Probes for imaging huntingtin protein

Patent metadata

Field	Value
Publication number	US-12036291-B2
Application number	US-202117353611-A
Country	US
Kind code	B2
Filing date	Jun 21, 2021
Priority date	Aug 29, 2014
Publication date	Jul 16, 2024
Grant date	Jul 16, 2024

Abstract

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

First claim

What is claimed is:

1. A compound of Formula:

or a pharmaceutically acceptable salt thereof, wherein
Z 1 , Z 2 , Z 3 , and Z 4 are independently chosen from C, CH, and N, provided that one of Z 1 , Z 2 , Z 3 , and Z 4 is C and at least one of Z 1 , Z 2 , Z 3 , and Z 4 is CH;
R 1 is chosen from 5-cyano-pyrimidin-4-yl, pyridin-4-yl, 5-bromo-1,2-dihydropyridin-2-one-3-yl, 3-acetamido-pyridin-4-yl, 2-acetamido-pyridin-6-yl, 3-cyano-pyridin-4-yl, 3-cyano-pyridin-6-yl, 3-bromo-pyridin-4-yl, 3-bromo-pyridin-2-yl, 3-cyano-pyridin-2-yl, 3-fluoro-pyridin-4-yl, 2-cyano-pyridin-4-yl, 4-cyano-pyridin-3-yl, 3-ethynyl-pyridin-4-yl, or 2,3-dihydropyridazin-3-one-6-yl optionally substituted with lower alkyl;
L 1 is O;
L 2 is (CH 2 ) m where m is 0, 1, or 2;
R 2 is chosen from hydrogen, aryl, aryl substituted with hydroxyl or lower alkoxy, heteroaryl, and heteroaryl substituted with hydroxyl or lower alkoxy;
R 5 is oxo; and
n is 0 or 1.

2. The compound of claim 1 , wherein R 1 is chosen from 5-cyano-pyrimidin-4-yl, pyridin-4-yl, 5-bromo-1,2-dihydropyridin-2-one-3-yl, 3-acetamido-pyridin-4-yl, 2-acetamido-pyridin-6-yl, 3-cyano-pyridin-4-yl, 3-cyano-pyridin-6-yl, 3-bromo-pyridin-4-yl, 3-bromo-pyridin-2-yl, 3-cyano-pyridin-2-yl, 3-fluoro-pyridin-4-yl, 2-cyano-pyridin-4-yl, 4-cyano-pyridin-3-yl, and 3-ethynyl-pyridin-4-yl.

3. The compound of claim 2 , wherein R 1 is pyridin-4-yl, 5-cyano-pyrimidin-4-yl, or 3-cyano-pyridin-4-yl.

4. The compound of claim 1 , wherein R 1 is 2,3-dihydropyridazin-3-one-6-yl optionally substituted with lower alkyl.

5. The compound of claim 1 , wherein m is 1.

6. The compound of claim 1 , wherein R 2 is chosen from hydrogen, phenyl, pyridin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyrimidin-5-yl, each of which, other than hydrogen, is optionally substituted with hydroxyl or lower alkoxy.

7. The compound of claim 1 , wherein three of Z 1 , Z 2 , Z 3 , and Z 4 are CH and one is C.

8. The compound of claim 1 , wherein Z 1 is N; and two of Z 2 , Z 3 , and Z 4 are CH and one is C.

9. The compound of claim 1 , wherein Z 2 is N; and Z 1 , Z 3 , and Z 4 are CH or C.

10. The compound of claim 1 , wherein Z 2 and Z 4 are N; and one of Z 1 and Z 3 is CH and the other is C.

11. A compound, or a pharmaceutically acceptable salt thereof, chosen from:
2-(5-methoxy-2,3-dihydro-1H-isoindol-2-yl)pyridine-3-carbonitrile;
2-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyridine-3-carbonitrile;
2-[5-(pyrimidin-5-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]pyridine-3-carbonitrile;
4-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyridine-3-carbonitrile;
4-(5-methoxy-2,3-dihydro-1H-isoindol-2-yl)pyrimidine-5-carbonitrile;
4-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyrimidine-5-carbonitrile;
4-{5-[(5-hydroxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyridine-3-carbonitrile;
4-(5-methoxy-2,3-dihydro-1H-isoindol-2-yl)pyridine-3-carbonitrile;
4-[5-(pyrimidin-5-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]pyridine-3-carbonitrile;
5-[(5-methoxypyrazin-2-yl)methoxy]-2-(pyridin-4-yl)-2,3-dihydro-1H-isoindole;
4-[5-(benzyloxy)-2,3-dihydro-1H-isoindol-2-yl]pyrimidine-5-carbonitrile;
4-{5-[(5-hydroxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyrimidine-5-carbonitrile;
6-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one; and
5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridin-4-yl)-2,3-dihydro-1H-isoindol-1-one.

Assignees

• Chdi Foundation Inc

Inventors

• Dominguez Celia
• Wityak John
• Bard Jonathan
• Brown Christopher John
• Krülle Thomas Martin
• Clark-Frew Daniel
• Hayes Sarah

Classifications

• C07D513/14

  Ortho-condensed systems · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07B2200/05

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

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title