Spirocyclic EBI2 modulators

Patent metadata

Field	Value
Publication number	US-10196369-B2
Application number	US-201414910658-A
Country	US
Kind code	B2
Filing date	Sep 26, 2014
Priority date	Sep 26, 2013
Publication date	Feb 5, 2019
Grant date	Feb 5, 2019

Abstract

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.

First claim

What is claimed is:

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-

Assignees

• Sanford Burnham Prebys Medical Discovery Inst

Inventors

• Pinkerton Anthony B
• Ardecky Robert
• Sergienko Eduard A
• Gonzalez-Lopez Marcos
• Ganji Santhi Reddy
• Zou Jiwen

Classifications

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D295/16 Primary

  acylated on ring nitrogen atoms · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D333/56

  Radicals substituted by oxygen atoms · CPC title

• C07D295/26

  Sulfur atoms · CPC title