Inhibitors of NLRP3 inflammasome
The present disclosure relates to compounds of Formula I: that act as inhibitors of NLRP3 inflammasomes; pharmaceutical compositions comprising the compounds; and methods of treating disorders associated with inflammation and inflammaging, including hearing loss and other diseases associated with aging.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof;
wherein
X, Y, and Z, together with the ring to which they are attached, form
Ring A is selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 4-10 cycloalkyl, and 4-10 membered heterocycloalkyl;
Ring B is selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl;
alternatively, Ring B is absent and m is 0;
R 1 is selected from the group consisting of H, C 1-6 alkyl, and C 3-6 cycloalkyl, wherein alkyl and cycloalkyl are each optionally substituted with R 6 ;
R 2 and R 3 are each independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl;
alternatively, R 2 and R 3 , together with the atom to which they are attached, form a ring selected from the group consisting of C 3-7 cycloalkyl and 3-7 membered heterocycloalkyl;
each R 4 is independently selected from the group consisting of C 1-6 alkyl, halo, —OH, —OR 6 , —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NHCOR 6 , —CN, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, and —COR 6 ;
each R 5 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, halo, —OH, —OR 6 , —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NHCOR 6 , —CN, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, —COR 6 , and —SO 2 R 6 ;
alternatively, two R 5 , together with the atoms to which they are attached, form a ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl, and 4-6 membered heterocycloalkyl all of which are optionally substituted with one, two, or three R 7 ;
each R 6 is independently selected from the group consisting of C 1-6 alkyl, C 0-6 alkyl-C 6-10 aryl, C 0-6 alkyl-5-10 membered heteroaryl, —OC 1-6 alkyl, C 3-6 cycloalkyl, halo, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;
each R 7 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, halo, —OH, —OC 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —CN, —COR 8 , and —SO 2 R 8 ;
each R 8 is independently selected from the group consisting of C 1-6 alkyl, —OC 1-6 alkyl, halo, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;
each R 9 is independently selected from the group consisting of C 1-6 alkyl, —OC 1-6 alkyl, halo, —CN, —OH, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;
m is 0, 1, 2, or 3;
n is 1, 2, or 3; and
p is 0, 1, 2, or 3.
2. The compound of claim 1 , wherein Ring A is selected from the group consisting of phenyl, pyridine, pyrimidine, and pyrazine.
3. The compound of claim 1 , wherein Ring A is selected from the group consisting of phenyl, pyridine, pyridazine, pyrimidine, imidazole, and pyrazole.
4. The compound of claim 1 , wherein R 1 is C 1-6 alkyl or C 3-6 cycloalkyl, optionally substituted with C 1-6 alkyl.
5. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula Ic:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein R 4 is —OC 1-6 alkyl.
7. The compound of claim 1 , wherein R 5 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, halo, —NH 2 , —CN, —CONH 2 , —CONH(C 1-6 alkyl), and —SO 2 NH 2 .
8. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the compound of Formula I is
or a pharmaceutically acceptable salt thereof.