Spirocyclic EBI2 modulators
Provided herein are small molecule Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) modulator compounds, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds. In some embodiments, EBI2 is a therapeutic target for the treatment of diseases or conditions such as, but not limited to, autoimmune diseases or conditions, cancer, and cardiovascular disease.
1. A compound having the structure of Formula (I):
wherein:
X is a —CH═CH— or —C≡C—;
Y is a bond or —C(═O);
R 1 is optionally substituted phenyl, optionally substituted indolyl, optionally substituted benzofuranyl, or optionally substituted benzothiophenyl, where R 1 is optionally substituted with one or more substituents selected from F, Cl, Br, —NR 4 R 5 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl, and R 4 and R 5 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, or heteroaryl;
R 2 is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, wherein R 2 is optionally substituted with one or more substituents selected from F, Cl, Br, —NR 4 R 5 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl, and R 4 and R 5 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, or heteroaryl;
each p is an integer independently 1 or 2; and
each t is an integer independently 1 or 2;
or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein R 1 is phenyl substituted with one or more substituents selected from F, Cl, Br, —NH 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl.
3. The compound of claim 2 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein R 2 is phenyl substituted with one or more substituents selected from F, Cl, Br, —NH 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein X is —CH═CH—.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein X is —C≡C—.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein R 1 is indolyl substituted with one or more substituents selected from F, Cl, Br, —NH 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein R 2 is phenyl substituted with one or more substituents selected from F, Cl, Br, —NH 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein Y is a bond.
9. The compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein Y is —C(═O)—.
10. The compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein each p is 1 and each t is 2, or each p is 2 and each t is 1.
11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient.
12. A compound having the structure of Formula (I):
wherein:
X is a —CH═CH— or —C≡C—;
Y is a bond, —C(═O)—, or —CH 2 —;
R 1 is optionally substituted phenyl, optionally substituted indolyl, optionally substituted benzofuranyl, or optionally substituted benzothiophenyl, where R 1 is optionally substituted with one or more substituents selected from F, Cl, Br, —NR 4 R 5 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl, and R 4 and R 5 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, or heteroaryl;
R 2 is phenyl optionally substituted with one or more substituents selected from F, Cl, Br, —NR 4 R 5 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl, and R 4 and R 5 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, or heteroaryl;
each p is 2; and
each t is 1;
or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof.
13. The compound of claim 12 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein R 1 is phenyl substituted with one or more substituents selected from F, Cl, Br, —NH 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl; and R 2 is phenyl substituted with one or more substituents selected from F, Cl, Br, —NH 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl.
14. The compound of claim 13 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein X is —CH═CH—.
15. The compound of claim 12 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein R 2 is phenyl substituted with one or more substituents selected from F, Cl, Br, —NH 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, and heteroaryl.
16. A pharmaceutical composition comprising a compound of claim 12 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient.
17. The compound of claim 1 , or a pharmaceutically accceptable salt, or a pharmaceutically accepetable solvate thereof, wherein the compound is:
C2
(2E)-3-(4-bromophenyl)-1-{7-[(3-bromophenyl)carbonyl]-2,7-
diazaspiro[3.5]non-2-yl}prop-2-en-1-one
C3
3-(4-chlorophenyl)-1-{7-[(4-fluorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-2-
yl}prop-2-en-1-one
C7
(2E)-3-(4-bromophenyl)-1-[2-(phenylcarbonyl)-2,7-diazaspiro[3.5]non-7-
yl]prop-2-en-1-one
C9
(2E)-1-{2-[(3,4-dimethoxyphenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-yl]-3-(4-
bromophenyl)prop-2-en-1-one
C10
(2E)-1-{2-[(3,5-dichlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-yl]-3-(4-
bromophenyl)prop-2-en-1-one
C12
(2E)-3-(4-bromophenyl)-1-{2-[(3-methylphenyl)carbonyl]-2,7-
diazaspiro[3.5]non-7-yl}prop-2-en-1-one
C19
(2E)-3-(4-bromophenyl)-1-{7-[(4-chlorophenyl)carbonyl]-2,7-
diazaspiro[3.5]non-2-yl}prop-2-en-1-one
C20
(2E)-3-(4-bromophenyl)-1-{7-[(4-fluorophenyl)carbonyl]-2,7-
diazaspiro[3.5]non-2-yl}prop-2-en-1-one
C21
(2E)-3-(4-bromophenyl)-1-(7-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-2-yl)prop-2-en-1-one
C22
(2E)-3-(4-bromophenyl)-1-(7-{[4-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-
2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one
C23
(2E)-3-(4-bromophenyl)-1-{7-[(4-(1H-1,2,3,4-tetraazol-5-yl)phenyl)carbonyl]-
2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one
C28
(2E)-3-(3,4-dichlorophenyl)-1-{7-[(4-fluorophenyl)carbonyl]-2,7-
diazaspiro[3.5]non-2-yl}prop-2-en-1-one
C29
(2E)-3-(3,4-dichlorophenyl)-1-{7-[(4-chlorophenyl)carbonyl]-2,7-
diazaspiro[3.5]non-2-yl}prop-2-en-1-one
C30
(2E)-3-(3,4-dichlorophenyl)-1-(7-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-2-yl)prop-2-en-1-one
C31
(2E)-3-(3,4-dichlorophenyl)-1-{7-[(4-(1H-1,2,3,4-tetraazol-5-
yl)phenyl)carbonyl]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one
C43
4-({2-[(2E)-3-(4-bromophenyl)prop-2-enoyl]-2,7-diazaspiro[3.5]non-7-
yl}carbonyl)-2-fluorobenzenecarbonitrile
C44
(2E)-1-{7-[(3,5-difluorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-2-yl}-3-(4-
bromophenyl)prop-2-en-1-one
C45
(2E)-3-(4-bromophenyl)-1-(7-{[4-fluoro-2-(trifluoromethyl)phenyl]carbonyl}-
2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one
C51
(2E)-1-{7-[(4-aminophenyl)carbonyl]-2,7-diazaspiro[3.5]non-2-yl}-3-(4-
bromophenyl)prop-2-en-1-one
C52
(2E)-3-(4-bromophenyl)-1-(2-{[4-fluoro-2-(trifluoromethyl)phenyl]carbonyl}-
2,7-diazaspiro[3.5]non-7-yl)prop-2-en-1-one
C53
(2E)-3-(4-bromophenyl)-1-{2-[(4-fluorophenyl)carbonyl]-2,7-
diazaspiro[3.5]non-7-yl}prop-2-en-1-one
C54
(2E)-3-(4-bromophenyl)-1-(2-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-en-1-one
C64
3-(4-bromophenyl)-1-{7-[(4-chlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-2-
yl}prop-2-yn-1-one
C65
3-(4-bromophenyl)-1-(7-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-2-yl)prop-2-yn-1-one
C67
3-(4-bromophenyl)-1-{2-[(4-fluorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C70
3-(4-bromophenyl)-1-{2-[(4-chlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C71
3-(4-bromophenyl)-1-(2-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-yn-1-one
C74
3-(4-bromophenyl)-1-{2-[(4-methoxyphenyl)carbonyl]-2,7-diazaspiro[3.5]non-
7-yl}prop-2-yn-1-one
C76
3-(4-chlorophenyl)-1-{2-[(4-chlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C77
3-(4-chlorophenyl)-1-{2-[(4-fluorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C79
3-(4-chlorophenyl)-1-(2-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-yn-1-one
C80
3-(4-chlorophenyl)-1-(7-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-2-yl)prop-2-yn-1-one
C84
3-(4-chlorophenyl)-1-{7-[(4-chlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-2-
yl}prop-2-yn-1-one
C86
3-(4-fluorophenyl)-1-{2-[(4-fluorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C87
1-{2[(4-chlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-yl}-3-(4-
fluorophenyl)prop-2-yn-1-one
C88
3-(4-fluorophenyl)-1-(2-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-yn-1-one
C89
3-(4-fluorophenyl)-1-{2-[(4-methoxyphenyl)carbonyl]-2,7-diazaspiro[3.5]non-
7-yl}prop-2-yn-1-one
C91
3-(4-chlorophenyl)-1-{7-[(4-methoxyphenyl)carbonyl]-2,7-diazaspiro[3.5]non-
2-yl}prop-2-yn-1-one
C92
3-(4-fluorophenyl)-1-{7-[(4-methoxyphenyl)carbonyl]-2,7-diazaspiro[3.5]non-
2-yl}prop-2-yn-1-one
C93
3-(4-fluorophenyl)-1-{7-[(4-fluorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-2-
yl}prop-2-yn-1-one
C94
1- {7-[(4-chlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-2-yl}-3-(4-
fluorophenyl)prop-2-yn-1-one
C95
1- {7-[(4-bromophenyl)carbonyl]-2,7-diazaspiro[3.5]non-2-yl}-3-(4-
fluorophenyl)prop-2-yn-1-one
C96
3-(4-fluorophenyl)-1-(7-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-2-yl)prop-2-yn-1-one
C97
3-(2,4-difluorophenyl)-1-{7-[(4-methoxyphenyl)carbonyl]-2,7-
diazaspiro[3.5]non-2-yl}prop-2-yn-1-one
C99
1-{2-[(4-bromophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-yl}-3-(4-
fluorophenyl)prop-2-yn-1-one or
L1
(2E)-3-(4-bromophenyl)-1-{2-[(4-chlorophenyl)carbonyl]-2,7-
diazaspiro[3.5]non-7-yl}prop-2-en-1-one.
18. The compound of claim 12 , or a pharmaceutically accceptable salt, or a pharmaceutically accepetable solvate thereof, wherein the compound is:
C6
(2E)-3-(4-bromophenyl)-1-{2-[(4-chlorophenyl)methyl]-2,7-
diazaspiro[3.5]non-7-yl}prop-2-en-1-one
C7
(2E)-3-(4-bromophenyl)-1-[2-(phenylcarbonyl)-2,7-diazaspiro[3.5]non-7-
yl]prop-2-en-1-one
C8
(2E)-3-(4-bromophenyl)-1-{2-[(4-fluorophenyl)methyl]-2,7-
diazaspiro[3.5]non-7-yl}prop-2-en-1-one
C9
(2E)-1-{2-[(3,4-dimethoxyphenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-yl}-3-(4-
bromophenyl)prop-2-en-1-one
C10
(2E)-1-{2-[(3,5-dichlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-yl}-3-(4-
bromophenyl)prop-2-en-1-one
C11
(2E)-1-{2-[(2,6-dichlorophenyl)methyl]-2,7-diazaspiro[3.5]non-7-yl}-3-(4-
bromophenyl)prop-2-en-1-one
C12
(2E)-3-(4-bromophenyl)-1-{2-[(3-methylphenyl)carbonyl]-2,7-
diazaspiro[3.5]non-7-yl}prop-2-en-1-one
C52
(2E)-3-(4-bromophenyl)-1-(2-{[4-fluoro-2-(trifluoromethyl)phenyl]carbonyl}-
2,7-diazaspiro[3.5]non-7-yl)prop-2-en-1-one
C53
(2E)-3-(4-bromophenyl)-1-{2-[(4-fluorophenyl)carbonyl]-2,7-
diazaspiro[3.5]non-7-yl}prop-2-en-1-one
C54
(2E)-3-(4-bromophenyl)-1-(2-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-en-1-one
C67
3-(4-bromophenyl)-1-{2-[(4-fluorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C68
3-(4-bromophenyl)-1-{2-[(4-fluorophenyl)methyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C69
3-(4-bromophenyl)-1-{2-[(4-chlorophenyl)methyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C70
3-(4-bromophenyl)-1-{2-[(4-chlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C71
3-(4-bromophenyl)-1-(2-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-yn-1-one
C72
3-(4-bromophenyl)-1-{2-[(4-bromophenyl)methyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C73
3-(4-bromophenyl)-1-(2-{[4-(trifluoromethyl)phenyl]methyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-yn-1-one
C74
3-(4-bromophenyl)-1-{2-[(4-methoxyphenyl)carbonyl]-2,7-diazaspiro[3.5]non-
7-yl}prop-2-yn-1-one
C75
3-(4-bromophenyl)-1-{2-[(4-methoxyphenyl)methyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C76
3-(4-chlorophenyl)-1-{2-[(4-chlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C77
3-(4-chlorophenyl)-1-{2-[(4-fluorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C78
3-(4-chlorophenyl)-1-(2-{[4-(trifluoromethyl)phenyl]methyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-yn-1-one
C79
3-(4-chlorophenyl)-1-(2-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-yn-1-one
C82
3-(4-chlorophenyl)-1-{2-[(4-chlorophenyl)methyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C86
3-(4-fluorophenyl)-1-{2-[(4-fluorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-
yl}prop-2-yn-1-one
C87
1-}2-[(4-chlorophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-yl}-3-(4-
fluorophenyl)prop-2-yn-1-one
C88
3-(4-fluorophenyl)-1-(2-{[4-(trifluoromethyl)phenyl]carbonyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-yn-1-one
C89
3-(4-fluorophenyl)-1-{2-[(4-methoxyphenyl)carbonyl]-2,7-diazaspiro[3.5]non-
7-yl}prop-2-yn-1-one
C90
3-(4-fluorophenyl)-1-(2-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-2,7-
diazaspiro[3.5]non-7-yl)prop-2-yn-1-one
C99
1-{2-[(4-bromophenyl)carbonyl]-2,7-diazaspiro[3.5]non-7-yl}-3-(4-
fluorophenyl)prop-2-yn-1-one or
L1
(2E)-3-(4-bromophenyl)-1-{2-[(4-chlorophenyl)carbonyl]-2,7-
diazaspiro[3.5]non-7-yl}prop-2-en-1-one.