IP Library › Granted Patent US 10,881,658

Granted Patent B2

US 10,881,658 · App. 16/710,515 · Granted Jan 5, 2021

Methods for treating Huntington's disease

Inventors: Suresh Babu (Pennington, NJ); Anuradha Bhattacharyya (Edison, NJ); Seongwoo Hwang (Edison, NJ); Minakshi Jani (Iselin, NJ); Young-choon Moon (Belle Mead, NJ); Nadiya Sydorenko (Princeton, NJ)

Assignee: PTC Therapeutics, Inc.

A61K31/506 A61K31/415 A61K31/433 A61K31/4439 A61K31/4709 A61K31/50 A61K31/501 A61K31/517 A61K31/5377 A61K31/5513 A61P25/28 C07D237/20 C07D401/04 C07D401/12 C07D401/14 C07D403/10 C07D403/12 C07D403/14 C07D405/12 C07D405/14 C07D409/14 C07D413/14 C07D417/04 C07D417/10 C07D417/12 C07D417/14 C07D471/08 C07D471/10 C07D487/04 C07D487/08 C07D487/10 G01N33/6896 G01N2800/2835

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 10,881,658
App. No.: 16/710,515
Granted: Jan 5, 2021
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present description relates to compounds, forms, and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease. In particular, the present description relates to substituted monocyclic heteroaryl compounds of Formula (I), forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease.

Claims (203)

1. A compound of Formula (Ia11):

or a form thereof, wherein (when present),

X is selected from O, NR 5a , or a bond;

A is selected from phenyl, thiophenyl, indazolyl, pyridinyl, pyrimidinyl or phenoxy,

wherein phenyl and phenoxy are each optionally substituted with 1, 2 or 3 substituents each selected from R 1a ,

wherein thiophenyl, indazolyl, pyridinyl, pyrimidinyl are each optionally substituted with 1 or 2 substituents each selected from R 1a ,

R 1a is selected from halogen, hydroxyl, C 1-4 alkyl, halo-C 1-4 alkyl, amino, C 1-4 alkoxy, or heteroaryl,

wherein heteroaryl is a monocyclic, bicyclic, or polycyclic carbon atom ring structure radical having one or more heteroatoms selected from O, S, and N, optionally substituted with 1 or 2 substituents each selected from R 3a ;

wherein when A is phenyl, R 1a is not chloro or pyrazolyl;

R 3a is selected from nitro or C 1-4 alkyl;

R 4a is C 1-4 alkyl;

R 5a is hydrogen, C 1-4 alkyl, or hydroxyl-C 1-4 alkyl;

wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

2. The compound of claim 1 wherein (when present):

R 1a is selected from fluoro, chloro, hydroxyl, methyl, difluoromethyl, amino, methoxy, 1H-pyrazolyl or 1H-imidazol-1-yl,

wherein 1H-pyrazolyl is optionally substituted with 1 or 2 substituents each selected from R 3a ;

R 3a is selected from nitro or methyl; and,

R 4a is methyl or ethyl;

R 5a is hydrogen or methyl;

wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

3. A compound, or form thereof, selected from the group consisting of:

2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl(methyl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol,

2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol,

5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol,

5-(1-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol,

2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol,

5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol,

5-(1H-imidazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol,

5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol,

2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H-pyrazol-1-yl)phenol,

6-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,

5-(4-amino-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol,

2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol,

5-(4-nitro-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol,

5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol,

2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol,

2-{6-[methyl(piperidin-4-yl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol,

2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol,

6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,

2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol,

6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,

3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

2-[6-(piperidin-4-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol,

2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol,

6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,

3-[4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol,

3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

3-[4-(i-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol,

3-fluoro-4-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol,

2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-1-yl)phenol,

N-methyl-6-(2-methyl-2H-indazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,

2-methyl-5-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}-2H-indazole,

3-(4-chloro-2-methoxyphenyl)-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

N-methyl-6-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,

6-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}imidazo[1,2-a]pyridine,

3-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

3-[5-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol,

6-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,

3-methoxy-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol,

3-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}benzene-1,3-diol,

6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,

2-(1H-pyrazol-4-yl)-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}pyrimidin-5-amine,

3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine,

2-[6-(2,6-diazaspiro[3.4]oct-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol,

3-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4-yl)pyridin-2-ol,

6-(1H-pyrazol-4-yl)-3-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}pyridin-2-ol,

N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2-yl}piperidin-4-amine,

N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2-yl}piperidin-4-amine,

3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine, and

6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;

wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

4. The compound of claim 3 , wherein the compound is a compound salt selected from the group consisting of:

2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl(methyl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol hydrochloride,

2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride,

5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol hydrochloride,

2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride,

2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H-pyrazol-1-yl)phenol dihydrochloride,

2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride,

5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol trihydrochloride,

2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride,

2-{6-[methyl(piperidin-4-yl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride,

2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride,

6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine tetrahydrochloride,

2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride,

6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride,

3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine trihydrochloride,

2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol hydrochloride,

6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride,

2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol trihydrochloride,

3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine hydrochloride,

2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride,

3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine hydrochloride,

3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine hydrochloride,

6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine trihydrochloride,

3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine trihydrochloride,

3-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4-yl)pyridin-2-ol hydrochloride,

N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2-yl}piperidin-4-amine hydrochloride,

N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2-yl}piperidin-4-amine hydrochloride,

3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine hydrochloride, and

6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride;

wherein a form of the compound salt is selected from the group consisting of a hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

5. The compound of claim 1 , wherein A is selected from thiophenyl, indazolyl, pyridinyl, pyrimidinyl and phenoxy.

6. The compound of claim 1 , wherein when A is phenyl, R 1a is not hydroxyl.

7. A compound of Formula (Ia11):

or a form thereof, wherein (when present),

X is selected from O, NR 5a , or a bond;

A is selected from phenyl, thiophenyl, indazolyl, pyridinyl, pyrimidinyl or phenoxy,

wherein phenyl and phenoxy are each optionally substituted with 1, 2 or 3 substituents each selected from R 1a ,

wherein thiophenyl, indazolyl, pyridinyl, pyrimidinyl are each optionally substituted with 1 or 2 substituents each selected from R 1a ,

R 1a is selected from halogen, hydroxyl, C 1-4 alkyl, halo-C 1-4 alkyl, amino, C 1-4 alkoxy, or heteroaryl,

wherein when A is phenyl, R 1a is not hydroxyl;

R 3a is selected from nitro or C 1-4 alkyl;

R 4a is C 1-4 alkyl;

R 5a is hydrogen, C 1-4 alkyl, or hydroxyl-C 1-4 alkyl;

wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

8. The compound of claim 7 , wherein A is selected from thiophenyl, indazolyl, pyridinyl, pyrimidinyl and phenoxy.

9. The compound of claim 7 , wherein (when present):

R 1a is selected from fluoro, chloro, hydroxyl, methyl, difluoromethyl, amino, methoxy, 1H-pyrazolyl or 1H-imidazol-1-yl,

wherein 1H-pyrazolyl is optionally substituted with 1 or 2 substituents each selected from R 3a ;

R 3a is selected from nitro or methyl; and,

R 4a is methyl or ethyl;

R 5a is hydrogen or methyl;

wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

10. A compound selected from a compound Formula (Ia15) and Formula (Ia18):

or a form thereof, wherein (when present),

X is selected from O, NR 5a , or a bond;

B is selected from 1H-pyrazolyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, 2,6-diazaspiro[3.4]octyl or 2,7-diazaspiro[3.5]nonyl, each optionally substituted with 1 or 2 substituents each selected from R 4a ;

R 1a is selected from halogen, hydroxyl, C 1-4 alkyl, halo-C 1-4 alkyl, amino, C 1-4 alkoxy, or heteroaryl,

wherein R 1a is not chloro or pyrazole;

R 3a is selected from nitro or C 1-4 alkyl; and,

R 4a is C 1-4 alkyl;

R 5a is hydrogen, C 1-4 alkyl, or hydroxyl-C 1-4 alkyl;

wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

11. The compound of claim 10 , wherein (when present):

R 1a is selected from fluoro, hydroxyl, methyl, difluoromethyl, amino, methoxy, or 1H-imidazol-1-yl,

R 3a is selected from nitro or methyl; and,

R 4a is methyl or ethyl;

R 5a is hydrogen or methyl;

wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

12. The compound, or form thereof, of claim 3 selected from the group consisting of: