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