Indazolones as modulators of TNF signaling
The disclosure provides compounds of Formula (I) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the disclosure are useful for treating immunological and oncological conditions.
1. A compound of Formula (I),
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
X is —CR 4 , and Y and Z are independently —CR 4 — or N;
provided that Y and Z are not both N;
A is —C(R z ) 2 —;
E is CH 2 or O and G is CH; or E is CH 2 and G is CH or N;
R 1 is optionally substituted aryl or optionally substituted heteroaryl;
R 2 is —R 2a —R 2b , wherein:
R 2a is an optionally substituted saturated, unsaturated or partially saturated heterocyclyl, or optionally substituted heteroaryl; and
R 2b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 5 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, —(CH 2 ) p -optionally substituted heteroaryl, or
—(CH 2 ) p -optionally substituted heterocyclyl;
wherein R a and R b are independently selected from the group consisting of H, optionally substituted (C 1 -C 5 )alkyl, and —(CH 2 ) n -optionally substituted heterocyclyl;
each instance of R 4 is independently H, halo, CF 3 , or (C 1 -C 3 )alkyl;
each instance of R z is independently H, halo, CF 3 , or (C 1 -C 3 )alkyl;
n is 1; and
p is 0 or 1;
wherein heterocyclyl is:
a non-aromatic monocyclic, bicyclic, tricyclic, or spirocyclic ring having 5 to 12 ring atoms which include at least one nitrogen, oxygen, or sulfur ring atom; or
an azetidinyl ring.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 2b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 5 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, or —(CH 2 ) p -optionally substituted heterocyclyl; and
R a and R b are independently selected from the group consisting of H, optionally substituted (C 1 -C 5 )alkyl, and —(CH 2 ) n -optionally substituted heterocyclyl.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein E is CH 2 , and G is CH or N.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CH, Y is CH, and Z is CR 4 .
5. The compound according to claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is F.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CH, Y is CH, and Z is CH.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein E is CH 2 , and G is N.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, or optionally substituted thiazolyl.
9. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is optionally substituted phenyl.
10. The compound according to claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is optionally substituted by one or more substituents independently selected from the group consisting of —CF 3 , —CN, —C(O)NH 2 , —OCHF 2 , —OCH 3 , and (C 1 -C 3 )alkyl.
11. The compound according to claim 10 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is optionally substituted by one or more substituents independently selected from the group consisting of —CH 3 and —OCHF 2 .
12. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2a is optionally substituted pyrimidinyl or optionally substituted dihydropyranyl.
13. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2a is 1,2,4-oxadiazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted 1,2,4-thiadiazolyl.
14. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2b is N(R a )(R b ), optionally substituted (C 1 -C 4 )alkyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, 1,1-dioxidothiomorpholinyl, optionally substituted hexahydroimidazo[1,5-a]pyrazin-3 (2H)-one, optionally substituted 7-azaspiro[3.5]nonane, or optionally substituted pyrrolidinyl.
15. The compound according to claim 14 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R a is H or (C 1 -C 3 )alkyl, R b is (C 1 -C 3 )alkyl, methoxypropyl, 5-oxopyrrolidin-3-ylmethyl, or tetrahydrofuranyl, and R 2b is optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl.
16. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2a is optionally substituted pyrimidinyl.
17. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2b is optionally substituted morpholinyl, optionally substituted piperidinyl, or 1,1-dioxidothiomorpholinyl.
18. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
X is CH;
Y is CH;
Z is CR 4 , wherein R 4 is H or F;
A is —C(R z ) 2 — wherein R z is H;
E is CH 2 ;
G is N;
R 1 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of —CF 3 , —CN, —C(O)NH 2 , —OCHF 2 , —OCH 3 , and (C 1 -C 3 )alkyl;
R 2 is —R 2a —R 2b , wherein R 2a is pyrimidinyl, and R 2b is selected from the group consisting of:
—N(R a )(R b ) wherein R a is H or (C 1 -C 3 )alkyl, and R b is (C 1 -C 3 )alkyl, methoxypropyl, 5-oxopyrrolidin-3-ylmethyl, or tetrahydrofuranyl;
(C 1 -C 3 )alkyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl;
7-azaspiro[3.5]nonanyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl;
morpholinyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl;
piperazinyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl;
piperidinyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl;
hexahydroimidazo[1,5-a]pyrazin-3(2H)-one optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl; and
pyrrolidinyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl.
19. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein optionally substituted refers to substitution with one or more substituents selected from the group consisting of (C 1 -C 8 )alkyl; (C 2 -C 8 )alkenyl; (C 2 -C 8 )alkynyl; (C 3 -C 10 )cycloalkyl; F; Cl; Br; I; halogenated (C 1 -C 8 )alkyl; —O—(C 1 -C 8 )alkyl; ═O; ═CH 2 ; —OH; —CH 2 OH; —CH 2 OCH 3 ; —CH 2 NH 2 ; (C 1 -C 4 )alkyl-OH; —CH 2 CH 2 OCH 2 CH 3 ; —S—(C 1 -C 8 )alkyl; —SH; —NH(C 1 -C 8 )alkyl; —N((C 1 -C 8 )alkyl) 2 ; —NH 2 ; —C(O)NH 2 ; —CH 2 NHC(O)(C 1 -C 4 )alkyl; —CH 2 NHC(O)CH 2 Cl; —CH 2 NHC(O)CH 2 CN; —CH 2 NHC(O)CH 2 CH 2 N(CH 3 ) 2 ; —CH 2 NHC(O)C(═CH 2 )CH 3 ; —CH 2 NHC(O)(C 2 -C 4 )alkynyl; —CH 2 NHC(O)CH 2 CH 2 -piperidinyl; —(C 1 -C 4 )alkyl-morpholinyl; —CH 2 NHC(O)CH 2 O-phenyl wherein the phenyl is optionally substituted with halogen; (C 1 -C 4 )alkoxy; —C(O)(C 1 -C 4 )alkyl; —C(O)(C 1 -C 4 )alkoxy; —C(O)N(CH 3 ) 2 ; —N(CH 3 ) 2 ; —NHC(O)(C 1 -C 4 )alkyl; —NHC(O)(C 2 -C 4 )alkenyl; —NHC(O)CH 2 CN; —S(O) 2 (C 1 -C 4 )alkyl; 4-methylpiperazinecarbonyl; —(C 1 -C 4 )alkylC(O)NH 2 ; —C(O)NH(C 1 -C 8 )alkyl; —C(O)N((C 1 -C 8 )alkyl) 2 ; —C(O)N(H)(C 3 -C 8 )cycloalkyl; —C(O)(C 1 -C 4 )alkyl-OH; —(C 1 -C 4 )alkyl(C 1 -C 4 )alkoxy; —NHC(O)H; —NHC(O)(C 1 -C 8 )alkyl; —NHC(O)(C 3 -C 8 )cycloalkyl; —N((C 1 -C 8 )alkyl)C(O)H; —N((C 1 -C 8 )alkyl)C(O)(C 1 —C)alkyl; —NHC(O)NH 2 ; —NHC(O)NH(C 1 -C 8 )alkyl; —N((C 1 -C 8 )alkyl)C(O)NH 2 ; —NHC(O)N((C 1 -C 8 )alkyl) 2 ; —N((C 1 -C 8 )alkyl)C(O)N((C 1 -C 8 )alkyl) 2 ; —N((C 1 -C 8 )alkyl)C(O)NH((C 1 -C 8 )alkyl); —NHCH 2 -heteroaryl; benzyl; —OCH 2 -heteroaryl; —C(O)H; —C(O)(C 1 -C 8 )alkyl groups; —CN; —NO 2 ; —S(O)(C 1 -C 8 )alkyl; —S(O) 2 (C 1 -C 8 )alkyl; —S(O) 2 N((C 1 -C 8 )alkyl) 2 ; —S(O) 2 NH(C 1 -C 8 )alkyl; —S(O) 2 NH(C 3 -C 8 )cycloalkyl; —S(O) 2 NH 2 ; —NHS(O) 2 (C 1 -C 8 )alkyl; —N((C 1 -C 8 )alkyl)S(O) 2 (C 1 -C 8 )alkyl; —(C 1 -C 8 )alkyl-O—(C 1 -C 8 )alkyl; —O—(C 1 -C 8 )alkyl-O—(C 1 -C 8 )alkyl; —C(O)OH; —C(O)O(C 1 -C 8 )alkyl; NHOH; NHO(C 1 -C 8 )alkyl; —O-halogenated (C 1 -C 8 )alkyl; —S(O) 2 -halogenated (C 1 -C 8 )alkyl; —S-halogenated (C 1 -C 8 )alkyl; —NHC(O)O—(C 1 -C 6 )alkyl; —N((C 1 -C 6 )alkyl)C(O)O—(C 1 -C 6 )alkyl; —C(═NH)—(C 1 -C 6 )alkyl; —C(═NOH)—(C 1 -C 6 )alkyl; and —C(═N—O—(C 1 -C 6 )alkyl)-(C 1 -C 6 )alkyl.
20. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof; and one or more pharmaceutically acceptable excipients.
22. A pharmaceutical composition comprising a compound according to claim 20 , or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients.