Novel sulfoneurea compounds

Abstract

The present invention relates to compounds of formula (I): wherein A, B, L, X, Y, R1, R2 and R4 are as defined in the specification. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP3.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
 A is a phenyl or 5- or 6-membered heteroaryl group, wherein A is substituted in the α position with B and in the α′ position with R 4 , and wherein A is optionally further substituted; 
 B is a phenyl, 5- or 6-membered heteroaryl, or 4- to 6-membered saturated heterocyclic group, wherein B is substituted with -L-R 2 , and wherein B is optionally further substituted; 
 X is O, NH or N(CN); 
 Y is O or S; 
 R 1  is a C 1 -C 4  alkyl, C 2 -C 4  alkenyl, —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , or —R 20 -R 21  group, all optionally halo-substituted; 
 L is a bond, —O—, —OC(R 12 ) 2 —, —OC(Ph)(R 12 )—, —OC(R 12 ) 2 C(R 12 ) 2 —, —C(R 12 ) 2 —, —C≡C— or —NR 13 —; 
 R 2  is a C 3 -C 6  cycloalkyl, phenyl, 4- to 6-membered saturated heterocyclic, or 5- or 6-membered heteroaryl group, all optionally halo-substituted and/or optionally substituted with one, two or three substituents independently selected from cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 3 -C 4  cycloalkyl, C 2 -C 4  alkenyl, C 2 -C 4  haloalkenyl, phenyl, benzyl, 4- to 6-membered saturated heterocyclyl, —CO(C 1 -C 4  alkyl), —CO(C 1 -C 4  haloalkyl), —CO 2 (C 1 -C 4  alkyl), —CO 2 (C 1 -C 4  haloalkyl), —CO 2 (benzyl), —OH, —O(C 1 -C 4  alkyl), —O(C 1 -C 4  haloalkyl), —NH 2 , —NH(C 1 -C 4  alkyl), —NH(C 1 -C 4  haloalkyl), —N(C 1 -C 4  alkyl) 2 , —N(C 1 -C 4  alkyl)(C 1 -C 4  haloalkyl) and —N(C 1 -C 4  haloalkyl) 2 ; 
 either R 4  is monovalent, and attached to A in the α′ position, and selected from C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 3 -C 6  cycloalkyl and phenyl, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from oxo, —OH, —O(C 1 -C 4  alkyl) and —O(C 1 -C 4  haloalkyl); 
 or R 4  is divalent, and attached to A in the α′ and β′ positions, and selected from —CH 2 CH 2 CH 2 —, —CH═CHCH 2 —, —CH 2 CH═CH—, —CH 2 CH 2 O—, —OCH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 — and —CH═CH—CH═CH—, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from oxo, —OH, —O(C 1 -C 4  alkyl) and —O(C 1 -C 4  haloalkyl); 
 each R 12  is independently selected from hydrogen, halogen, methyl and halomethyl; 
 R 13  is hydrogen or methyl; 
 R 20  is a bond, C 1 -C 4  alkylene or C 1 -C 4  haloalkylene; 
 R 21  is a C 3 -C 6  cycloalkyl, phenyl, 4- to 6-membered saturated heterocyclic, or 5- or 6-membered heteroaryl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 2 -C 4  alkenyl, C 2 -C 4  haloalkenyl, —R 22 —OH, —R 22 —O(C 1 -C 4  alkyl), —R 22 —O(C 1 -C 4  haloalkyl), —R 22 —NH 2 , —R 22 —NH(C 1 -C 4  alkyl), —R 22 —NH(C 1 -C 4  haloalkyl), —R 22 —N(C 1 -C 4  alkyl) 2 , —R 22 —N(C 1 -C 4  alkyl)(C 1 -C 4  haloalkyl), —R 22 —N(C 1 -C 4  haloalkyl) 2  and —R 22 -R 23 ; 
 R 22  is a bond, C 1 -C 4  alkylene or C 1 -C 4  haloalkylene; and 
 R 23  is a C 3 -C 6  cycloalkyl or 4- to 6-membered saturated heterocyclic group, all optionally halo-substituted. 
 
       
     
     
         2 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 1 , wherein A is a phenyl group, substituted in the α position with B, substituted in the α′ position with R 4 , and optionally further substituted. 
     
     
         3 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 1 , wherein B is a pyridinyl group, substituted with -L-R 2 , and optionally further substituted. 
     
     
         4 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 1 , wherein Y is O. 
     
     
         5 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 1 , wherein:
 either R 4  is monovalent, and attached to A in the α′ position, and selected from isopropyl, cyclopentyl, cyclohexyl and phenyl;   or R 4  is divalent, and attached to A in the α′ and β′ positions, and selected from —CH 2 CH 2 CH 2 —, —CH 2 CH 2 O— and —OCH 2 CH 2 —.   
     
     
         6 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 1 , wherein the compound is of formula (II): 
       
         
           
           
               
               
           
         
         wherein:
 X is O, NH or N(CN); 
 R 1  is a C 1 -C 4  alkyl, C 2 -C 4  alkenyl, —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , or —R 20 -R 21  group, all optionally halo-substituted; 
 L is a bond, —O—, —OC(R 12 ) 2 — or —NR 13 —; 
 R 2  is a C 3 -C 6  cycloalkyl or 4- to 6-membered saturated heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally halo-substituted and/or optionally substituted with one, two or three substituents independently selected from cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 3 -C 4  cycloalkyl, C 2 -C 4  alkenyl, C 2 -C 4  haloalkenyl, phenyl, benzyl, —OH, —O(C 1 -C 4  alkyl), —O(C 1 -C 4  haloalkyl), —NH 2 , —NH(C 1 -C 4  alkyl), —NH(C 1 -C 4  haloalkyl), —N(C 1 -C 4  alkyl) 2 , —N(C 1 -C 4  alkyl)(C 1 -C 4  haloalkyl) and —N(C 1 -C 4  haloalkyl) 2 ; 
 R 3  is hydrogen or methyl; 
 R 4a  is C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl or phenyl, all optionally halo-substituted; 
 R 5  is hydrogen; or 
 R 4a  and R 5  together form —CH 2 CH 2 CH 2 —, —CH═CHCH 2 —, —CH 2 CH═CH—, —CH 2 CH 2 O—, —OCH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 — or —CH═CH—CH═CH—, all optionally halo-substituted; 
 R 6  is hydrogen, halogen or cyano; 
 R 7  is hydrogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 3 -C 6  cycloalkyl, C 3 -C 6  halocycloalkyl or halogen; 
 each R 12  is independently selected from hydrogen, halogen, methyl and halomethyl; 
 R 13  is hydrogen or methyl; 
 R 20  is a bond, C 1 -C 4  alkylene or C 1 -C 4  haloalkylene; 
 R 21  is a C 3 -C 6  cycloalkyl, phenyl, 4- to 6-membered saturated heterocyclic, or 5- or 6-membered heteroaryl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 2 -C 4  alkenyl, C 2 -C 4  haloalkenyl, —R 22 —OH, —R 22 —O(C 1 -C 4  alkyl), —R 22 —O(C 1 -C 4  haloalkyl), —R 22 —NH 2 , —R 22 —NH(C 1 -C 4  alkyl), —R 22 —NH(C 1 -C 4  haloalkyl), —R 22 —N(C 1 -C 4  alkyl) 2 , —R 22 —N(C 1 -C 4  alkyl)(C 1 -C 4  haloalkyl), —R 22 —N(C 1 -C 4  haloalkyl) 2  and —R 22 -R 23 ; 
 R 22  is a bond, C 1 -C 4  alkylene or C 1 -C 4  haloalkylene; and 
 R 23  is a C 3 -C 6  cycloalkyl or 4- to 6-membered saturated heterocyclic group, all optionally halo-substituted. 
 
       
     
     
         7 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 6 , wherein:
 either R 5  is hydrogen and R 4a  is isopropyl, cyclopentyl, cyclohexyl or phenyl;   or R 4a  and R 5  together form —CH 2 CH 2 CH 2 —, —CH 2 CH 2 O— or —OCH 2 CH 2 —.   
     
     
         8 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 6 , wherein R 6  is hydrogen or fluoro. 
     
     
         9 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 6 , wherein R 7  is hydrogen, methyl, cyclopropyl or fluoro. 
     
     
         10 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 1 , wherein X is O. 
     
     
         11 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 1 , wherein R 1  is C 1 -C 4  alkyl, C 2 -C 4  alkenyl, —NHMe, —NMe 2 , —NHEt, —NEt 2  or —NMeEt, all optionally halo-substituted; or R 1  is a C 3 -C 6  cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, thiophenyl, pyrazolyl or imidazolyl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from C 1 -C 3  alkyl, —R 22 —OH, —R 22 —O(C 1 -C 3  alkyl), —R 22 —NH(C 1 -C 3  alkyl), —R 22 —N(C 1 -C 3  alkyl) 2  and —R 22 -R 23 ; wherein R 22  is a bond or C 1 -C 4  alkylene; and R 23  is a C 3 -C 6  cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl group. 
     
     
         12 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 1 , wherein L is a bond, —O— or —OCH 2 —. 
     
     
         13 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 1 , wherein R 2  is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl group, all optionally substituted with one or two substituents independently selected from fluoro, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, phenyl, benzyl, —OH, —O(C 1 -C 3  alkyl), —NH 2 , —NH(C 1 -C 3  alkyl) and —N(C 1 -C 3  alkyl) 2 . 
     
     
         14 . The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . (canceled) 
     
     
         16 . 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. 
     
     
         17 . A pharmaceutical composition as claimed in  claim 16 , wherein the pharmaceutical composition is an oral or topical pharmaceutical composition. 
     
     
         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 as claimed in  claim 1  to the subject, thereby treating or preventing the disease, disorder or condition, optionally wherein the disease, disorder or condition is responsive to NLRP3 inhibition. 
     
     
         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.