Chemical compounds as inhibitors of interleukin-1 activity
The present disclosure relates to novel sulfonylurea and sulfonyl thiourea compounds and related compounds and their use in treating a disease or condition responsive to modulation of cytokines such as IL-1β and IL-18, modulation of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.
1. A compound of formula (Ib):
or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein:
X 1 is O or S;
R 1 is selected from the group consisting of
wherein represents a single bond or a double bond provided that the ring comprising one or more A 2 is a non-aromatic ring;
each A is independently CR 5a or N;
each A 2 is independently CR 5a , C(R 5a ) 2 , N, NR 5a , O, S, or S(O) 2 ;
R 2 is
X 2 is N or CR 5b ;
R 3 and R 4 are H;
each R 5a is independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH 2 —C 3 -C 8 cycloalkyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl); or
two R 5a together with the atoms to which they are attached can form C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or
two geminal R 5a can form an oxo group;
each R 5b is independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, and C 2 -C 6 alkynyl are optionally substituted with D, halogen, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;
R 6 and R 7 are independently, at each occurrence, H, D, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OH, —O—C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or
R 6 and R 7 together with the atom to which they are attached can form heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P, and O; and
n is an integer from 0 to 5;
provided that when the ring comprising A is an imidazole, then at least one A 2 is N, NR 5a , O, S, or S(O) 2 .
2. The compound of claim 1 , wherein the compound is of Formula (I):
or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein;
X 1 is O or S;
R 1 is selected from the group consisting of
wherein represents a single bond or a double bond provided that the ring comprising one or more A 2 is a non-aromatic ring;
each A is independently CR 5 or N;
each A 2 is independently CR 5 , C(R 5 ) 2 , N, NR 5 , O, S, or S(O) 2 ;
R 2 is
X 2 is N or CR 5 ;
R 3 and R 4 are H;
each R 5 is independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, or C 2 -C 6 alkynyl;
R 6 and R 7 are independently, at each occurrence, H, D, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; or
R 6 and R 7 together with the atom to which they are attached can form heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P, and O; and
n is an integer from 0 to 5;
provided that when the ring comprising A is an imidazole, then at least one A 2 is N, NR 5 , O, S, or S(O) 2 .
3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 2 is
4. The compound of claim 3 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X 2 is CR 5b and R 5b is H, fluoro, chloro, or methyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 2 is
6. The compound of claim 2 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 2 is
7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 2 is
8. The compound of claim 7 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein each R 5b is independently selected from the group consisting of H, D, halogen, —OH, —CN, NO 2 , OR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 4 -C 8 cycloalkenyl.
9. The compound of claim 7 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 2 is
10. The compound of claim 9 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein each R 5b is independently selected from the group consisting of H, D, halogen, C 1 -C 6 alkyl, and —CN.
11. The compound of claim 8 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 2 is selected from the group consisting of
12. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein
X 1 is O;
R 1 is selected from the group consisting of
wherein represents a single bond;
each A 2 is independently C(R 5a ) 2 or O;
X 2 is CR 5b ;
each R 5a is independently H, halogen, —OH, —OR 6 , —NR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, or heterocyclyl; wherein the C 1 -C 6 alkyl and heterocyclyl are optionally substituted with D, halogen, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or
two R 5a together with the atoms to which they are attached can form C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or
two geminal R 5a can form an oxo group;
each R 5b is independently H, D, halogen, —CN, —OR 6 , or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with D, halogen, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; and
R 6 and R 7 are independently, at each occurrence, H, D, C 1 -C 8 alkyl, C 2 -C 8 alkynyl, or aryl; wherein C 1 -C 6 alkyl, C 2 -C 6 alkynyl, and aryl are optionally substituted with D, halogen, or C 1 -C 6 alkyl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 1 is
14. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 1 is
15. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein each A 2 is independently C(R 5a ) 2 , NR 5a , or O.
16. The compound of claim 15 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein each R 5a is independently H, —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, or heterocyclyl containing N, wherein the C 1 -C 6 alkyl is substituted with —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 , and wherein the heterocyclyl is optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 .
17. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 1 is
wherein:
R 5a1a is H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH 2 —C 3 -C 8 cycloalkyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;
R 5a2c and R 5a2d are each independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH 2 —C 3 -C 8 cycloalkyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or
R 5a2c and R 5a2d together with the atom to which they are attached can form C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or
R 5a2c and R 5a2d can form an oxo group.
18. The compound of claim 17 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein each R 5a2c and R 5a2d is independently H, halogen, —OH, —OR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl.
19. The compound of claim 17 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 5a2c and R 5a2d together with the atom to which they are attached form C 3 -C 8 cycloalkyl or heterocyclyl.
20. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 1 is
wherein:
R 5a2a and R 5a2b are each independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH 2 —C 3 -C 8 cycloalkyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH2, —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or
R 5a2a and R 5a2b together with the atom to which they are attached can form C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH2, —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or
R 5a2a and R 5a2b can form an oxo group.
21. The compound of claim 20 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein each R 5a2a and R 5a2b is independently H, halogen, —OH, —OR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl.
22. The compound of claim 20 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 5a2a and R 5a2b together with the atom to which they are attached form C 3 -C 8 cycloalkyl or heterocyclyl.
23. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 1 is
wherein
R 5a2e and R 5a2f are each independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH 2 —C 3 -C 8 cycloalkyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or
R 5a2e and R 5a2f together with the atom to which they are attached can form C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH2, —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or
R 5a2e and R 5a2f can form an oxo group.
24. The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein each R 5a2e and R 5a2f is independently H, halogen, —OH, —OR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl.
25. The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 5a2e and R 5a2f together with the atom to which they are attached form C 3 -C 8 cycloalkyl or heterocyclyl.
26. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 1 is selected from the group consisting of:
27. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 1 is selected from the group consisting of
28. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X 1 is O.
29. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
30. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
31. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
32. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
33. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
34. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
35. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
36. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
37. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
38. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
39. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
40. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
41. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
42. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
43. A pharmaceutical composition comprising a compound of claim 30 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising the compound of claim 31 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
45. A pharmaceutical composition comprising the compound of claim 32 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
46. A pharmaceutical composition comprising the compound of claim 33 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
47. A pharmaceutical composition comprising the compound of claim 34 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
48. A pharmaceutical composition comprising the compound of claim 35 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
49. A pharmaceutical composition comprising the compound of claim 36 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
50. A pharmaceutical composition comprising the compound of claim 37 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
51. A pharmaceutical composition comprising the compound of claim 38 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
52. A pharmaceutical composition comprising the compound of claim 39 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
53. A pharmaceutical composition comprising the compound of claim 40 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
54. A pharmaceutical composition comprising the compound of claim 41 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
55. A pharmaceutical composition comprising the compound of claim 42 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
56. The compound of claim 5 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X is O and R 1 is
57. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X is O and R 1 is
58. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
59. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
60. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.
61. A pharmaceutical composition comprising a compound of claim 58 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
62. A pharmaceutical composition comprising a compound of claim 59 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
63. A pharmaceutical composition comprising a compound of claim 60 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
64. The compound of claim 1 , wherein the compound is
65. The compound of claim 1 , wherein the compound is
66. The compound of claim 1 , wherein the compound is
67. The compound of claim 1 , wherein the compound is
68. The compound of claim 1 , wherein the compound is
69. The compound of claim 1 , wherein the compound is
70. The compound of claim 1 , wherein the compound is
71. The compound of claim 1 , wherein the compound is
72. The compound of claim 1 , wherein the compound is
73. The compound of claim 1 , wherein the compound is
74. The compound of claim 1 , wherein the compound is