Inhibitors of NLRP3 inflammasome
The present disclosure relates to compounds 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; wherein the inhibitors of NLRP3 inflammasomes are compounds of Formula VII: or a Pharmaceutically acceptable salt thereof.
1 . A method of treating inflammaging in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula VII:
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 C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 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;
Ring D is pyridinyl;
R 1 is selected from the group consisting of H, C 1-6 alkyl, and C 3-6 cycloalkyl,
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;
each R 4 is independently selected from the group consisting of C 1-6 alkyl, halo, —OH, —OR 6 , C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, and —COR 6 ;
each R 5 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, halo, —CN, —COR 6 , and —SO 2 R 6 ;
each R 6 is independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, —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, C 1-6 haloalkyl, C 1-6 alkyl-OH, —OC 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, O(C 3-6 cycloalkyl), 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 0, 1, 2, or 3; and
p is 0, 1, 2, or 3.
2 . The method of claim 1 , wherein the compound of Formula VII is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
3 . The method of claim 1 , wherein the compound of Formula VII is administered in a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4 . The method of claim 1 , wherein
Ring A is phenyl or 5-6 membered heteroaryl;
Ring B is phenyl or 5-6 membered heteroaryl;
Ring D is pyridinyl;
R 1 is H or C 1-3 alkyl;
R 2 and R 3 are each independently selected from the group consisting of H and C 1-3 alkyl;
each R 4 is independently selected from the group consisting of halo, —OR 6 C 3-7 cycloalkyl, and —COR 6 ;
each R 5 is independently selected from the group consisting of C 1-3 haloalkyl, halo, —CN, and —COR 6 ;
each R 6 is independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, and —NH(C 1-3 alkyl);
each R 9 is independently selected from the group consisting of C 1-6 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-OH, —OC 1-3 alkyl, O(C 3-6 cycloalkyl), and —CN;
m is 0, 1, or 2;
n is 0, 1, or 2; and
p is0 or 1.
5 . The method of claim 1 , wherein Ring A is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, and pyrazinyl.
6 . The method of claim 1 , wherein Ring B is selected from phenyl and 5-6 membered heteroaryl.
7 . The method of claim 1 , wherein R 1 is C 1-6 alkyl or C 3-6 cycloalkyl.
8 . The method of claim 1 , wherein R 2 and R 3 are each independently selected from the group consisting of H and C 1-3 alkyl.
9 . The method of claim 1 , wherein R 4 is —OC 1-6 alkyl.
10 . The method of claim 3 , wherein R 5 is selected from the group consisting of C 1-6 haloalkyl, halo, —CN, —CONH 2 , and —CONH(C 1-6 alkyl).
11 . The method of claim 1 , wherein each R 9 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, —OC 1-6 alkyl, O(C 3 cycloalkyl), and —CN.
12 . The method of claim 1 , wherein the compound of Formula VII is selected from the group consisting of:
and
or a pharmaceutically acceptable salt thereof.
13 . The method of claim 1 , wherein the compound of Formula VII is
or a pharmaceutically acceptable salt thereof.
14 . The method of claim 1 , wherein the compound of Formula VII is
or a pharmaceutically acceptable salt thereof.