Sulfonylurea compounds as inhibitors of interleukin-1 activity
The present disclosure relates to novel sulfonylurea compounds and related compounds useful in treating a disorder 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 having the structure of Formula (I),
or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein:
R 1 is
R 1z is H, D, or halogen;
each R 1a , R 1b , R 1c , R 1e , R 1f , R 1g , is independently selected from the group consisting of H, D, halogen, —CN, —NO 2 , —SR 11a , —OR 11a , —C(O)R 11b , —NR 11a R 12a , —NR 11a C(O)R 12a , —NR 11a C(O)OR 12a , —NR 11a C(O)NR 12a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, and 3-7-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, and 3-7-membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C 1 -C 6 alkyl, —OR 11a , —C(O)R 11b , —NR 11a R 12a , —NR 11a C(O)R 12a , —NR 11a C(O)OR 12a , —NR 11a C(O)NR 12a , C 3 -C 10 cycloalkyl, and 3-7-membered heterocyclyl; or
two of the following groups, R 1a , R 1b R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , when present, together with the atoms to which they are attached can form a C3-C10cycloalkyl or a 3-7-membered heterocyclyl; wherein the C3-C10cycloalkyl and 3-7-membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C 1 -C 6 alkyl, —OR 13a , —C(O)R 13b , —NR 13a R 14a , —NR 13a C(O)OR 14a , and —NR 13a C(O)NR 14a ; or
two geminal groups R 1a and R 1b ; R 1c and R 1d ; R 1e and R 1f ; or R 1g and R 1h , when present, can form an oxo group;
R 2 is C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 5-7-membered heterocyclyl, 5-membered heteroaryl, or 6-membered heteroaryl containing 6-11 annular atoms; wherein the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 5-7-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl containing 6-1 1 annular atoms are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, —OR 23a , —C(O)R 23b , —NR 23a R 24a , —NR 23a C(O)R 24a , —NR 23a C(O)OR 24a , —NR 23a C(O)NR 24a , —(CH 2 ) 1-4 C 3 -C 10 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl; or optionally two of the substituents when present, together with the atoms to which they are attached can form a ring;
R 11a , R 12a , R 13a , R 14a , R 23a , and R 24a are independently, at each occurrence, H, D, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 10 cycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 4 — C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C 1 -C 6 alkyl, —OH, —O—C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 3 -C 10 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl; and
R 11b , R 13b , and R 23b are independently, at each occurrence, H, D, —OH, —O(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHS( 0 ) 2 CH 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl; wherein the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 4 -C 8 cycloalkenyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C 1 -C 6 alkyl,—OH, —O—C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 3 -C 10 cycloalkyl, C 6 aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R 2 is C 1 -C 6 alkyl, which is unsubstituted or substituted with one or more C 6 aryl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R 2 is C 3 -C 10 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl and C 6 aryl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein the C 3 -C 10 cycloalkyl of R 2 is cyclohexyl, cycloheptyl, 2-adamantyl, 2,3-dihydro-1H-inden-2-yl, or 9-fluorenyl, each of which is independently unsubstituted or substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl and C 6 aryl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R 2 is 5-7-membered heterocyclyl, which is unsubstituted or substituted with one or more C 1 -C 6 alkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R 2 is 5-membered heteroaryl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 aryl, oxo, and —(CH 2 ) 1-4 C 3 -C 10 cycloalkyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein the 5-membered heteroaryl of R 2 contains 2 nitrogen atoms, and is unsubstituted or substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 aryl, oxo, and —(CH 2 ) 1-4 C 3 -C 1 cycloalkyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R 2 is 6-membered heteroaryl containing 6-11 annular atoms, which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 aryl, 5-6-membered heteroaryl, —OR 23 a, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, —CN, and —NR 23a R 24a .
9. The compound of claim 8 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein the 6-membered heteroaryl containing 6-11 annular atoms of R 2 contains 2 nitrogen atoms, and is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 aryl, 5-6-membered heteroaryl, —OR 23a , C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, —CN, and —NR 23a R 24a .
10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R 2 is selected from the group consisting of:
and wherein the selected R 2 is further unsubstituted or substituted.
11. The compound of claim 1 , or a pharmaceutically acceptable salt,
solvate, isomer, or tautomer thereof, wherein R 1 is
12. The compound of claim 11 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein:
R 1z is H, and
each R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently selected from the group consisting of H, halogen, —OR 11a , —NR 11a R 12a , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and 3-7-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and 3-7-membered heterocyclyl; are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C 1 -C 6 alkyl, —OR 11a ,—NR 11a R 12a , C 3 -C 10 cycloalkyl, and 3-7-membered heterocyclyl.
13. The compound of claim 12 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein:
R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 5-7-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl containing 6-11 annular atoms; wherein the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 5-7-membered heterocyclyl, 5-membered heteroaryl, or 6-membered heteroaryl containing 6-11 annular atoms is unsubstituted or substituted with one or more substituents independently selected from the group consisting of D, —CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, oxo, OR 23a , —(CH 2 ) 1-4 C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl, —NR 23a R 24a C 6 aryl, and 5-6-membered heteroaryl,
wherein R 23a and R 24a are independently, at each occurrence, H, D, C 1 -C 8 alkyl, or C 3 -C 10 cycloalkyl; wherein the C 1 -C 8 alkyl and C 3 -C 10 cycloalkyl are independently unsubstituted or substituted with one or more halogen.
14. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R 1 is
and R 1z is H.
15. The compound of claim 1 , or a pharmaceutically acceptable salt,
solvate, isomer, or tautomer thereof, wherein R 1 is
16. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, wherein R 1 is selected from the group consisting of:
17. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof.
18. The compound of claim 17 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof.
19. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
20. A pharmaceutical composition, comprising a compound of claim 17 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
21. A pharmaceutical composition, comprising a compound of claim 18 , or a pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, and a pharmaceutically acceptable carrier.