Compounds

Abstract

The present invention relates to phenylsulfonylureas and phenylsulfonylthioureas, wherein the phenyl ring is substituted with a monovalent group comprising either (i) an aryl or a heteroaryl group, or (ii) a nitrogen-containing heterocyclic group, and wherein the group attached to the terminal nitrogen atom of the urea group is a 6-membered cyclic group substituted at the 2- and 4-positions. 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 NLRP3 inhibition.

Claims

1-28. (canceled)

29. A compound of formula (I): ##STR00032## or a pharmaceutically acceptable salt or solvate thereof, wherein: Q is selected from O or S; R.sup.1 is a monovalent group comprising an aryl or a heteroaryl group; R.sup.2 is a fused phenyl or a fused 6-membered heteroaryl group, wherein a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the phenyl or the 6-membered heteroaryl group across the 2,3-positions, relative to the point of attachment of the phenyl or the 6-membered heteroaryl group to the remainder of the molecule, wherein the phenyl or the 6-membered heteroaryl group is further substituted at the 4-position, and wherein R.sup.2 may optionally be further substituted; m is 0, 1, 2, 3 or 4; each R.sup.3 is independently a halo, OH, NO.sub.2, NH.sub.2, N.sub.3, SH, SO.sub.2H, SO.sub.2NH, 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; and wherein optionally any R.sup.3, and any two adjacent carbon atoms of ring A, may together form a 4- to 12-membered saturated or unsaturated cyclic group fused to ring A, wherein the cyclic group fused to ring A may optionally be substituted.

30. The compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, wherein Q is O.

31. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, wherein: (i) the aryl or the heteroaryl group of R.sup.1 is monocyclic; and/or (ii) a ring atom of the aryl group or a ring atom of the heteroaryl group of R.sup.1 is directly attached to a ring atom of ring A.

32. The compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, wherein the compound is a compound of formula (Ia): ##STR00033## wherein R.sup.1, R.sup.2, R.sup.3, m and Q are defined in claim 1.

33. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, wherein 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.; SO2H; SO.sub.2R; 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.SO2R.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.; Ra_ 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.7cycloalkyl, O(C.sub.1-C.sub.4 alkyl), O(C.sub.1-C.sub.4 haloalkyl), O(C.sub.3-C.sub.7cycloalkyl), halo, OH, NH.sub.2, CN, CCH, oxo (O), or 4- to 6-membered heterocyclic group.

34. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, wherein the compound is a compound of formula (Ib): ##STR00034## wherein R.sup.1, R.sup.2 and Q are as defined in claim 1, and wherein R.sup.3 is a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, wherein the hydrocarbyl group includes at least one oxygen atom in its carbon skeleton, and wherein the hydrocarbyl group may optionally include one or more additional heteroatoms N or O in its carbon skeleton.

35. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, wherein: (i) the substituent at the 4-position of the phenyl or the 6-membered heteroaryl group of R.sup.2 is a halo, OH, NO.sub.2, NH.sub.2, N.sub.3, SH, SO.sub.2H, SO.sub.2NH, 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; or (ii) the substituent at the 4-position of the phenyl or the 6-membered heteroaryl group of R.sup.2 is a halo, NO.sub.2, CN, COOR.sup.21, CONH.sub.2, CONHR.sup.21 or CON (R.sup.21).sub.2 group, wherein each R.sup.21 is independently selected from a C.sub.1-C.sub.4 alkyl group, and wherein any R.sup.21 may optionally be substituted with one or more halo groups.

36. The compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, wherein the phenyl or the 6-membered heteroaryl group of R.sup.2 is substituted at the 6-position.

37. The compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 36, wherein R.sup.2 is a fused phenyl group, wherein a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the phenyl group across the 2,3-positions and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the phenyl group across the 5,6-positions, wherein the phenyl group is further substituted at the 4-position, and wherein R.sup.2 may optionally be further substituted.

38. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 36, wherein the substituent at the 6-position of the phenyl or the 6-membered heteroaryl group of R.sup.2 is a monovalent heterocyclic group or a monovalent aromatic group, wherein a ring atom of the monovalent heterocyclic or monovalent aromatic group is directly attached to the ring atom at the 6-position of the phenyl or the 6-membered heteroaryl group of R.sup.2, wherein the monovalent heterocyclic or monovalent aromatic group may optionally be substituted.

39. The compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, which is (a) a compound selected from the group consisting of: ##STR00035## ##STR00036## or (b) a pharmaceutically acceptable salt or solvate of the selected compound.

40. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, wherein the substituent at the 6-position of the phenyl or the 6-membered heteroaryl group of R.sup.2 is selected from a R.sup.4, OR.sup.4 or COR.sup.4 group, wherein each R.sup.4 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group and wherein each R4 is optionally further substituted with one or more halo groups.

41. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, wherein ring A is monocyclic.

42. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, and a pharmaceutically acceptable excipient.

43. 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 the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, to the subject, thereby treating or preventing the disease, disorder or condition, optionally wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

44. The method as claimed in claim 43, wherein the disease, disorder or condition is selected from the group consisting of: (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; and (xvi) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

45. The method as claimed in claim 43, wherein the disease, disorder or condition is selected from the group consisting of: (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).

46. A method of inhibiting NLRP3 in a subject, the method comprising administering a compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 29, to the subject thereby inhibiting NLRP3.

47. 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 or solvate thereof, as claimed in claim 29, and analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 in the cell or non-human animal by the compound.

48. The method as claimed in claim 47, wherein the compound or the pharmaceutically acceptable salt or solvate thereof is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

Description

Compound Synthesis

[0348] The compounds of the invention may be synthesised, for example, by methods analogous to those outlined in WO 2016/131098 A1.

Biological Studies

[0349] The compounds of the invention may be evaluated using the following protocol.

NLRP3 and Pyroptosis

[0350] 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

[0351] THP-1 cells (ATCC #TIB-202) are grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma #S8636) and penicillin (100units/ml)/streptomycin (0.1 mg/ml) (Sigma #P4333) in 10% Fetal Bovine Serum (FBS) (Sigma #F0804). The cells are routinely passaged and grown to confluency (106cells/ml). On the day of the experiment, THP-1 cells are harvested and resuspended into RPMI medium (without FBS). The cells are then counted and viability (>90%) checked by Trypan blue (Sigma #T8154). Appropriate dilutions are made to give a concentration of 625,000cells/ml. To this diluted cell solution is added LPS (Sigma #L4524) to give a 1g/ml Final Assay Concentration (FAC). 40 l of the final preparation is aliquoted into each well of a 96-well plate. The plate thus prepared is used for compound screening.

THP-1 Cells Pyroptosis Assay

[0352] The following method step-by-step assay may be followed for compound screening. [0353] 1. Seed THP-1 cells (25,000cells/well) containing 1.0g/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) [0354] 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 [0355] 3. Incubate for 3 hrs at 37 C. in 5% CO.sub.2 [0356] 4. Add 5 l nigericin (Sigma #N7143) (FAC 5 M) to all wells [0357] 5. Incubate for 1 hr at 37 C. and 5% CO2 [0358] 6. At the end of the incubation period, spin plates at 300g for 3 mins and remove supernatant [0359] 7. Then add 50 l of resazurin (Sigma #R.sup.7017) (FAC 100 UM resazurin in RPMI medium without FBS) and incubate plates for a further 1-1.5h at 37 C. and 5% CO.sub.2 [0360] 8. Read plates in an Envision reader at Ex 560nm and Em 590nm [0361] 9. Fit IC.sub.50 data to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

96-Well Plate Map

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

[0362] The results of the pyroptosis assay performed may be summarised as THP IC.sub.50.

Human Whole Blood IL1 Release Assay

[0363] 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 the compounds of the invention in human whole blood may be investigated in accordance with the following protocol.

[0364] Human whole blood in Li-heparin tubes is obtained from healthy donors from a volunteer donor panel. [0365] 1. Plate out 80 l of whole blood containing 1 g/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [0366] 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 [0367] 3. Incubate for 3 hrs at 37 C., 5% CO.sub.2 [0368] 4. Add 10 l Nigericin (Sigma #N7143) (10 M FAC) to all wells [0369] 5. Incubate for 1 hr at 37 C., 5% CO.sub.2 [0370] 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) [0371] 7. Measure IL-1 according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [0372] 8. Fit IC.sub.50 data to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[0373] The results of the human whole blood assay may be summarised as HWB IC.sub.50.

[0374] 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.