PYRIDO-[3,4-d]PYRIDAZINE AMINE DERIVATIVES USEFUL AS NLRP3 INHIBITORS
The present disclosure relates to inhibitors of NLRP3 of Formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein Ring A is a 5- to 8-membered monocyclic heterocycloalkyl comprising at least one O ring atom, p is 0 or 1, and R 1 , R 2 , R 3 , R 4 , and X are as defined herein, useful in the treatment of diseases and disorders inhibited by said protein.
1 .- 42 . (canceled)
43 . A compound of Formula (IV-c1):
or a pharmaceutically acceptable salt or isotopically labeled compound thereof, wherein:
R 3 is C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
X is H, halogen, or C 1-6 alkyl; and
R 4 is H,
wherein each instance of alkyl or alk-is independently substituted with 0, 1, 2, or 3 halogen atoms.
44 . The compound of claim 43 , or a pharmaceutically acceptable salt or isotopically labeled compound thereof, wherein R 3 is methyl, —CF 3 , —CHF 2 , or —OCHF 2 .
45 . The compound of claim 43 , or a pharmaceutically acceptable salt or isotopically labeled compound thereof, wherein X is H, —F, —Cl, or —CH 3 .
46 . The compound of claim 45 , or a pharmaceutically acceptable salt or isotopically labeled compound thereof, wherein X is H.
47 . The compound of claim 45 , or a pharmaceutically acceptable salt or isotopically labeled compound thereof, wherein X is —F.
48 . The compound of claim 44 , or a pharmaceutically acceptable salt or isotopically labeled compound thereof, wherein X is H, —F, —Cl, or —CH 3 .
49 . The compound of claim 48 , or a pharmaceutically acceptable salt or isotopically labeled compound thereof, wherein X is H.
50 . The compound of claim 48 , or a pharmaceutically acceptable salt or isotopically labeled compound thereof, wherein X is —F.
51 . The compound of claim 43 , wherein the compound is:
or a pharmaceutically acceptable salt or isotopically labeled compound thereof.
52 . The compound of claim 43 , wherein the compound is:
or a pharmaceutically acceptable salt or isotopically labeled compound thereof.
53 . The compound of claim 43 , wherein the compound is:
or a pharmaceutically acceptable salt or isotopically labeled compound thereof.
54 . The compound of claim 43 , wherein the compound is:
or a pharmaceutically acceptable salt or isotopically labeled compound thereof.
55 . The compound of claim 43 , wherein the compound is:
or a pharmaceutically acceptable salt or isotopically labeled compound thereof.
56 . The compound of claim 43 , wherein the compound is:
or a pharmaceutically acceptable salt or isotopically labeled compound thereof.
57 . A pharmaceutical composition comprising the compound of claim 43 , or a pharmaceutically acceptable salt or isotopically labeled compound thereof, and one or more pharmaceutically acceptable carriers.
58 . A method of treating a disease or disorder by inhibiting NLRP3 activity in a subject, the method comprising administering to the subject a compound of claim 43 , or a pharmaceutically acceptable salt or isotopically labeled compound thereof.
59 . The method of claim 58 , wherein disease or disorder is inflammation, a disease or disorder of the central nervous system, a skin disease, a rheumatic disease, or a cryopyrin-associated autoinflammatory syndrome.
60 . The method of claim 59 , wherein the disease or disorder is inflammation.
61 . The method of claim 59 , wherein the disease or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.
62 . The method of claim 59 , wherein the skin disease is hidradenitis suppurativa.
63 . The method of claim 59 , wherein the rheumatic disease is Still's disease.
64 . The method of claim 59 , wherein the cryopyrin-associated autoinflammatory syndrome is neonatal onset multisystem inflammatory disease.
65 . The method of claim 58 , wherein the disease or disorder is refractory epilepsy or headache/pain.