Probes for imaging huntingtin protein

Patent metadata

Field	Value
Publication number	US-11059836-B2
Application number	US-201916530594-A
Country	US
Kind code	B2
Filing date	Aug 2, 2019
Priority date	Aug 29, 2014
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

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 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 chosen from heteroaryl, heterocycloalkenyl, and 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, amino, alkylamino, di(alkyl)amino, haloalkyl, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl,
L 1 is —O— and L 2 is —(CR 7 R 8 ) m —;
L 3 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.

2. The compound of claim 1 , wherein R 1 is chosen from 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, quinolone-2-yl, and 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, alkylamino, di(alkyl)amino, and amino.

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

wherein
W is chosen from N and N(O);
p is chosen from 0, 1, and 2;
for each occurrence, R 9 is independently chosen from cyano, halo, lower alkyl, lower haloalkyl, 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; and
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 chosen from 0, 1, and 2; and
for each occurrence, R 9 is independently chosen from lower alkyl.

5. The compound of claim 1 , wherein R 2 is 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 lower alkyl, hydroxyl, lower alkoxy, lower alkoxy substituted with amino, (alkyl)amino, (dialkyl)amino, or lower alkoxy, lower alkyl, and lower alkyl substituted with hydroxyl, lower alkoxy, amino, (alkyl)amino, or (dialkyl)amino.

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

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

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 the compound is labeled with one or more positron-emitting radionuclides selected from: 11 C, 13 N, 15 O, and 18 F.

11. 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 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, 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 —NR 3 — and L 2 is —C(O)—, C—(R 7 R 8 ) m —, or —C(O)(R 7 R 8 ) m —;
L 3 is —CH═CH— or L 3 is absent;
R 2 is chosen from heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted with one or two groups chosen from
—OC(O)—R 6 ,
—C(O)O—R 6 ,
amino,
halo,
haloalkyl,
phenyl,
heteroaryl,
cyano,
(lower alkyl)thio,
phenoxy,
phenoxymethyl,
heteroaryloxy,
heteroaryloxy substituted with lower alkyl,
hydroxyl,
lower alkenyloxy,
lower alkoxy,
lower alkoxy substituted with lower alkoxy, amino, (alkyl)amino, (dialkyl)amino, heterocycloalkyl, heteroaryl, or halo,
lower alkyl, and
lower alkyl substituted with amino, (alkyl)amino, (dialkyl)amino, hydroxyl or lower alkoxy;

R 3 is chosen from hydrogen and lower alkyl;
R 4 is chosen from hydrogen, halo, cyano, and lower alkyl;
R 5 is chosen from lower alkyl, lower alkoxy, and halo;
R 6 is lower alkyl;
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.

12. The compound of claim 1 , wherein R 1 is heterocycloalkenyl.

13. The compound of claim 1 , wherein R 1 is 2,3-dihydropyridazin-3-one-6-yl optionally substituted with one or two groups independently chosen from halo, lower alkyl, lower alkoxy, alkylamino, di(alkyl)amino, and amino.

14. The compound of claim 1 , wherein R 1 is 2,3-dihydropyridazin-3-one-6-yl substituted with one or two lower alkyl groups.

15. The compound of claim 1 , wherein R 2 is pyridin-2-yl 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.

16. The compound of claim 1 , wherein R 2 is pyridin-2-yl substituted with lower alkoxy.

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

18. The compound of claim 11 , wherein R 1 is heterocycloalkenyl.

19. The compound of claim 11 , w

Assignees

• Chdi Foundation Inc

Inventors

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

Classifications

• C07D413/04 Primary

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

• A61K51/0455 Primary

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

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title