Probes for imaging Huntingtin protein

Patent metadata

Field	Value
Publication number	US-10137211-B2
Application number	US-201615249223-A
Country	US
Kind code	B2
Filing date	Aug 26, 2016
Priority date	Aug 28, 2015
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

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. An imaging agent comprising 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, cycloalkoxy, or lower alkyl, wherein the lower alkoxy, cycloalkoxy, lower alkyl, 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;
R 2 is hydrogen or lower alkyl; and
R 3 is alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, or heteroaralkyl, each of which is optionally substituted with one, two, or three groups independently chosen from hydroxy, lower alkoxy optionally substituted with lower alkoxy or halo, lower alkyl optionally substituted with halo, halo, heteroaryl, —(CH 2 ) t NR 4 R 5 , oxo, cyano, or —C(O)—NR 4 R 5 , or
R 2 and R 3 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 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;
wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is labeled with one or more positron-emitting radionuclides.

2. An imaging agent of claim 1 , wherein the compound is of Formula I(a):

3. An imaging agent of claim 1 , wherein Y is CH.

4. An imaging agent of claim 1 , wherein Y is N.

5. An imaging agent of claim 1 , wherein Z is CH.

6. An imaging agent of claim 1 , wherein Z is N.

7. An imaging agent of claim 1 , wherein the compound is of Formula I(a):

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

9. An imaging agent of claim 1 , wherein X is S.

10. An imaging agent of claim 1 , wherein X is N.

11. An imaging agent of claim 1 , wherein R 2 is hydrogen.

12. An imaging agent of claim 1 , wherein R 2 is methyl.

13. An imaging agent of claim 1 , wherein R 3 is chosen from pyridin-3-yl, pyri din-3-ylmethyl, 1-benzofuran-5-yl, 1H-pyrazol-4-yl, 6-oxo-1,6-dihydropyridazin-3-yl, pyrimidin-5-yl, ethyl, 6-oxo-1,6-dihydropyridin-3-yl, pyridin-2-yl, pyridin-4-yl, pyrazin-2-yl, 2-oxo-1,2-dihydropyrimidin-5-yl, or phenyl, each of which is optionally substituted with one or two 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, or —C(O)—NR 4 R 5 .

14. An imaging agent 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, pyridin-3-ylmethyl, 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, 2-(dimethylamino)ethyl, 2-methoxyethyl, 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, 3-pyridinyl-1-oxide, 1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl, 3-[(methylamino)methyl]phenyl, 5-(2-methoxyethoxy)pyridin-3-yl, or 6-(2-methoxyethoxy)pyridin-3-yl.

15. An imaging agent of claim 1 , wherein R 2 and R 3 taken together with the nitrogen to which they are bound form a heterocycloalkyl ring chosen from 2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl, indolin-1-yl, 4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl, or 4,6-dihydropyrrolo[3,4-b]pyrrol-5(1H)-yl, each of which is optionally substituted with one, two, or three groups independently chosen from hydroxy, lower alkoxy, lower alkyl, or halo.

16. An imaging agent of claim 1 , wherein n is 1.

17. An imaging agent of claim 1 , wherein n is 2.

18. An imaging agent of claim 1 , wherein m is 1.

19. An imaging agent of claim 1 , wherein m is 2.

20. An imaging agent of claim 18 , wherein R 1 is halo, lower alkoxy, hydroxy, aryl, heteroaryl, or lower alkyl, wherein the lower alkoxy, lower alkyl, aryl, or heteroaryl are each optionally substituted with one or two groups independently selected from lower alkoxy, alkenyl, —NR 4 R 5 , halo, or heteroaryl optionally substituted with one or two lower alkoxy.

21. An imaging agent of claim 18 , wherein R 1 is bromo, methoxy, 2-fluoroethoxy, prop-2-en-1-yloxy, (dimethylamino)methyl, phenyl, 5-methoxypyridin-3-yl, (5-methoxypyridin-2-yl)methoxy, or hydroxy.

22. An imaging agent of claim 1 , wherein m is 0.

23. An imaging agent of claim 1 , wherein each R 4 is independently chosen from hydrogen or C 1-3 alkyl.

24. An imaging agent of claim 1 , wherein each R 5 is independently chosen from hydrogen or C 1-3 alkyl.

25. An imaging agent of claim 1 , wherein each R 6 is independently chosen from hydrogen or C 1-3 alkyl.

26. An imaging agent of claim 1 , wherein each R 7 is independently chosen from hydrogen or C 1-3 alkyl.

27. An imaging agent, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
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 ]dod

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

• C07D487/04

  Ortho-condensed systems · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title

• A61K51/0459

  having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine · CPC title