N-oxide inhibitors of NLRP3 inflammasome

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 I:

or a pharmaceutically acceptable salt thereof;

wherein the inflammaging is associated with cardiovascular disease, cancer arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension, or Alzheimer's disease; and wherein

is an optional double bond;

X, Y, and Z are each independently selected from the group consisting of NH, NR 3 , N, CH, and CR 3 , provided at least one of X, Y, or Z are CH or CR 3 ;

Ring A is selected from the group consisting of C 6-10 aryl, 5-6 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 C is pyridine N-oxide;

R 1 is selected from the group consisting of H, C 3-6 cycloalkyl, and C 1-6 alkyl;

R 2 and R 2a are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;

alternatively, R 2 and R 2a , together with the atom to which they are attached form C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

each R 3 is independently C 1-6 alkyl and C 3-6 cycloalkyl;

each R 4 is independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkynyl, 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 C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 2-6 alkynyl, halo, OH, OR 7 , NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , NHCOR 7 , CN, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, COR 7 , and SO 2 R 7 ;

each R 6 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 0-6 alkyl-C 6-10 aryl, C 0-6 alkyl-5-10 membered heteroaryl, C 1-6 alkoxy, C 0-6 alkyl-C 3-6 cycloalkyl, C 0-6 alkyl-3-10 membered heterocycloalkyl, 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, C 0-6 alkyl-C 6-10 aryl, C 0-6 alkyl-5-10 membered heteroaryl, C 1-6 alkoxy, C 3-6 cycloalkyl, 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, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkyl-OH, 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 1, 2, or 3; and

p is 0, 1, 2, or 3.

2. The method of claim 1 , wherein the compound of Formula I is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the compound of Formula I is a compound of Formula Ib:

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the compound of Formula I is a compound of Formula Ic:

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein Ring A is C 6-10 aryl.

6. The method of claim 1 , wherein Ring A is phenyl.

7. The method of claim 1 , wherein Ring B is phenyl or 5-6 membered heteroaryl.

8. The method of claim 1 , wherein Ring B is phenyl.

9. The method of claim 1 , wherein

R 1 is C 1-6 alkyl;

R 2 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;

R 2a is H;

each R 4 is independently selected from the group consisting of C 1-6 alkyl, halo, and OR 6 ;

each R 5 is independently selected from the group consisting of C 1-6 haloalkyl, halo, CN, and COR 7 ;

each R 6 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl;

each R 7 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and NH(C 1-6 alkyl);

each R 9 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkyl-OH, C 3-6 cycloalkyl, and CN;

m is 0, 1, or 2; and

n is 1 or 2.

10. The method of claim 1 , wherein

R 1 is C 1-6 alkyl;

R 2 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;

each R 4 is independently selected from the group consisting of C 1-6 alkyl, halo, and OR 6 ;

each R 5 is independently selected from the group consisting of C 1-6 haloalkyl, halo, CN, and COR 7 ;

each R 6 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl;

each R 7 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and NH(C 1-6 alkyl);

each R 9 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkyl-OH, C 3-6 cycloalkyl, and CN;

m is 0, 1, or 2; and

n is 1 or 2.

11. The method of claim 1 , wherein R 1 is C 1-3 alkyl.

12. The method of claim 1 , wherein R 2 is H.

13. The method of claim 1 , wherein each R 4 is independently selected from the group consisting of C 1-6 alkyl, halo, and OR 6 .

14. The method of claim 1 , wherein each R 4 is independently selected from the group consisting of O(ethyl), O(cyclopropyl), O(oxetanyl), and O(C 1-3 haloalkyl).

15. The method of claim 1 , wherein each R 5 is independently selected from the group consisting of C 1-6 haloalkyl, halo, CN, and COR 7 .

16. The method of claim 1 , wherein each R 5 is independently selected from the group consisting of C 1-6 haloalkyl, halo, CN, and CONH(C 1-6 alkyl).

17. The method of claim 1 , wherein each R 9 is independently C 1-6 alkyl.

18. The method of claim 1 , wherein m is 1 or 2.

19. The method of claim 1 , wherein n is 1 or 2.

20. The method of claim 1 , wherein p is 0 or 1.

21. The method of claim 2 , wherein

Ring A is phenyl;

Ring B is phenyl or thienyl;

R 1 is C 1-3 alkyl;

R 2 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;

each R 4 is independently selected from the group consisting of C 1-6 alkyl, halo, and OR 6 ;

each R 5 is independently selected from the group consisting of C 1-6 haloalkyl, halo, CN, and COR 7 ;

each R 6 is independently selected from the group consisting of C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl;

each R 7 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and NH(C 1-6 alkyl);

each R 9 is independently selected from the group consisting of C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-6 alkyl-OH, C 3-6 cycloalkyl, and CN;

m is 1 or 2;

n is 1 or 2; and

p is 0 or 1.

22. The method of claim 1 , wherein

X is N;

Y and Z are each independently selected from the group consisting of NH and CH.

23. The method of claim 1 , wherein the compound of Formula I has one of the following core structures:

24. The method of claim 1 , wherein the compound of Formula I has the following core structure:

25. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.