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1. (WO2019008029) SULFONYLUREAS AND SULFONYLTHIOUREAS AS NLRP3 INHIBITORS
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

Claims

1. A compound of formula (I):

R1 N N

H H

Formula (I)

wherein:

Q is O or S;

R1 is a 6-membered heteroaryl group containing at least one nitrogen atom in the 6-membered ring structure, wherein R1 may optionally be substituted; and R2 is a cyclic group substituted at the a-position, wherein R2 may optionally be further substituted;

with the proviso that the compound is not:


2. A compound as claimed in claim 1, wherein R1 is a 6-membered heteroaryl group containing at least two nitrogen atoms in the 6-membered ring structure, wherein R1 may optionally be substituted.

3. A compound as claimed in claim 2, wherein at least one of the two nitrogen atoms is located at the 3, 4 or 5-position of the 6-membered ring structure.

4. A compound as claimed in claim 2, wherein a first nitrogen atom is located at the 2-position and a second nitrogen atom is located at the 6-position of the 6-membered ring structure, and wherein the 6-membered heteroaryl group is substituted with one or more monovalent groups at the 3- and/or 5-positions of the 6-membered ring structure.

5. A compound as claimed in any preceding claim, wherein the 6-membered heteroaryl group of R1 is substituted with at least one monovalent group X, wherein X is at each occurrence any group that can mesomerically donate a lone pair of electrons from a nitrogen, oxygen or sulphur atom onto at least one nitrogen atom in the 6-membered ring structure, and wherein the 6-membered heteroaryl group may optionally be further substituted.

6. A compound as claimed in any preceding claim, wherein:

the 6-membered heteroaryl group of R1 is substituted with at least one monovalent group X' at a position ortho- or para- to at least one nitrogen atom in the 6-membered ring structure;

the 6-membered heteroaryl group of R1 may optionally be further substituted; X is at each occurrence independently selected from a -OR3, -SR3, -N(Rs)2, -O-L-OR3, -O-L-SR3, -0-L-N(R3)2, -S-L-OR3, -S-L-SR3, -S-L-N(R3)2,

-NRs-L-OR3, -NRs-L-SR3 or -NR3-L-N(Rs)2 group;

each R3 is independently selected from hydrogen or an alkyl, alkenyl, alkynyl or cyclic group, or any two R3 in the same group X' may together with the atom or atoms to which they are attached form a heterocyclic group;

each L is independently selected from an alkylene, alkenylene or alkynylene group; and

any L or R3 may optionally be substituted.

7. A compound as claimed in any preceding claim, wherein at least one nitrogen atom is located at the 4-position of the 6-membered ring structure of R1.

8. A compound as claimed in any preceding claim, wherein the 6-membered heteroaryl group of R1 is monocyclic.

9. A compound as claimed in any of claims 1 to 7, wherein the 6-membered heteroaryl group of R1 is substituted with one or more fused cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings such that the resultant group is bicyclic, tricyclic or polycyclic.

10. A compound as claimed in any preceding claim, wherein R2 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the a-position, and wherein R2 may optionally be further substituted.

11. A compound as claimed in claim 10, wherein R2 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the a and a' positions, and wherein R2 may optionally be further substituted.

12. A compound as claimed in claim 11, wherein R2 is a fused aryl or a fused heteroaryl group, wherein a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α,β positions and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α',β' positions, wherein R2may optionally be further substituted.

13. A compound as claimed in any of claims 1 to 11, wherein R2 is a cyclic group substituted at the a-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 a-ring atom of the cyclic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the cyclic group may optionally be further substituted.

14. A compound as claimed in any preceding claim, wherein R2 is a cyclic group substituted at the a and a' positions, wherein R2 may optionally be further substituted.

15. A compound as claimed in any preceding claim, wherein Q is O.

16. A compound selected from the group consisting of:

-186-

-187-

-188-

claimed in any preceding claim.

18. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 17, and a pharmaceutically acceptable excipient.

19. A compound as claimed in any of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 17, or a pharmaceutical composition as claimed in claim 18, for use in medicine.

20. A compound, pharmaceutically acceptable salt, solvate, prodrug or pharmaceutical composition as claimed in claim 19, for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

21. A compound, pharmaceutically acceptable salt, solvate, prodrug or

pharmaceutical composition as claimed in claim 19 or 20, for use in the treatment or prevention of a disease, disorder or condition, 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.

22. A compound, pharmaceutically acceptable salt, solvate, prodrug or

pharmaceutical composition as claimed in claim 19 or 20, for use in the treatment or prevention of a disease, disorder or condition, 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 j uvenile 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) .

23. A method of inhibiting NLRP3, the method comprising the use of a compound as claimed in any of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or prodrug as claimed in claim 17, or a pharmaceutical composition as claimed in claim 18, to inhibit NLRP3.