US 2019/0167821 A1Published application

Probes for imaging huntingtin protein

AssigneeCHDI Foundation, Inc.

InventorsCelia Dominguez, John Wityak, Jonathan Bard, Christopher John Brown, Michael Edward Prime, Peter David Johnson, Thomas Martin Krulle, Daniel Clark-Frew, Duane Higgins, Matthew Robert Mills, Richard Waldron Marston, Samuel Coe, Samantha Brown, Sarah Hayes

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Abstract

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

Claims32

Dependent claims

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 —CH2—;
X is S or N;
Y is CH or N;
Z is CH or N;
W is N or S;
for each occurrence, R1 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, —NR4R5, halo, or heteroaryl optionally substituted with one to three lower alkoxy;
R2 is hydrogen or lower alkyl;
and
R3 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, —(CH2)tNR4R5, oxo, cyano, or —C(O)—NR4R5, or
R2 and R3 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)—NR4R5;
t is 0, 1, or 2;
each R4 is independently chosen from hydrogen or lower alkyl;
each R5 is independently chosen from hydrogen or lower alkyl;
or
R4 and R5 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)—NR6R7;
each R6 is independently chosen from hydrogen or lower alkyl;
and
each R7 is independently chosen from hydrogen or lower alkyl.

18 more elements

A compound, or a pharmaceutically acceptable salt thereof, selected from:

10-methoxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(pyridin-3-ylmethyl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-methyl-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-(1-benzofuran-5-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-hydroxy-N-(6-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(6-fluoropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
10-hydroxy-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(1-methyl-1H-pyrazol-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-(6-fluoropyridin-3-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(pyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-[6-(methylcarbamoyl)pyridin-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-4-{1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene;
10-methoxy-N-(6-methylpyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene;
10-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(2-methylpyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(pyrimidin-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-[2-(dimethylamino)ethyl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(2-methoxyethyl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(6-oxo-1,6-dihydropyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-[5-(pyridin-3-yl)pyridin-2-yl]-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
5-methoxy-N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-[6-(methylcarbamoyl)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(3-cyanopyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(5,6-dimethoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
5-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
5-methoxy-11-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene;
4-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
5-methoxy-N-(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-[6-(1H-imidazol-1-yl)pyridin-3-yl]-5-methoxy-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(3-cyanopyridin-4-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-(3-cyano-2-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
5-methoxy-N-(6-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
10-methoxy-N-(5-methoxypyridin-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(pyridin-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(pyrazin-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
3-{10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-amido}pyridin-1-ium-1-olate;
10-(2-fluoroethoxy)-N-(pyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;
N-({10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaen-4-yl}methyl)pyridin-3-amine;
10-[(5-methoxypyridin-2-yl)methoxy]-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
11-bromo-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-10-(prop-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-(5-methoxypyridin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide;
10-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,6,8,10-pentaene-4-carboxamide;
10-methoxy-N-(2-methylpyrimidin-5-yl)-5-thia-2,7-diazatricyclo[6.4.0.02,6]dodeca-1(8),3,6,9,11-pentaene-4-carboxamide;
N-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
11-methoxy-N-(5-methoxypyridin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
11-methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
10-methoxy-N-{3-[(methylamino)methyl]phenyl}-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;
10-[(dimethylamino)methyl]-N-(5-methoxypyridin-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N-(5-methoxypyridin-3-yl)-10-phenyl-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxamide;
N,5-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N,4-bis(5-methoxypyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide;
N-[5-(2-methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide and
N-[6-(2-methoxyethoxy)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide.

66 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/172,425Filed 26 Oct 2018
Priority: 28 Aug 2015
Published: 6 Jun 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

A61K 51/0455
Having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins: having six-membered rings with one nitrogen as the only ring hetero atom
A61K 51/0459
Having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins: having six-membered rings with two nitrogen atoms as the only ring hetero…
C07B 59/002
Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se: heterocyclic compounds
C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems

Family

Application62/211,118Us provisional application · filed 28 Aug 2015
Application15/249,223Continuation · filed 26 Aug 2016
Application16/172,425Continuation
US 10,137,211 B2Related patent
US 10,765,764 B2Related patent
US 2017/0056535 A1Published application
US 2019/0167821 A1This patent

From the US filing history. Foreign family members aren’t listed.

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