Probes for imaging huntingtin protein

Patent metadata

Field	Value
Publication number	US-11344637-B2
Application number	US-202016987277-A
Country	US
Kind code	B2
Filing date	Aug 6, 2020
Priority date	Aug 28, 2015
Publication date	May 31, 2022
Grant date	May 31, 2022

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 II(a):

or a pharmaceutically acceptable salt thereof, wherein
m is 0, 1, or 2;
n is 2;
X is N;
for each occurrence, R 1 is independently selected from halo, C 1 -C 6 alkoxy, hydroxy, aryl, heteroaryl, cycloalkoxy, and C 1 -C 6 alkyl, wherein the C 1 -C 6 alkoxy, aryl, heteroaryl, cycloalkoxy, and C 1 -C 6 alkyl are each optionally substituted with one, two, or three groups independently selected from C 1 -C 6 alkoxy, alkenyl, —NR 4 R 5 , halo, and heteroaryl optionally substituted with one to three C 1 -C 6 alkoxy;
R 2 is hydrogen or C 1 -C 6 alkyl; and
R 3 is aryl, heteroaryl, or heteroaralkyl, each of which is optionally substituted with one, two, or three groups independently selected from hydroxy, C 1 -C 6 alkoxy optionally substituted with C 1 -C 6 alkoxy or halo, C 1 -C 6 alkyl optionally substituted with halo, halo, heteroaryl, —(CH 2 ) t NR 4 R 5 , cyano, and —C(O)—NR 4 R 5 ;
tis 0, 1, or 2;
each R 4 is independently hydrogen or C 1 -C 6 alkyl;
each R 5 is independently hydrogen or C 1 -C 6 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 selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, halo, and —C(O)—NR 6 R 7 ;
each R 6 is independently hydrogen or C 1 -C 6 alkyl; and
each R 7 is independently hydrogen or C 1 -C 6 alkyl;

wherein the compound of Formula II(a), or a pharmaceutically acceptable salt thereof, is labeled with one or more positron-emitting radionuclides.

2. The imaging agent of claim 1 , wherein R 3 is aryl optionally substituted with one, two, or three groups independently selected from hydroxy, C 1 -C 6 alkoxy optionally substituted with C 1 -C 6 alkoxy or halo, C 1 -C 6 alkyl optionally substituted with halo, halo, heteroaryl, —(CH 2 ) t NR 4 R 5 , cyano, and —C(O)—NR 4 R 5 .

3. The imaging agent of claim 1 , wherein R 3 is heteroaryl optionally substituted with one, two, or three groups independently selected from hydroxy, C 1 -C 6 alkoxy optionally substituted with C 1 -C 6 alkoxy or halo, C 1 -C 6 alkyl optionally substituted with halo, halo, heteroaryl, —(CH 2 ) t NR 4 R 5 , cyano, and —C(O)—NR 4 R 5 .

4. The imaging agent of claim 1 , wherein R 3 is heteroaralkyl optionally substituted with one, two, or three groups independently selected from hydroxy, C 1 -C 6 alkoxy optionally substituted with C 1 -C 6 alkoxy or halo, C 1 -C 6 alkyl optionally substituted with halo, halo, heteroaryl, —(CH 2 ) t NR 4 R 5 , cyano, and —C(O)—NR 4 R 5 .

5. The imaging agent of claim 1 , wherein R 2 is hydrogen.

6. The imaging agent of claim 1 , wherein R 2 is methyl.

7. The imaging agent of claim 1 , wherein R 3 is pyridin-3-yl, pyridin-3-ylmethyl, 1-benzofuran-5-yl, 1H-pyrazol-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-4-yl, or pyrazin-2-yl, each of which is optionally substituted with one, two, or three groups independently selected from hydroxy, C 1 -C 6 alkoxy optionally substituted with C 1 -C 6 alkoxy, C 1 -C 6 alkyl optionally substituted with halo, halo, heteroaryl, —(CH 2 ) t NR 4 R 5 , cyano, and —C(O)—NR 4 R 5 .

8. The imaging agent of claim 1 , wherein R 3 is 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-1H-pyrazol-4-yl, 2-methylpyrimidin-5-yl, 6-(1H-imidazol-1-yl)pyridin-3-yl, 5-(pyridin-3-yl)pyridin-2-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, 3-[(methylamino)methyl]phenyl, 5-(2-methoxyethoxy)pyridin-3-yl, or 6-(2-methoxyethoxy)pyridin-3-yl.

9. The imaging agent of claim 1 , wherein m is 1.

10. The imaging agent of claim 1 , wherein m is 2.

11. The imaging agent of claim 1 , wherein, for each occurrence, R 1 is independently selected from halo, C 1 -C 6 alkoxy, hydroxy, aryl, heteroaryl, and C 1 -C 6 alkyl, wherein the C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, or heteroaryl are each optionally substituted with one to two groups independently selected from C 1 -C 6 alkoxy, alkenyl, —NR 4 R 5 , halo, and heteroaryl optionally substituted with one to two C 1 -C 6 alkoxy.

12. The imaging agent of claim 1 , wherein, for each occurrence, R 1 is independently selected from bromo, methoxy, 2-fluoroethoxy, prop-2-en-1-yloxy, (dimethylamino)methyl, phenyl, 5-methoxypyridin-3-yl, (5-methoxypyridin-2-yl)methoxy, and hydroxy.

13. The imaging agent of claim 1 , wherein m is 0.

14. An imaging agent comprising a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
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;
5-methoxy-N-(pyridin-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-(methylcarbamoyl)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(5-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-(1-methyl-6-oxo-1,6-dihydropyridazin-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-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(3-cyanopyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(5,6-dimethoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
5-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
5-methoxy-11-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene;
4-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
5-methoxy-N-(5-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-(1H-imidazol-1-yl)pyridin-3-yl]-5-methoxy-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(3-cyanopyridin-4-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(3-cyano-2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
5-methoxy-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-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N,5-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]trideca-2

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

• A61K51/0455 Primary

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

• A61K51/0459

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

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title