Probes for imaging huntingtin protein

Patent metadata

Field	Value
Publication number	US-2019167821-A1
Application number	US-201816172425-A
Country	US
Kind code	A1
Filing date	Oct 26, 2018
Priority date	Aug 28, 2015
Publication date	Jun 6, 2019
Grant date	—

Abstract

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

First claim

1 . A compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein
m is 0, 1, or 2;
n is 1 or 2;
J is C(═O) or —CH 2 —;
X is S or N;
Y is CH or N;
Z is CH or N;
W is N or S;
for each occurrence, R 1 is independently chosen from halo, lower alkoxy, hydroxy, aryl, heteroaryl, cycloalkoxy, or lower alkyl, wherein the lower alkoxy, cycloalkoxy, lower alkyl, aryl, or heteroaryl are each optionally substituted with one, two, or three groups independently selected from lower alkoxy, alkenyl, —NR 4 R 5 , halo, or heteroaryl optionally substituted with one to three lower alkoxy;
R 2 is hydrogen or lower alkyl; and
R 3 is alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, or heteroaralkyl, each of which is optionally substituted with one, two, or three groups independently chosen from hydroxy, lower alkoxy optionally substituted with lower alkoxy or halo, lower alkyl optionally substituted with halo, halo, heteroaryl, —(CH 2 ) t NR 4 R 5 , oxo, cyano, or —C(O)—NR 4 R 5 , or
R 2 and R 3 taken together with the nitrogen to which they are bound form a heterocycloalkyl ring, optionally substituted with one, two, or three groups independently chosen from hydroxy, lower alkoxy, lower alkyl, halo, or —C(O)—NR 4 R 5 ;
t is 0, 1, or 2;
each R 4 is independently chosen from hydrogen or lower alkyl;
each R 5 is independently chosen from hydrogen or lower 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 chosen from hydroxy, lower alkoxy, lower alkyl, halo, or —C(O)—NR 6 R 7 ;
each R 6 is independently chosen from hydrogen or lower alkyl; and
each R 7 is independently chosen from hydrogen or lower alkyl.

2 . A compound of claim 1 , wherein the compound is of Formula I(a):

3 . A compound of claim 1 , wherein Y is CH.

4 . A compound of claim 1 , wherein Y is N.

5 . A compound of claim 1 , wherein Z is CH.

6 . A compound of claim 1 , wherein Z is N.

7 . A compound of claim 1 , wherein W is N.

8 . A compound of claim 1 , wherein W is S.

9 . A compound of claim 1 , wherein the compound is of Formula II(a):

10 . A compound of claim 1 , wherein the compound is Formula II(b):

11 . A compound of claim 1 , wherein X is S.

12 . A compound of claim 1 , wherein X is N.

13 . A compound of claim 1 , wherein R 2 is hydrogen.

14 . A compound of claim 1 , wherein R 2 is methyl.

15 . A compound of claim 1 , wherein R 3 is chosen from pyridin-3-yl, pyridin-3-ylmethyl, 1-benzofuran-5-yl, 1H-pyrazol-4-yl, 6-oxo-1,6-dihydropyridazin-3-yl, pyrimidin-5-yl, ethyl, 6-oxo-1,6-dihydropyridin-3-yl, pyridin-2-yl, pyridin-4-yl, pyrazin-2-yl, 2-oxo-1,2-dihydropyrimidin-5-yl, or phenyl, each of which is optionally substituted with one, two, or three groups independently chosen from hydroxy, lower alkoxy optionally substituted with lower alkoxy, lower alkyl optionally substituted with halo, halo, heteroaryl, —(CH 2 ) t NR 4 R 5 , cyano, or —C(O)—NR 4 R 5 .

16 . A compound of claim 1 , wherein R 3 is chosen from 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-6-oxo-1,6-dihydropyridazin-3-yl, 1-methyl-1H-pyrazol-4-yl, 2-methylpyrimidin-5-yl, 6-(1H-imidazol-1-yl)pyridin-3-yl, 2-(dimethylamino)ethyl, 2-methoxyethyl, 6-oxo-1,6-dihydropyridin-3-yl, 5-(pyridin-3-yl)pyridin-2-yl, 6-(methylcarbamoyl)pyridin-3-yl, 6-oxo-1,6-dihydropyridazin-3-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, 1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl, 3-[(methylamino)methyl]phenyl, 5-(2-methoxyethoxy)pyridin-3-yl, or 6-(2-methoxyethoxy)pyridin-3-yl.

17 . A compound of claim 1 , wherein R 2 and R 3 taken together with the nitrogen to which they are bound form a heterocyclo alkyl ring chosen from 2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl, indolin-1-yl, 4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl, or 4,6-dihydropyrrolo[3,4-b]pyrrol-5(1H)-yl, each of which is optionally substituted with one, two, or three groups independently chosen from hydroxy, lower alkoxy, lower alkyl, or halo.

18 . A compound of claim 1 , wherein n is 1.

19 . A compound of claim 1 , wherein n is 2.

20 . A compound of claim 1 , wherein m is 1.

21 . A compound of claim 1 , wherein m is 2.

22 . A compound of claim 20 , wherein, for each occurrence, R 1 is independently chosen from halo, lower alkoxy, hydroxy, aryl, heteroaryl, or lower alkyl, wherein the lower alkoxy, lower alkyl, aryl, or heteroaryl are each optionally substituted with one to two groups independently selected from lower alkoxy, alkenyl, —NR 4 R 5 , halo, or heteroaryl optionally substituted with one to two lower alkoxy.

23 . A compound of claim 20 , wherein, for each occurrence, R 1 is independently chosen from bromo, methoxy, 2-fluoroethoxy, prop-2-en-1-yloxy, (dimethylamino)methyl, phenyl, 5-methoxypyridin-3-yl, (5-methoxypyridin-2-yl)methoxy, or hydroxy.

24 . A compound of claim 1 , wherein m is 0.

25 . A compound of claim 1 , wherein each R 4 is independently chosen from hydrogen or C 1-3 alkyl.

26 . A compound of claim 1 , wherein each R 5 is independently chosen from hydrogen or C 1-3 alkyl.

27 . A compound of claim 1 , wherein each R 6 is independently chosen from hydrogen or C 1-3 alkyl.

28 . A compound of claim 1 , wherein each R 7 is independently chosen from hydrogen or C 1-3 alkyl.

29 . A compound, or a pharmaceutically acceptable salt thereof, selected from:
10-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-methoxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-methoxy-N-(pyridin-3-ylmethyl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-methoxy-N-methyl-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N-(1-benzofuran-5-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-hydroxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 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; 10-hydroxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-methoxy-N-(1-methyl-1H-pyrazol-4-yl)-7-thia-

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

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title

• C07D513/14

  Ortho-condensed systems · CPC title

• A61K51/0459

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