.; CONH.sub.2; CONHR.sup.; CON(R.sup.).sub.2; R.sup.CONH.sub.2; R.sup.CONHR.sup.; R.sup.CON(R.sup.).sub.2; a C.sub.3-C.sub.7 cycloalkyl group optionally substituted with one or more C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl groups; a C.sub.3-C.sub.7 cycloalkenyl group optionally substituted with one or more C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl groups; ##STR00077## oxo (O); a C.sub.1-C.sub.4 alkylene bridge; or a C.sub.2-C.sub.4 alkenylene bridge; wherein each R.sup. is independently selected from C.sub.1-C.sub.3 alkylene; 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.3-C.sub.6 cycloalkyl 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.6 cycloalkyl, O(C.sub.1-C.sub.4 alkyl), halo, OH, CN, CCH, phenyl, pyridyl or oxo (O); wherein each R.sup. is independently selected from hydrogen, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 haloalkyl, CO(C.sub.1-C.sub.3 alkyl) or C.sub.3-C.sub.6 cycloalkyl; wherein each R.sup. is independently selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; wherein each m is independently selected from 1, 2 or 3; and wherein each n is independently selected from 1, 2 or 3.

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

11. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 10, wherein R.sup.2 is a fused aryl or a fused heteroaryl group, wherein a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the , 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. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.2 is a cyclic group substituted at the -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 is substituted at the -position and may optionally be further substituted.

13. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.3 and R.sup.4 are hydrogen.

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

15. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the compound is selected from the group consisting of: ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082##

16. (canceled)

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

18. (canceled)

19. A method of treating or preventing a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof 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.

20. The method as claimed in claim 19, 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.

21. The method as claimed in claim 19, 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).

22. (canceled)

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

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

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

Description

EXAMPLESCOMPOUND SYNTHESIS

[0344] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0345] 2-MeTHF 2-methyltetrahydrofuran [0346] Ac.sub.2O acetic anhydride [0347] AcOH acetic acid [0348] aq aqueous [0349] Boc tert-butyloxycarbonyl [0350] br broad [0351] Cbz carboxybenzyl [0352] CDI 1,1-carbonyl-diimidazole [0353] conc concentrated [0354] d doublet [0355] DABCO 1,4-diazabicyclo[2.2.2]octane [0356] DCE 1,2-dichloroethane, also called ethylene dichloride [0357] DCM dichloromethane [0358] DIPEA N,N-diisopropylethylamine, also called Hnig's base [0359] DMA dimethylacetamide [0360] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0361] DME dimethoxyethane [0362] DMF N,N-dimethylformamide [0363] DMSO dimethyl sulfoxide [0364] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0365] eq or equiv equivalent [0366] (ES.sup.+) electrospray ionization, positive mode [0367] Et ethyl [0368] EtOAc ethyl acetate [0369] EtOH ethanol [0370] h hour(s) [0371] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0372] HPLC high performance liquid chromatography [0373] LC liquid chromatography [0374] m multiplet [0375] m-CPBA 3-chloroperoxybenzoic acid [0376] Me methyl [0377] MeCN acetonitrile [0378] MeOH methanol [0379] (M+H).sup.+ protonated molecular ion [0380] MHz megahertz [0381] min minute(s) [0382] MS mass spectrometry [0383] Ms mesyl, also called methanesulfonyl [0384] MsCl mesyl chloride, also called methanesulfonyl chloride [0385] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0386] m/z mass-to-charge ratio [0387] NaO.sup.tBu sodium tert-butoxide [0388] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0389] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0390] NMP N-methylpyrrolidine [0391] NMR nuclear magnetic resonance (spectroscopy) [0392] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o) [0393] Pd(dppf)Cl.sub.2 [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [0394] PE petroleum ether [0395] Ph phenyl [0396] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0397] prep-HPLC preparative high performance liquid chromatography [0398] prep-TLC preparative thin layer chromatography [0399] PTSA p-toluenesulfonic acid [0400] q quartet [0401] RP reversed phase [0402] RT room temperature [0403] s singlet [0404] sat saturated [0405] SCX solid supported cation exchange (resin) [0406] sept septuplet [0407] t triplet [0408] T3P propylphosphonic anhydride [0409] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0410] TEA triethylamine [0411] TFA 2,2,2-trifluoroacetic acid [0412] THF tetrahydrofuran [0413] TLC thin layer chromatography [0414] wt % weight percent or percent by weight [0415] Xphos 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

Experimental Methods

[0416] Analytical Methods

[0417] NMR spectra were recorded at 300 MHz with chemical shifts reported in parts per million. Spectra were collected using one of the machines below: [0418] 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. [0419] An Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

[0420] HPLC and LC-MS were recorded on an Agilent 1290 series with UV detector and HP 6130 MSD mass detector. Mobile phase A: ammonium acetate (10 mM);

water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM);
water/MeOH/acetonitrile (100:540:360); column, Waters XBridge BEH C18 XP (2.150 mm, 2.5 m). [0421] Pump flow: 0.6 mL/min UV detection: 215, 238 nm [0422] Injection volume: 0.2 L Run time: 4.0 min [0423] Column temperature: 35 C. Mass detection: API-ES+ve and ive

[0424] Pump Program:

TABLE-US-00001 Gradient Time (min) % A % B 0.0 80 20 0.5 80 20 2.0 0 100

[0425] Purification Method 1

[0426] Automated reversed phase column chromatography was carried out using a Buchi Sepracore X50 system driven by a C-605 pump module, C-620 Sepracore control package, C-640 UV photometer detection unit and C-660 fraction collector.

[0427] Revelis C18 Reversed-Phase 12 g Cartridge [0428] Carbon loading 18% [0429] Surface area 568 m.sup.2/g [0430] Pore diameter 65 Angstrom [0431] pH (5% slurry) 5.1 [0432] Average particle size 40 m

[0433] The column was conditioned before use with MeOH (5 min), then brought to H.sub.2O (in 5 min) and kept 5 min at H.sub.2O. Flow rate=30 mL/min.

[0434] Separation Runs:

TABLE-US-00002 Time (min) A: water (%) B: MeOH (%) 0 100 0 5 l00 0 30 30 70 30.1 0 l00 35 0 l00

[0435] Detection wavelength: 215, 235, 254 and 280 nm. Before each new run, the cartridge was cleaned using the conditioning method.

Synthesis of Intermediates

Intermediate A1: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid, trifluoroacetic acid salt

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

[0436] ##STR00057##

[0437] 2,6-Dibromo-4-fluoroaniline (10.0 g, 37.2 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (6.87 g, 40.9 mmol) and potassium carbonate (15.4 g, 112 mmol) were dissolved in dioxane (8 mL) and water (4 mL) and degassed four times under argon atmosphere. Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (1.52 g, 1.86 mmol) was added and the mixture was refluxed for 48 hours. Water (20 mL) and ethyl acetate (40 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were dried over sodium sulfate, evaporated to dryness and subjected to column chromatography (SiO.sub.2, heptanes with 15% ethyl acetate) to yield the title compound (3.5 g, 41%) as a light brown oil.

[0438] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.10 (dd, 1H), 6.76 (dd, 1H), 5.36 (bs, 1H), 5.08 (bs, 1H), 4.05 (bs, 2H), 2.05 (s, 3H).

Step B: 4-Fluoro-2-(2-methoxypyridin-4-yl)-6-(prop-1-en-2-yl)aniline

[0439] ##STR00058##

[0440] 2-Bromo-4-fluoro-6-(prop-1-en-2-yl)aniline (8.56 g, 37.2 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10.5 g, 44.6 mmol) were dissolved in dioxane (10 mL) under N.sub.2 atmosphere. Potassium carbonate (15.4 g, 112 mmol) in water (10 mL) was added. Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (1.52 g, 1.86 mmol) was added and the mixture was stirred overnight at reflux. The dioxane was largely removed by rotary evaporation. Ethyl acetate (100 mL) was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness to yield the title compound (8.0 g, 83%) as a brown oil.

[0441] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.20 (d, 1H), 7.00 (m, 2H), 6.82 (s, 1H), 6.72 (d, 1H), 5.34 (bs, 1H), 5.09 (bs, 1H), 3.98 (s, 3H), 3.80 (bs, 2H), 2.05 (s, 3H).

[0442] LCMS: m/z 259 (M+H).sup.+(ES.sup.+).

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

[0443] ##STR00059##

[0444] 4-Fluoro-2-(2-methoxypyridin-4-yl)-6-(prop-1-en-2-yl)aniline (8.0 g, 31 mmol) was dissolved in methanol (50 mL). Pd/C (0.4 g, 0.4 mmol) was added and the mixture was stirred overnight under H.sub.2 atmosphere. The product was filtered over Celite and subjected to column chromatography (SiO.sub.2, heptanes with 15% ethyl acetate) yielding the title compound (7.9 g, 99%) as a colourless oil.

[0445] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.21 (d, 1H), 6.98 (dd, 1H), 6.92 (dd, 1H), 6.82 (s, 1H), 6.70 (dd, 1H), 3.98 (s, 3H), 3.61 (bs, 2H), 2.91 (m, 1H), 1.25 (d, 6H).

[0446] LCMS: m/z 261 (M+H).sup.+ (ES.sup.+).

Step D: 4-(2-Bromo-5-fluoro-3-isopropylphenyl)-2-methoxypyridine

[0447] ##STR00060##

[0448] 4-Fluoro-2-(2-methoxypyridin-4-yl)-6-(isopropyl)aniline (200 mg, 768 mol) in acetonitrile (12 mL) at 0 C. was treated with concentrated HBr (1.3 g) in water (1 mL). Sodium nitrite (58.3 mg, 845 mol) in water (1 mL) was added and the mixture was stirred at 0 C. for 45 minutes. Copper(I) bromide (110 mg, 768 mol) and copper(II) bromide (172 mg, 768 mol) were added and the mixture was allowed to reach room temperature over 2 hours. The mixture was poured into saturated sodium carbonate solution (50 mL). The mixture was extracted with DCM (250 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness in vacuo to yield the title compound (160 mg, 64%) as a brown oil.

[0449] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.20 (d, 1H), 7.02 (dd, 1H), 6.85 (d, 1H), 6.82 (dd, 1H), 6.73 (s, 1H), 3.98 (s, 3H), 3.42 (m, 1H), 1.24 (d, 6H).

[0450] LCMS: m/z 324 (M+H).sup.+ (ES.sup.+).

Step E: (2-(tert-Butoxy)-2-oxoethyl) zinc (II) bromide

[0451] ##STR00061##

[0452] To a mixture of Zn (55 g, 841.11 mmol, 2.98 eq) in THF (550 mL) was added TMSCl (3.06 g, 28.20 mmol, 0.1 eq) and 1,2-dibromoethane (5.30 g, 28.20 mmol, 0.1 eq) under N.sub.2 atmosphere. The mixture was refluxed for 1 hour. After cooling to 40 C., tert-butyl 2-bromoacetate (55 g, 281.97 mmol, 1 eq) was added and the mixture was refluxed for 2 hours. The mixture was cooled, decanted and the supernatant was used into the next step without further purification (crude).

Step F: tert-Butyl 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate

[0453] ##STR00062##

[0454] 4-(2-Bromo-5-fluoro-3-isopropylphenyl)-2-methoxypyridine (3-1, 9.6 mmol) was dissolved in THF (25 mL) under N.sub.2 atmosphere. Pd.sub.2dba.sub.3 (chloroform adduct) (0.55 g, 0.53 mmol) and Xphos (0.50 g, 1.1 mmol) were added. (2-(tert-Butoxy)-2-oxoethyl) zinc (II) bromide (5.5 g, 21 mmol) in THF (20 ml) (prepared in step E) was added and the mixture was heated to 80 C. and stirred overnight. Then the mixture was cooled to room temperature, filtered over Celite and evaporated to dryness in vacuo. The crude product was subjected to column chromatography (SiO.sub.2, heptanes with a 0 to 20% gradient of ethyl acetate) yielding the title compound (1.7 g, 48%) as a colourless oil.

[0455] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.19 (d, 1H), 7.03 (dd, 1H), 6.82 (d, 1H), 6.78 (dd, 1H), 6.68 (s, 1H), 3.98 (s, 3H), 3.42 (s, 2H), 3.02 (m, 1H), 1.41 (s, 9H), 1.23 (d, 6H).

[0456] LCMS: m/z 360 (M+H).sup.+ (ES.sup.+).

Step G: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid, trifluoroacetic acid salt

[0457] ##STR00063##

[0458] tert-Butyl 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (3.4 g, 9.5 mmol) was dissolved in DCM (20 mL) and TFA (15 g, 10 mL, 0.13 mol) and stirred for 6 hours at room temperature. The mixture was evaporated to dryness, yielding the title compound (3.9 g, 99%) as a colourless oil.

[0459] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.19 (d, 1H), 7.03 (dd, 1H), 6.81 (d, 1H), 6.78 (dd, 1H), 6.68 (s, 1H), 3.98 (s, 3H), 3.59 (s, 2H), 3.02 (m, 1H), 1.23 (d, 6H).

[0460] LCMS: m/z 302 (MH).sup. (ES.sup.).

Intermediate P1: 1-Methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

Step A: N,N-bis(4-Methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[0461] ##STR00064##

[0462] bis(4-Methoxybenzyl)amine (366 mg, 1.42 mmol) was dissolved in THF (20 mL) and triethylamine (261 mg, 2.58 mmol). Next, 6-oxo-1,6-dihydropyridine-3-sulfonyl chloride (250 mg, 1.29 mmol) was added portionwise. The reaction was stirred for 18 hours at room temperature. The solids were filtered off and the THF was evaporated. The residue was purified over silica using ethyl acetate as the eluent to afford the title compound (360 mg, 67%) as a pale yellow solid.

[0463] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.84 (s, 1H), 7.57 (d, 1H), 7.09 (d, 4H), 6.84 (d, 4H), 6.56 (d, 1H), 4.27 (s, 4H) 3.79 (s, 6H).

Step B: N,N-bis(4-Methoxybenzyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[0464] ##STR00065##

[0465] N,N-bis(4-Methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (100 mg, 0.24 mmol) in THF (20 mL) was cooled to 45 C. A solution of lithium bis(trimethylsilyl)amide in THF/ethylbenzene (0.3 mL, 1M), was added dropwise. During 20 minutes stirring, the temperature was allowed to rise from 45 to 10 C., and methyl iodide (230 mg. 1.62 mmol) was added. The reaction was stirred for 2 days at room temperature. The mixture was poured into saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate as the eluent to afford the title compound (30 mg, 29%) as an oil.

[0466] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.66 (d, 1H), 7.45 (dd, 1H), 7.10 (d, 4H), 6.82 (d, 4H), 6.53 (d, 1H), 4.29 (s, 4H) 3.80 (s, 6H), 3.45 (s, 3H).

[0467] LCMS: m/z 429.3 (M+H).sup.+ (ES.sup.+).

Step C: 1-Methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[0468] ##STR00066##

[0469] N,N-bis(4-Methoxybenzyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (30 mg, 0.07 mmol) was dissolved in TFA (5 ml). The reaction mixture was stirred for 2 days at room temperature. The TFA was evaporated and the residue was triturated in water. The aqueous layer was lyophilized to afford the title compound (13 mg, 98%) as a white solid.

[0470] .sup.1H NMR (300 MHz, D.sub.2O) 8.22 (d, 1H), 7.77 (dd, 1H), 6.58 (d, 1H), 3.48 (s, 3H).

Intermediate P2: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

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

[0471] ##STR00067##

[0472] To N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P1, step A) (158.0 mg, 0.38 mmol) in dry DMF (1 ml) and 1,2-dimethoxyethane (4 ml), was added lithium bromide (66.21 mg, 0.76 mmol). The reaction mixture was cooled to 0 C. Sodium hydride (17 mg, 0.42 mmol) was added and the reaction mixture was stirred for 10 minutes 0 C. After 10 minutes stirring at room temperature, 2-iodopropane (234 mg, 1.38 mmol) was added. The reaction mixture was warmed at 100 C. for 36 hours. Then the reaction mixture was poured into saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate as the eluent to afford the title compound (27 mg, 16%) as an oil.

[0473] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.91 (d, 1H), 7.43 (d, 1H), 7.08 (d, 4H), 6.83 (d, 4H), 6.56 (d, 1H), 5.19 (m, 1H), 4.27 (s, 4H) 3.79 (s, 6H), 1.35 (d, 6H).

[0474] LCMS: m/z 457.4 (M+H).sup.+ (ES.sup.+).

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

[0475] ##STR00068##

[0476] 1-Isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (27, 0.06 mmol) was dissolved in TFA (5 ml). The reaction mixture was stirred for 20 hours at room temperature. The TFA was evaporated and the residue was triturated in water. The aqueous layer was lyophilized to afford the title compound (12 mg, 94%) as a white solid.

[0477] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.21 (d, 1H), 7.79 (dd, 1H), 6.60 (d, 1H), 5.14 (m, 1H), 1.41 (d, 6H).

SYNTHESIS OF EXAMPLES

Example 1:2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((1-methyl-6-oxo-,6-dihydropyridin-3-yl)sulfonyl)acetamide, potassium salt

[0478] ##STR00069##

[0479] 1-Methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P1) (20 mg, 0.11 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (62 mg, 0.11 mmol) were stirred in DCM (6 mL). EDC (71 mg, 0.37 mmol) and DMAP (45 mg, 0.37 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (48 mg, 0.43 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (31 mg, 62%) as a white solid.

[0480] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.22 (d, 1H), 8.05 (dd, 1H), 7.84 (dd, 1H), 7.08-6.95 (m, 1H), 6.86 (dd, 1H), 6.78-6.67 (m, 2H), 6.52 (d, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 3.42 (s, 2H), 3.08-2.95 (m, 1H), 1.12 (d, 6H).

[0481] LCMS: m/z 474 (M+H).sup.+ (ES.sup.+); 472 (MH).sup. (ES.sup.).

Example 2: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)sulfonyl)acetamide, potassium salt

[0482] ##STR00070##

[0483] 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P2) (17 mg, 0.079 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (24 mg, 0.079 mmol) were stirred in DCM (6 mL). EDC (30 mg, 0.16 mmol) and DMAP (19 mg, 0.16 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.3 mL) and KOtBu (26 mg, 0.24 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (20 mg, 51%) as a white solid.

[0484] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.27 (d, 1H), 8.04 (dd, 1H), 7.79 (dd, 1H), 7.02 (dd, 1H), 6.88 (dd, 1H), 6.77-6.69 (m, 2H), 6.52 (d, 1H), 5.14 (m, 1H), 3.89 (s, 3H), 3.41 (s, 2H), 3.10-2.94 (m, 1H), 1.40 (d, 6H), 1.12 (d, 6H).

[0485] LCMS: m/z 502 (M+H).sup.+ (ES.sup.+); 500 (MH).sup. (ES.sup.).

Example 3: N-((1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) acetamide

[0486] ##STR00071##

[0487] 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonamide (35 mg, 0.16 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (48 mg, 0.16 mmol) were stirred in DCM (6 mL). EDC (61 mg, 0.32 mmol) and DMAP (39 mg, 0.32 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1), followed by a second purification with the same method to afford the title compound (14 mg, 17%) as a white solid.

[0488] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.26 (s, 1H), 8.14-8.03 (m, 1H), 7.04 (dd, 1H), 6.98-6.84 (m, 1H), 6.81-6.67 (m, 2H), 3.90 (s, 3H), 3.47 (s, 2H), 3.44 (s, 3H), 3.21 (s, 3H), 3.18-3.00 (m, 1H), 1.15 (d, 6H).

[0489] LCMS: m/z 505 (M+H).sup.+ (ES.sup.+); 503 (MH).sup. (ES.sup.).

[0490] Further compounds of the invention may be synthesised by methods analogous to those outlined above.

ExamplesBiological Studies

[0491] NLRP3 and Pyroptosis

[0492] 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.

[0493] THP-1 Cells: Culture and Preparation

[0494] 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.

[0495] THP-1 Cells Pyroptosis Assay

[0496] The following method step-by-step assay was followed for compound screening. [0497] 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) [0498] 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 [0499] 3. Incubate for 3 hrs at 37 C., 5% CO.sub.2 [0500] 4. Add 5 l nigericin (Sigma #N7143) (FAC 5 M) to all wells [0501] 5. Incubate for 1 hr at 37 C., 5% CO.sub.2 [0502] 6. At the end of the incubation period, spin plates at 300g for 3 mins and remove supernatant [0503] 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 [0504] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [0505] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[0506] 96-Well Plate Map

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

[0507] The results of the pyroptosis assay are summarised in Table 1 below as THP IC.sub.50.

TABLE-US-00004 TABLE 1 NLRP.sub.3 inhibitory activity (1 M = +++, 5 M = ++, 10 M = +). Example No Structure THP IC.sub.50 1 [00072] + 2 [00073] ++ 3 [00074] +++

[0508] 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.

[0509] 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.