Probes for imaging huntingtin protein

Patent metadata

Field	Value
Publication number	US-10765764-B2
Application number	US-201816172425-A
Country	US
Kind code	B2
Filing date	Oct 26, 2018
Priority date	Aug 28, 2015
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

Provided are imaging agents comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and methods of their use.

First claim

The invention claimed is:

1. A compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein
m is 0, 1, or 2;
n is 1 or 2;
J is C(═O) or —CH 2 —;
X is S or N;
Y is CH or N;
Z is CH or N;
W is N;
for each occurrence, R 1 is independently chosen from halo, lower alkoxy, hydroxy, aryl, heteroaryl, or cycloalkoxy, wherein the lower alkoxy, cycloalkoxy, aryl, or heteroaryl are each optionally substituted with one, two, or three groups independently selected from lower alkoxy, alkenyl, —NR 4 R 5 , halo, or heteroaryl optionally substituted with one to three lower alkoxy; or R 1 is lower alkyl optionally substituted with —NR 4 R 5 ;
R 2 is hydrogen or lower alkyl; and
R 3 is pyridin-3-yl, pyridin-3-ylmethyl, 1-benzofuran-5-yl, 1H-pyrazol-4-yl, 6-oxo-1,6-dihydropyridazin-3-yl, pyrimidin-5-yl, 6-oxo-1,6-dihydropyridin-3-yl, pyridin-2-yl, pyridin-4-yl, pyrazin-2-yl, or 2-oxo-1,2-dihydropyrimidin-5-yl, each of which is optionally substituted with one, two, or three groups independently chosen from hydroxy, lower alkoxy optionally substituted with lower alkoxy, lower alkyl optionally substituted with halo, halo, heteroaryl, —(CH 2 ) t NR 4 R 5 , cyano, and —C(O)—NR 4 R 5 ;
t is 0, 1, or 2;
each R 4 is independently chosen from hydrogen or lower alkyl;
each R 5 is independently chosen from hydrogen or lower alkyl; or
R 4 and R 5 taken together with the nitrogen to which they are bound form a heterocycloalkyl ring, optionally substituted with one, two, or three groups independently chosen from hydroxy, lower alkoxy, lower alkyl, halo, or —C(O)—NR 6 R 7 ;
each R 6 is independently chosen from hydrogen or lower alkyl; and
each R 7 is independently chosen from hydrogen or lower alkyl.

2. A compound of claim 1 , wherein the compound is of Formula 1(a):

3. A compound of claim 1 , wherein Y is CH.

4. A compound of claim 1 , wherein Y is N.

5. A compound of claim 1 , wherein Z is CH.

6. A compound of claim 1 , wherein Z is N.

7. A compound of claim 1 , wherein the compound is of Formula II(a):

8. A compound of claim 1 , wherein the compound is Formula II(b):

9. A compound of claim 1 , wherein X is S.

10. A compound of claim 1 , wherein X is N.

11. A compound of claim 1 , wherein R 2 is hydrogen.

12. A compound of claim 1 , wherein R 2 is methyl.

13. A compound of claim 1 , wherein R 3 is chosen from pyridin-3-yl, 5-methoxypyridin-3-yl, 6-methoxypyridin-3-yl, 6-fluoropyridin-3-yl, 6-methylpyridin-3-yl, 6-(methylcarbamoyl)pyridin-3-yl, 1-benzofuran-5-yl, 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, 1-methyl-1H-pyrazol-4-yl, 2-methylpyrimidin-5-yl, 6-(1H-imidazol-1-yl)pyridin-3-yl, 6-oxo-1,6-dihydropyridin-3-yl, 5-(pyridin-3-yl)pyridin-2-yl, 6-(methylcarbamoyl)pyridin-3-yl, 6-oxo-1,6-dihydropyridazin-3-yl, 2-methoxypyridin-4-yl, 5,6-dimethoxypyridin-3-yl, 3-cyanopyridin-4-yl, 3-cyano-2-methoxypyridin-4-yl, 5-methoxypyridin-2-yl, pyridin-4-yl, pyrazin-2-yl, 1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl, 5-(2-methoxyethoxy)pyridin-3-yl, or 6-(2-methoxyethoxy)pyridin-3-yl.

14. A compound of claim 1 , wherein n is 1.

15. A compound of claim 1 , wherein n is 2.

16. A compound of claim 1 , wherein m is 1.

17. A compound of claim 1 , wherein m is 2.

18. A compound of claim 16 , wherein, for each occurrence, R 1 is independently chosen from halo, lower alkoxy, hydroxy, aryl, or heteroaryl, wherein the lower alkoxy, aryl, or heteroaryl are each optionally substituted with one to two groups independently selected from lower alkoxy, alkenyl, —NR 4 R 5 , halo, or heteroaryl optionally substituted with one to two lower alkoxy.

19. A compound of claim 16 , wherein, for each occurrence, R 1 is independently chosen from bromo, methoxy, 2-fluoroethoxy, prop-2-en-1-yloxy, (dimethylamino)methyl, phenyl, 5-methoxypyridin-3-yl, (5-methoxypyridin-2-yl)methoxy, or hydroxy.

20. A compound of claim 1 , wherein m is 0.

21. A compound of claim 1 , wherein each R 4 is independently chosen from hydrogen or C 1-3 alkyl.

22. A compound of claim 1 , wherein each R 5 is independently chosen from hydrogen or C 1-3 alkyl.

23. A compound of claim 1 , wherein each R 6 is independently chosen from hydrogen or C 1-3 alkyl.

24. A compound of claim 1 , wherein each R 7 is independently chosen from hydrogen or C 1-3 alkyl.

25. A compound, or a pharmaceutically acceptable salt thereof, selected from:
10-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(pyridin-3-ylmethyl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-methyl-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-(1-benzofuran-5-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-hydroxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(6-fluoropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
10-hydroxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(1-methyl-1H-pyrazol-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-(6-fluoropyridin-3-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(pyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-[6-(methylcarbamoyl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-4-{1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene;
10-methoxy-N-(6-methylpyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene;
10-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(2-methylpyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(pyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,

Assignees

• Chdi Foundation Inc

Inventors

• Dominguez Celia
• Wityak John
• Bard Jonathan
• Brown Christopher John
• Prime Michael Edward
• Johnson Peter David
• Krulle Thomas Martin
• Clark-Frew Daniel
• Higgins Duane
• Mills Matthew Robert
• Marston Richard Waldron
• Coe Samuel
• Brown Samantha
• Hayes Sarah

Classifications

• C07D513/14

  Ortho-condensed systems · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61K51/0455 Primary

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title