Compounds for inhibiting NLRP3 and uses thereof
The present disclosure relates to inhibitors of NLRP3 useful in the treatment of diseases and disorders inhibited by said protein and having the Formula (I):
1. A compound of formula (II-h):
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein:
each R 2a is hydrogen;
R 1 is C 1 -C 6 alkyl, —(CH 2 ) n —(C 3 -C 10 cycloalkyl), —(CH 2 ) n —(C 6 -C 10 aryl), —(CH 2 ) n -(3- to 8-membered heterocycloalkyl), or —(CH 2 ) n -(5- to 9-membered heteroaryl), wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more halo, CN, C 1 -C 6 alkyl, C 6 -C 10 aryl, —R 4 OR 5 or —NR 5 R 6 ; and
Y is C 6 -C 10 aryl, wherein the aryl is optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or —R 4 OR 5 ;
R 4 is a bond, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 5 and R 6 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; and
n is an integer from 0 to 4.
2. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl optionally substituted with one or more halo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, —NR 4 R 5 , or —R 4 OR 5 .
3. The compound of claim 2 , wherein R 1 is C 1 -C 6 alkyl optionally substituted with one or more CN, C 1 -C 6 alkyl, or —R 4 OR 5 .
4. The compound of claim 3 , wherein R 4 is a bond.
5. The compound of claim 3 , wherein R 5 is hydrogen or C 1 -C 6 alkyl.
6. The compound of claim 1 , wherein R 1 is —(CH 2 ) n (3- to 8-membered heterocycloalkyl).
7. The compound of claim 6 , wherein heterocycloalkyl is substituted with one or more halo, C 1 -C 6 alkyl, or —R 4 OR 5 .
8. The compound of claim 6 , wherein n is an integer selected from 0 or 1.
9. The compound of claim 1 , wherein R 1 is —(CH 2 ) n —(C 3 -C 10 cycloalkyl).
10. The compound of claim 9 , wherein the cycloalkyl is substituted with one or more halo, C 1 -C 6 alkyl, or —R 4 OR 5 .
11. The compound of claim 1 , wherein Y is C 6 -C 10 aryl.
12. The compound of claim 11 , wherein Y is phenyl.
13. The compound of claim 12 , wherein the phenyl is substituted with one or more halo, C 1 -C 6 alkyl, or —R 4 OR 5 .
14. The compound of claim 1 , selecting from
15. The compound of claim 14 , selecting from
5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol,
5-chloro-2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;
5-methoxy-2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;
2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol;
(S)-5-chloro-2-(4-((tetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol,
(S)-5-chloro-2-(4-(((3,3-difluorocyclopentyl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;
(R)-5-chloro-2-(4-(((3-fluorotetrahydrofuran-3-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;
5-chloro-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;
5-chloro-2-(4-((oxazol-4-ylmethyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; and
5-chloro-2-(4-((4-fluorobenzyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.
16. The compound of claim 15 , selecting from
5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol,
5-methoxy-2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;
(S)-5-chloro-2-(4-((tetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;
5-chloro-2-(4-((oxazol-4-ylmethyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; and
5-chloro-2-(4-((4-fluorobenzyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.
17. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising a compound of claim 14 , and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a compound of claim 15 , and a pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising a compound of claim 16 , and a pharmaceutically acceptable carrier.