Probes for imaging huntingtin protein

Patent metadata

Field	Value
Publication number	US-10479802-B2
Application number	US-201515507208-A
Country	US
Kind code	B2
Filing date	Aug 28, 2015
Priority date	Aug 29, 2014
Publication date	Nov 19, 2019
Grant date	Nov 19, 2019

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 (I), or a pharmaceutically acceptable salt thereof,

wherein
X is NR 4 , O, or S;
Y is CR 4 or N;
Z 1 , Z 2 , Z 3 , and Z 4 are independently chosen from CH and N, provided that at least two of Z 1 , Z 2 , Z 3 , and Z 4 are CH;
R 1 is heteroaryl, heterocycloalkenyl, or heterocycloalkyl, each of which is optionally substituted with one or two groups independently chosen from cyano, halo, lower alkyl optionally substituted with amino, alkylamino, or di(alkyl)amino, lower alkoxy optionally substituted with lower alkoxy, optionally substituted amino, haloalkyl, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl, or
R 1 is phenyl optionally substituted with one or two groups independently chosen from cyano, heteroaryl, halo, phenoxy, benzyloxy, heteroaryl, lower alkyl optionally substituted with amino, (alkyl)amino, or di(alkyl)amino, lower alkoxy, optionally substituted amino, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl;
L 1 is —O—;
L 2 is —(CR 7 R 8 ) m —;
L 3 is —CH═CH— or is absent;
R 2 is phenyl, pyridin-2-yl, pyridin-3-yl, pyrazin-2-yl, pyrimidin-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, or 1H-pyrazol-4-yl, each of which is optionally substituted with one or two groups independently chosen from halo; haloalkyl; hydroxyl; lower alkoxy; lower alkoxy substituted with lower alkoxy, amino, (alkyl)amino, (dialkyl)amino, heterocycloalkyl, heteroaryl, or halo; lower alkyl; and lower alkyl substituted with hydroxyl, lower alkoxy, amino, (alkyl)amino, or (dialkyl)amino;
R 4 is chosen from hydrogen, halo, cyano, and lower alkyl;
R 5 is chosen from lower alkyl, lower alkoxy, and halo;
R 7 is chosen from hydrogen, hydroxyl, trifluoromethyl, and lower alkyl;
R 8 is chosen from hydrogen and lower alkyl;
n is 0 or 1; and
m is 0, 1, or 2;
wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is labeled with one or more positron-emitting radionuclides.

2. The compound of claim 1 , wherein R 1 is phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl-1-oxide, pyridin-4-yl, 1H-pyrazol-4-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, 2,3-dihydropyridazin-3-one-6-yl, 1,2-dihydropyridin-2-one-5-yl, 1,2-dihydropyrazin-2-one-5-yl, 1,3-thiazol-5-yl, 5,6,7,8-tetrahydro-1,7-naphthyridine-7-yl, 1H-imidazol-1-yl, 1-benzofuran-2-yl, 1-benzofuran-5-yl, 2,3-dihydro-1-benzofuran-2-yl, quinolin-2-yl, or 5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl, each of which is optionally substituted with one or two groups independently chosen from halo, lower alkyl, lower alkoxy, and optionally substituted amino.

3. The compound of claim 1 , wherein R 1 is

wherein
W is CH, N, or N(O);
p is 0, 1, or 2;
for each occurrence, R 9 is independently chosen from cyano, halo, lower alkyl, lower alkyl substituted with —NR 10 R 11 , lower alkoxy, —C(O)NR 10 R 11 , and —NR 10 R 11 ;
R 10 is chosen from hydrogen and lower alkyl;
R 11 is chosen from hydrogen and lower alkyl.

4. The compound of claim 1 , wherein R 1 is

wherein
W 1 and W 2 are chosen from CH and N, provided that at least one of W 1 and W 2 is CH;
p is 0, 1, or 2; and
for each occurrence, R 9 is independently chosen from lower alkyl.

5. The compound of claim 1 , wherein X is O.

6. The compound of claim 1 , wherein X is S.

7. The compound of claim 1 , wherein X is NR 4 .

8. The compound of claim 1 , wherein Y is CR 4 .

9. The compound of claim 1 , wherein Y is N.

10. The compound of claim 1 , wherein Z 1 , Z 2 , Z 3 , and Z 4 are CH.

11. The compound of claim 1 , wherein Z 1 is N and Z 2 , Z 3 , and Z 4 are CH.

12. The compound of claim 1 , wherein Z 2 is N and Z 1 , Z 3 , and Z 4 are CH.

13. The compound of claim 1 , wherein Z 2 and Z 4 are N and Z 1 and Z 3 are CH.

14. A compound selected from:
tert-butyl 4-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]piperazine-1-carboxylate;
4-methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide;
4-methoxy-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]benzamide;
N-[(4-methoxyphenyl)methyl]-2-(pyridin-3-yl)-1,3-benzoxazol-5-amine;
2-(3-bromopyridin-4-yl)-6-[2-(morpholin-4-yl)ethoxy]-1,3-benzothiazole;
5-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide;
6-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide;
2-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyrimidine-5-carboxamide;
5-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyrazine-2-carboxamide;
4-methoxy-N-[2-(3-methylphenyl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]benzamide;
5-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazole;
N-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazol-5-amine;
2-(pyridin-3-yl)-N-{[1,2,4]triazolo[4,3-a]pyridin-3-yl}-1,3-benzoxazol-5-amine;
2-(pyridin-3-yl)-N-(pyrimidin-4-yl)-1,3-benzoxazol-5-amine;
2-(pyridin-3-yl)-N-(pyrimidin-2-yl)-1,3-benzoxazol-5-amine;
5-(5-methoxypyridin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;
5-(2-methoxypyrimidin-5-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;
5-(5-methoxypyrimidin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;
5-(6-methoxypyridazin-3-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;
5-(5-methoxypyrazin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;
1-methyl-4-[5-(pyrimidin-5-ylmethoxy)-1-benzofuran-2-yl]-1H-pyrazole-3-carbonitrile;
4-[5-(pyrimidin-5-ylmethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;
4-{5-[(5-methoxypyridin-2-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile;
4-{5-[(5-methoxypyridin-2-yl)methoxy]-1-benzofuran-2-yl}pyridine;
4-{5-[(1-methyl-1H-imidazol-4-yl)methoxy]-1-benzofuran-2-yl)}pyridine-3-carbonitrile;
4-{5-[(1-methyl-1H-imidazol-2-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile;
5-methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-2,3-dihydro-1H-isoindol-1-one;
3-{6-[(E)-2-(4-methoxyphenyl)ethenyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;
4-[5-(pyridin-3-yloxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;
6-methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2,3,4-tetrahydroisoquinolin-1-one;
dimethyl({3-[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenoxy]propyl})amine;
5-[(1-methyl-1H-pyrazol-4-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;
5-[(4-methoxyphenyl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;
5-[(3-methoxyphenyl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;
5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;
2-(pyridin-3-yl)-5-(pyridin-3-ylmethoxy)-1,3-benzoxazole;
5-{5H,6H-imidazo[2,1-b][1,3]thiazol-3-ylmethoxy}-2-(pyridin-3-yl)-1,3-benzoxazole;
1-(pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-ol;
1-(pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-one;
6-methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2-dihydroisoquinolin-1-one;
2-(pyridin-3-yl)-N-[2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl]-[1,3]oxazolo[5,4-b]pyridin-6-amine;
3-{6-[2-(4-methoxyphenyl)ethynyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;
3-{6-[(Z)-2-(4-methoxyphenyl)ethenyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;
5-methoxy-2-[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]-2,3-dihydro-1H-isoindol-1-one;
5-[(5-methoxypyraz

Assignees

• Chdi Foundation Inc

Inventors

• Dominguez Celia
• Coe Samuel
• Bard Jonathan
• Johnson Peter David
• Prime Michael Edward
• Brown Christopher John
• Galan Sébastien René Gabriel
• Giles Paul Richard
• Gadouleau Elise Luciennen Paulette
• Krülle Thomas Martin
• Clark-Frew Daniel
• Wityak John
• Kiselyov Alex
• Hayes Sarah

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K51/0463

  having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines · CPC title