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 (I)
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein:
X is N(R a ), O, S or C(R b )(R c );
R a is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl; or
R a cyclizes with R 1 to form a 3- to 8-membered heterocycloalkyl;
R b is hydrogen or C 1 -C 6 alkyl;
R c is hydrogen or C 1 -C 6 alkyl;
or R b and R c , together with the atoms to which they are attached, form a C 3 -C 8 cycloalkyl;
Y is C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, 5- to 9-membered heteroaryl, halo, cyano, —R 4 OR 5 , —R 4 N(R 5 )(R 6 ), —R 4 SR 6 , —R 4 C(O)OR 6 , —R 4 C(O)N(R 7 )(R 8 ), —R 4 N(R 7 )C(O)R 8 , —R 4 S(O) t R 5 , —R 4 S(O) t N(R 7 )(R 8 ), —R 4 N(R 7 )S(O) t (R 8 ), —R 4 P(O)(R 5 ) 2 , or —R 4 SF 5 ;
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, —(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), —R 4 SR 6 , —R 4 C(O)OR 6 , —R 4 C(O)N(R 7 )(R 8 ), —R 4 N(R 7 )C(O)R 8 , —R 4 S(O) t R 5 , —R 4 S(O) t N(R 7 )(R 8 ), —R 4 N(R 7 )S(O) t (R 8 ), or —R 4 P(O)(R 5 ) 2 wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl is optionally substituted with one more halo, CN, C 1 -C 6 alkyl, —NR 4 R 5 , —R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, an optionally substituted C 5 -C 10 aryl, or an optionally substituted 5- to 9-membered heteroaryl;
R 2 is hydrogen, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, 5- to 9-membered heteroaryl, —R 4 OR 5 , —R 4 SR 6 , —R 4 C(O)OR 6 , —R 4 C(O)N(R 7 )(R 8 ), —R 4 N(R 7 )C(O)R 8 , —R 4 S(O) t R 5 , —R 4 S(O) t N(R 7 )(R 8 ), —R 4 N(R 7 )S(O) t (R 8 ), —R 4 P(O)(R 5 ) 2 , or —R 4 SF 5 , wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more C 1 -C 6 alkyl, halo, or C 1 -C 6 haloalkyl;
R 3 is hydrogen, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, 5- to 9-membered heteroaryl, —R 4 OR 5 , —R 4 SR 6 , —R 4 C(O)OR 6 , —R 4 C(O)N(R 7 )(R 8 ), —R 4 N(R 7 )C(O)R 8 , —R 4 S(O) t R 5 , —R 4 S(O) t N(R 7 )(R 8 ), —R 4 N(R 7 )S(O) t (R 8 ), —R 4 P(O)(R 5 ) 2 , or —R 4 SF 5 , wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more C 1 -C 6 alkyl, halo, or C 1 -C 6 haloalkyl; or
R 2 and R 3 , together with the atoms to which they are attached, form a C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R 2a ;
R 2a is hydrogen, C 1 -C 6 alkyl, halo or C 1 -C 6 haloalkyl;
R 4 is a bond, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein R 4 can only be a bond with —R 4 OR 5 ;
R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D;
R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl;
R 7 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl;
R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl; or
R 7 and R 8 , together with the atoms to which they are attached, form a 3- to 8-membered heterocycloalkyl;
n is an integer from 0 to 4; and
t is 1 or 2;
provided that R 1 is not C 2 or C 4 alkyl substituted with morpholinyl.
2 . The compound of claim 1 , wherein the compound is of formula (II):
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein:
Y is C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, 5- to 9-membered heteroaryl, halo, cyano, —R 4 OR 5 , —R 4 N(R 5 )(R 6 ), —R 4 SR 6 , —R 4 C(O)OR 6 , —R 4 C(O)N(R 7 )(R 8 ), —R 4 N(R 7 )C(O)R 8 , —R 4 S(O) t R 5 , —R 4 S(O) t N(R 7 )(R 8 ), —R 4 N(R 7 )S(O) t (R 8 ), —R 4 P(O)(R 5 ) 2 , or —R 4 SF 5 ;
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, —(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), —R 4 SR 6 , —R 4 C(O)OR 6 , —R 4 C(O)N(R 7 )(R 8 ), —R 4 N(R 7 )C(O)R 8 , —R 4 S(O) t R 5 , —R 4 S(O) t N(R 7 )(R 8 ), —R 4 N(R 7 )S(O) t (R 8 ), or —R 4 P(O)(R 5 ) 2 wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl is optionally substituted with one more halo, CN, C 1 -C 6 alkyl, —NR 4 R 5 , —R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, an optionally substituted C 5 -C 10 aryl, or an optionally substituted 5- to 9-membered heteroaryl;
R 2 is hydrogen, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, 5- to 9-membered heteroaryl, —R 4 OR 5 , —R 4 SR 6 , —R 4 C(O)OR 6 , —R 4 C(O)N(R 7 )(R 8 ), —R 4 N(R 7 )C(O)R 8 , —R 4 S(O) t R 5 , —R 4 S(O) t N(R 7 )(R 8 ), —R 4 N(R 7 )S(O) t (R 8 ), —R 4 P(O)(R 5 ) 2 , or —R 4 SF 5 , wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more C 1 -C 6 alkyl, halo, or C 1 -C 6 haloalkyl;
R 3 is hydrogen, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, 5- to 9-membered heteroaryl, —R 4 OR 5 , —R 4 SR 6 , —R 4 C(O)OR 6 , —R 4 C(O)N(R 7 )(R 8 ), —R 4 N(R 7 )C(O)R 8 , —R 4 S(O) t R 5 , —R 4 S(O) t N(R 7 )(R 8 ), —R 4 N(R 7 )S(O) t (R 8 ), —R 4 P(O)(R 5 ) 2 , or —R 4 SF 5 , wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more C 1 -C 6 alkyl, halo, or C 1 -C 6 haloalkyl; or
R 2 and R 3 , together with the atoms to which they are attached, form a C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R 2a ;
R 2a is hydrogen, C 1 -C 6 alkyl, halo or C 1 -C 6 haloalkyl;
R 4 is a bond, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein R 4 can only be a bond with —R 4 OR 5 ;
R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl wherein the alkyl is optionally substituted with one or more D;
R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl;
R 7 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl;
R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl; or
R 7 and R 8 , together with the atoms to which they are attached, form a 3- to 8-membered heterocycloalkyl;
n is an integer from 0 to 4; and
t is 1 or 2;
provided that R 1 is not C 2 or C 4 alkyl substituted with morpholinyl.
3 . The compound of claim 1 , wherein Y is C 6 -C 10 aryl.
4 . The compound of claim 3 , wherein Y is phenyl.
5 . The compound of claim 4 , wherein the phenyl is substituted with one or more C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, halo, cyano, or —R 4 OR 5 .
6 . The compound of claim 1 , wherein Y is
7 . The compound of claim 1 , wherein R 2 is hydrogen or C 1 -C 6 alkyl.
8 . The compound of claim 1 , wherein R 2 and R 3 , together with the atoms to which they are attached, form a C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, or 5- to 9-membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R 2a .
9 . The compound of claim 1 , wherein R 2a is hydrogen.
10 . The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, —(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).
11 . The compound of claim 10 , 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, —NR 4 R 5 , or —R 4 OR 5 .
12 . The compound of claim 1 , wherein R 4 is a bond, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl.
13 . The compound of claim 1 , wherein R 5 is 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.
14 . The compound of claim 1 , wherein the compound of formula (II) is a compound of formula (II-a):
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein:
R 1 is C 1 -C 6 alkyl substituted with one more halo, —R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; and
R 2 and R 3 , together with the atoms to which they are attached, form a C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 5 -C 10 aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R 2a .
15 . The compound of claim 4 , wherein the compound of formula (II) is 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, —NR 4 R 5 , or —R 4 OR 5 ; 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, wherein R 4 can only be a bond with —R 4 OR 5 ;
R 5 is 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.
16 . The compound of claim 15 , 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 .
17 . The compound of claim 15 , wherein R 1 is —(CH 2 ) n -(3- to 8-membered heterocycloalkyl) optionally substituted with one or more halo, C 1 -C 6 alkyl, or —R 4 OR 5 .
18 . The compound of claim 15 , wherein R 1 is —(CH 2 ) n —(C 3 -C 10 cycloalkyl) optionally substituted with one or more halo, C 1 -C 6 alkyl, or —R 4 OR 5 .
19 . The compound of claim 15 , wherein R 4 is a bond.
20 . The compound of claim 15 , wherein Y is C 6 -C 10 aryl optionally substituted with one or more halo, C 1 -C 6 alkyl, or —R 4 OR 5 .
21 . The compound of claim 1 selected from the group consisting of:
Cmp.
#
nomenclature
1
(S)-1-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-
d]pyridazin-4-amine
2
(S)-4-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-
d]pyridazin-1-amine
3
(R)-1-(4-chlorophenyl)-4-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-
d]pyridazine
4
(R)-4-(4-chlorophenyl)-1-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-
d]pyridazine
5
4-(4-chlorophenyl)-N-(tetrahydrofuran-2-ylmethyl)phthalazin-1-
amine
6
6-(4-bromophenyl)-N-[(2-methyltetrahydrofuran-2-
yl)methyl]pyridazin-3-amine
7
4-(4-bromophenyl)-N-(tetrahydrofuran-2-ylmethyl)phthalazin-1-
amine
8
4-(4-chlorophenyl)-N-[(2-methyltetrahydrofuran-2-
yl)methyl]phthalazin-1-amine
9
4-(4-chlorophenyl)-N-(tetrahydropyran-3-ylmethyl)phthalazin-1-
amine
10
4-(4-chlorophenyl)-N-(tetrahydropyran-4-ylmethyl)phthalazin-1-
amine
11
N-(tetrahydrofuran-2-ylmethyl)-4-[4-
(trifluoromethyl)phenyl]phthalazin-1-amine
12
4-(4-chlorophenyl)-N-[rac-(2R)-tetrahydrofuran-2-
yl]methyl]phthalazin-1-amine
13
4-(4-chlorophenyl)-N-[[rac-(2S)-tetrahydrofuran-2-
yl]methyl]phthalazin-1-amine
14
1-(4-chlorophenyl)-N-(tetrahydrofuran-2-ylmethyl)pyrido[3,4-
d]pyridazin-4-amine
15
4-(4-chlorophenyl)-N-(tetrahydrofuran-2-ylmethyl)pyrido[3,4-
d]pyridazin-1-amine
16
2-[[4-(4-chlorophenyl)phthalazin-1-yl]amino]ethanol
17
4-(4-chlorophenyl)-N-(tetrahydropyran-2-ylmethyl)phthalazin-1-
amine
18
4-(4-chlorophenyl)-N-(2-methoxyethyl)phthalazin-1-amine
19
4-(4-chlorophenyl)-N-methyl-N-(tetrahydrofuran-2-
ylmethyl)phthalazin-1-amine
20
4-(4-chloro-2-methyl-phenyl)-N-(tetrahydrofuran-2-
ylmethyl)phthalazin-1-amine
21
7-chloro-4-(4-chlorophenyl)-N-[rac-(2R)-tetrahydrofuran-2-
yl]methyl]phthalazin-1-amine
22
4-(4-chlorophenyl)-N-[(4-methyltetrahydrofuran-2-
yl)methyl]phthalazin-1-amine
23
(R)-N-((1,4-dioxan-2-yl)methyl)-4-(4-chlorophenyl)phthalazin-1-
amine
24
(S)-N-((1,4-dioxan-2-yl)methyl)-4-(4-chlorophenyl)phthalazin-1-
amine
25
4-(4-chlorophenyl)-N-[(5-methyltetrahydrofuran-2-
yl)methyl]phthalazin-1-amine
26
7-chloro-4-(4-chlorophenyl)-N-[rac-(2S)-tetrahydrofuran-2-
yl]methyl]phthalazin-1-amine
27
5-(4-chlorophenyl)-N-(tetrahydrofuran-2-ylmethyl)pyrido[2,3-
d]pyridazin-8-amine
28
8-(4-chlorophenyl)-N-(tetrahydrofuran-2-ylmethyl)pyrido[2,3-
d]pyridazin-5-amine
29
N-(tetrahydrofuran-2-ylmethyl)-4-[6-(trifluoromethyl)-3-
pyridyl]phthalazin-1-amine
30
4-(4-chlorophenyl)-N-(tetrahydrofuran-3-ylmethyl)phthalazin-1-
amine
31
N-(tetrahydrofuran-2-ylmethyl)-1-[4-
(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine
32
N-(tetrahydrofuran-2-ylmethyl)-4-[4-
(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-1-amine
33
N-(tetrahydrofuran-2-ylmethyl)-4-[5-(trifluoromethyl)-2-
pyridyl]phthalazin-1-amine
34
1-(4-chlorophenyl)-N-[rac-(2R)-tetrahydrofuran-2-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
35
1-[4-(1, 1-difluoroethyl)phenyl]-N-[rac-(2R)-tetrahydrofuran-2-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
36
N-[[rac-(2R)-tetrahydrofuran-2-yl]methyl]-1-[4-
(trifluoromethoxy)phenyl]pyrido[3,4-d]pyridazin-4-amine
37
rac-(2R)-1-[[1-(4-chlorophenyl)pyrido[3,4-d]pyridazin-4-
yl]amino]propan-2-ol
38
rac-(2S)-1-[[1-(4-chlorophenyl)pyrido[3,4-d]pyridazin-4-
yl]amino]propan-2-ol
39
1-(4-chlorophenyl)-N-(tetrahydropyran-4-ylmethyl)pyrido[3,4-
d]pyridazin-4-amine
40
rac-(2R)-1-[4-(4-chlorophenyl)pyrido[3,4-d]pyridazin-1-
yl]amino]propan-2-ol
41
rac-(2S)-1-[[4-(4-chlorophenyl)pyrido[3,4-d]pyridazin-1-
yl]amino]propan-2-ol
42
4-(4-chlorophenyl)-N-[[rac-(2R)-tetrahydrofuran-2-
yl]methyl]pyrido[3,4-d]pyridazin-1-amine
43
1-[4-(difluoromethoxy)phenyl]-N-[rac-(2R)-tetrahydrofuran-2-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
44
1-(4-cyclopropylphenyl)-N-[rac-(2R)-tetrahydrofuran-2-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
45
1-[4-(difluoromethyl)phenyl]-N-[[rac-(2R)-tetrahydrofuran-2-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
46
1-[[1-(4-chlorophenyl)pyrido[3,4-d]pyridazin-4-yl]amino]-2-methyl-
propan-2-ol
47
1-(4-chloro-3-fluoro-phenyl)-N-[[rac-(2R)-tetrahydrofuran-2-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
48
1-(4-chloro-2-methoxy-phenyl)-N-[[rac-(2R)-tetrahydrofuran-2-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
49
4-(4-chlorophenyl)-N-(2-furylmethyl)pyrido[3,4-d]pyridazin-1-amine
50
1-(4-chlorophenyl)-N-[rac-(3R)-tetrahydropyran-3-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
51
1-(4-chloro-2-fluoro-phenyl)-N-[rac-(2R)-tetrahydrofuran-2-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
52
1-[4-chloro-2-(trifluoromethyl)phenyl]-N-[[rac-(2R)-tetrahydrofuran-
2-yl]methyl]pyrido[3,4-d]pyridazin-4-amine
53
1-(4-chlorophenyl)-N-(2-oxabicyclo[2.1.1]hexan-1-
ylmethyl)pyrido[3,4-d]pyridazin-4-amine
54
1-(4-chlorophenyl)-N-[[rac-(3R)-tetrahydrofuran-3-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
55
4-(4-chlorophenyl)-N-[[rac-(2R)-tetrahydrofuran-2-
yl]methyl]thieno[2,3-d]pyridazin-7-amine
56
7-(4-chlorophenyl)-N-[[rac-(2R)-tetrahydrofuran-2-
yl]methyl]thieno[2,3-d]pyridazin-4-amine
57
6-(4-chlorophenyl)-4,5-dimethyl-N-[[rac-(2R)-tetrahydrofuran-2-
yl]methyl]pyridazin-3-amine
58
4-(4-chlorophenyl)-N-(2-oxabicyclo[2.1.1]hexan-1-
ylmethyl)pyrido[3,4-d]pyridazin-1-amine
59
N-[[rac-(2R)-tetrahydrofuran-2-yl]methyl]-1-[1-(2,2,2-trifluoroethyl)-
4-piperidyl]pyrido[3,4-d]pyridazin-4-amine
60
1-[4-chloro-2-(trifluoromethoxy)phenyl]-N-[rac-(2R)-
tetrahydrofuran-2-yl]methyl]pyrido[3,4-d]pyridazin-4-amine
61
4-(4-chlorophenyl)-N-[[rac-(2R)-tetrahydrofuran-2-
yl]methyl]furo[2,3-d]pyridazin-7-amine
62
1-(4-chlorophenyl)-N-[[rac-(3S)-tetrahydrofuran-3-
yl]methyl]pyrido[3,4-d]pyridazin-4-amine
63
1-(4-chlorophenyl)-N-[rac-(3S)-tetrahydrofuran-3-yl]pyrido[3,4-
d]pyridazin-4-amine
64
1-(4-chlorophenyl)-N-[rac-(3R)-tetrahydrofuran-3-yl]pyrido[3,4-
d]pyridazin-4-amine
65
3-[[1-(4-chlorophenyl)pyrido[3,4-d]pyridazin-4-yl]amino]propan-1-ol
66
1-(4-chlorophenyl)-N-(tetrahydrofuran-2-ylmethyl)-6,7-dihydro-5H-
cyclopenta[d]pyridazin-4-amine
67
4-(4-chlorophenyl)-N-[[rac-(3R)-tetrahydrofuran-3-
yl]methyl]pyrido[3,4-d]pyridazin-1-amine
68
4-(4-chlorophenyl)-N-[rac-(3S)-tetrahydrofuran-3-yl]pyrido[3,4-
d]pyridazin-1-amine
69
4-(4-chlorophenyl)-N-[rac-(3R)-tetrahydrofuran-3-yl]pyrido[3,4-
d]pyridazin-1-amine
70
3-[[4-(4-chlorophenyl)pyrido[3,4-d]pyridazin-1-yl]amino]propan-1-ol
71
4-[4-[[rac-(2R)-tetrahydrofuran-2-yl]methylamino]pyrido[3,4-
d]pyridazin-1-yl]benzonitrile
72
7-(4-chlorophenyl)-N-[[rac-(2R)-tetrahydrofuran-2-
yl]methyl]furo[2,3-d]pyridazin-4-amine
73
rac-(2R)-2-[[1-(4-chlorophenyl)pyrido[3,4-d]pyridazin-4-yl]amino]-
3,3,3-trifluoro-propan-1-ol
74
rac-(2S)-2-[[1-(4-chlorophenyl)pyrido[3,4-d]pyridazin-4-yl]amino]-
3,3,3-trifluoro-propan-1-ol
75
1-(4-chlorophenyl)-N-[[rac-(2R)-tetrahydrofuran-2-
yl]methyl]thieno[3,4-d]pyridazin-4-amine
76
6-(4-chlorophenyl)-N-[[rac-(2R)-tetrahydrofuran-2-yl]methyl]-5-
(trifluoromethyl)pyridazin-3-amine
77
4-(4-chlorophenyl)-N-[[rac-(3S)-tetrahydrofuran-3-
yl]methyl]pyrido[3,4-d]pyridazin-1-amine
78
1-(4-chlorophenyl)-N-[[rac-(2S)-1,4-dioxan-2-yl]methyl]pyrido[3,4-
d]pyridazin-4-amine
79
1-(4-chlorophenyl)-N-[[rac-(2R)-1,4-dioxan-2-yl]methyl]pyrido[3,4-
d]pyridazin-4-amine
80
1-(p-tolyl)-N-[[rac-(2R)-tetrahydrofuran-2-yl]methyl]pyrido[3,4-
d]pyridazin-4-amine,
81
4-(4-chlorophenyl)-N-[[rac-(2S)-1,4-dioxan-2-yl]methyl]pyrido[3,4-
d]pyridazin-1-amine
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.
22 . The compound of claim 15 , or a pharmaceutically acceptable salt or stereoisomer thereof selected from:
Cmp.
#
Structure
82
5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-
yl)phenol
83
5-chloro-2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-
yl)phenol
84
5-methoxy-2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-
yl)phenol
85
2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-
methylphenol
86
5-bromo-2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-
yl)phenol
87
2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-
(trifluoromethyl)phenol
88
2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-
(trifluoromethoxy)phenol
89
(S)-5-chloro-2-(4-((tetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-
yl)phenol
90
5-chloro-2-(4-((3-hydroxy-3-methylbutyl)amino)pyrido[3,4-d]pyridazin-1-
yl)phenol
91
(S)-5-chloro-2-(4-(((3,3-difluorocyclopentyl)methyl)amino)pyrido[3,4-
d]pyridazin-1-yl)phenol
92
(S)-5-chloro-2-(4-(((tetrahydrofuran-3-yl)methyl)amino)pyrido[3,4-
d]pyridazin-1-yl)phenol
93
(S)-5-chloro-2-(4-(((1-methylpyrrolidin-2-yl)methyl)amino)pyrido[3,4-
d]pyridazin-1-yl)phenol
94
(R)-5-chloro-2-(4-(((3-fluorotetrahydrofuran-3-yl)methyl)amino)pyrido[3,4-
d]pyridazin-1-yl)phenol
95
5-chloro-2-(4-(((1S,2S)-2-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-
yl)phenol
96
5-chloro-2-(4-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)pyrido[3,4-
d]pyridazin-1-yl)phenol
97
(R)-5-chloro-2-(4-((3,3,3-trifluoro-2-methoxypropyl)amino)pyrido[3,4-
d]pyridazin-1-yl)phenol
98
(S)-5-chloro-2-(4-((1-methylpyrrolidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-
yl)phenol
99
5-chloro-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-
1-yl)phenol
100
(R)-5-chloro-2-(4-((1-methoxypropan-2-yl)amino)pyrido[3,4-d]pyridazin-1-
yl)phenol
101
(R)-5-chloro-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-
d]pyridazin-1-yl)phenol
102
3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)-2,2-
dimethylpropanenitrile
103
(R)-5-chloro-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-
d]pyridazin-1-yl)phenol
104
5-chloro-2-(4-((4-fluorobenzyl)amino)pyrido[3,4-d]pyridazin-1-
yl)phenol
105
(R)-5-chloro-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-
d]pyridazin-1-yl)phenol
23 . The compound of claim 1 , wherein R 5 is C 1 -C 6 alkyl substituted with D.
24 . The compound of claim 15 , wherein R 5 is C 1 -C 6 alkyl substituted with D.
25 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
26 . A pharmaceutical composition comprising the compound of claim 21 and a pharmaceutically acceptable carrier.
27 . A pharmaceutical composition comprising the compound of claim 15 and a pharmaceutically acceptable carrier.
28 . A pharmaceutical composition comprising the compound of claim 22 and a pharmaceutically acceptable carrier.
29 . A method of treating or preventing an NLRP3-related disease or disorder, comprising administering to the subject at least one therapeutically effective amount of the compound of claim 1 .
30 . The method of claim 1 , wherein the NLRP3-related disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3.