# US 10,765,764 B2 · Probes for imaging huntingtin protein

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- Number: US 10,765,764 B2
- Document ID: US10765764B2
- Status: Granted
- Kind: B2
- Application number: 16/172,425
- Filed: 2018-10-26
- Published: 2019-06-06
- Granted: 2020-09-08
- Earliest claimed: 2015-08-28
- Assignees: CHDI Foundation, Inc.
- Applicants: CHDI Foundation, Inc.
- Inventors: Celia 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
- Web page: https://patentgrep.com/patent/US10765764B2

## CPC

- A61K 51/0455: {having six-membered rings with one nitrogen as the only ring hetero atom}
- A61K 51/0459: {having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine}
- C07B 59/002: {Heterocyclic compounds}
- C07D 487/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07D 513/14: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

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

## Claims

### 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 —CH2—;
X is S or N;
Y is CH or N;
Z is CH or N;
W is N;
for each occurrence, R1 is independently chosen from halo, lower alkoxy, hydroxy, aryl, heteroaryl, or cycloalkoxy, wherein the lower alkoxy, cycloalkoxy, 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; or R1 is lower alkyl optionally substituted with —NR4R5;
R2 is hydrogen or lower alkyl; and
R3 is pyridin-3-yl, pyridin-3-ylmethyl, 1-benzofuran-5-yl, 1H-pyrazol-4-yl, 6-oxo-1,6-dihydropyridazin-3-yl, pyrimidin-5-yl, 6-oxo-1,6-dihydropyridin-3-yl, pyridin-2-yl, pyridin-4-yl, pyrazin-2-yl, or 2-oxo-1,2-dihydropyrimidin-5-yl, 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, —(CH2)tNR4R5, cyano, and —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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

A compound of claim 1, wherein Y is CH.

### Claim 4 (depends on 1)

A compound of claim 1, wherein Y is N.

### Claim 5 (depends on 1)

A compound of claim 1, wherein Z is CH.

### Claim 6 (depends on 1)

A compound of claim 1, wherein Z is N.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

A compound of claim 1, wherein X is S.

### Claim 10 (depends on 1)

A compound of claim 1, wherein X is N.

### Claim 11 (depends on 1)

A compound of claim 1, wherein R2 is hydrogen.

### Claim 12 (depends on 1)

A compound of claim 1, wherein R2 is methyl.

### Claim 13 (depends on 1)

A compound of claim 1, wherein R3 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, 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, 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, 1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl, 5-(2-methoxyethoxy)pyridin-3-yl, or 6-(2-methoxyethoxy)pyridin-3-yl.

### Claim 14 (depends on 1)

A compound of claim 1, wherein n is 1.

### Claim 15 (depends on 1)

A compound of claim 1, wherein n is 2.

### Claim 16 (depends on 1)

A compound of claim 1, wherein m is 1.

### Claim 17 (depends on 1)

A compound of claim 1, wherein m is 2.

### Claim 18 (depends on 16)

A compound of claim 16, wherein, for each occurrence, R1 is independently chosen from halo, lower alkoxy, hydroxy, aryl, or heteroaryl, wherein the lower alkoxy, aryl, or heteroaryl are each optionally substituted with one to two groups independently selected from lower alkoxy, alkenyl, —NR4R5, halo, or heteroaryl optionally substituted with one to two lower alkoxy.

### Claim 19 (depends on 16)

A compound of claim 16, wherein, for each occurrence, R1 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.

### Claim 20 (depends on 1)

A compound of claim 1, wherein m is 0.

### Claim 21 (depends on 1)

A compound of claim 1, wherein each R4 is independently chosen from hydrogen or C1-3alkyl.

### Claim 22 (depends on 1)

A compound of claim 1, wherein each R5 is independently chosen from hydrogen or C1-3alkyl.

### Claim 23 (depends on 1)

A compound of claim 1, wherein each R6 is independently chosen from hydrogen or C1-3alkyl.

### Claim 24 (depends on 1)

A compound of claim 1, wherein each R7 is independently chosen from hydrogen or C1-3alkyl.

### Claim 25

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.

### Claim 26 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, excipient, or diluent.

### Claim 27 (depends on 25)

A pharmaceutical composition comprising a compound of claim 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, excipient, or diluent.