Thioeno[3,2-b] pyridin-7-amine compounds for treating familial dysautonomia

Patent metadata

Field	Value
Publication number	US-12384797-B2
Application number	US-202017430511-A
Country	US
Kind code	B2
Filing date	Feb 10, 2020
Priority date	Feb 13, 2019
Publication date	Aug 12, 2025
Grant date	Aug 12, 2025

Abstract

The present description relates' to compounds of formula (I) useful for improving pre-mRNA splicing in a cell. In particular, another aspect of the present description relates to substituted thieno[3,2-b]pyridine compounds, forms, and pharmaceutical compositions thereof and methods of use for treating or ameliorating familial dysautonomia.

First claim

What is claimed is:

1. A compound of Formula (I):

or a form thereof, wherein
R 1 is selected from the group consisting of phenyl and heteroaryl, optionally substituted with one, two, three, or four independently selected Ria substituents,
wherein heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure radical containing 1-3 heteroatoms selected from N, O, and S;
R 1a is selected from the group consisting of cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, and C 1-6 alkoxy;
R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 alkyl-amino,
wherein each instance of C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one, two, three, or four independently selected R 3a substituents, and
wherein each instance of C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl may optionally contain a chiral carbon having an (R) or(S) configuration;
R 3a is selected from the group consisting of cyano, halo, hydroxy, oxo, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, carboxyl, amino, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-amino, halo-C 1-6 alkyl-amino, (C 1-6 alkyl) 2-amino, phenyl-amino, heterocyclyl-amino, heteroaryl-amino, phenyl-(C 1-6 alkyl)-amino, heterocyclyl-(C 1-6 alkyl)-amino, heteroaryl-(C 1-6 alkyl)-amino, C 1-6 alkyl-thio, C 1-6 alkyl-sulfoxyl, and C 1-6 alkyl-sulfonyl,
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure radical containing 1-3 heteroatoms selected from N, O, and S,
wherein heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure radical containing 1-3 heteroatoms selected from N, O, and S, and
wherein each instance of phenyl, heterocyclyl, and heteroaryl is optionally substituted with one, two, three or four independently selected R 3a′ substituents;
R 3a′ is selected from the group consisting of cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, and amino;
R 4 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, amino, C 1-6 alkyl-amino, (C 1-6 alkyl) 2-amino, C 3-10 cycloalkyl, phenyl, heterocyclyl, and heteroaryl,
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure radical containing 1-3 heteroatoms selected from N, O, and S,
wherein heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure radical containing 1-3 heteroatoms selected from N, O, and S, and
wherein each instance of C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one, two, three, or four independently selected R 4a substituents;
R 4a is selected from the group consisting of cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, and C 1-6 alkoxy;
R 5 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, carbamoyl, C 3-10 cycloalkyl, and heterocyclyl,
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure radical containing 1-3 heteroatoms selected from N, O, and S;
R 6 is selected from the group consisting of hydrogen, halo, and C 1-6 alkyl; and
wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, and tautomer form thereof.

2. The compound of claim 1 wherein R 1 is selected from the group consisting of phenyl, furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, isoxazolyl, 1,3-thiazolyl, 1,3-oxazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

3. The compound of claim 2 wherein R 1 is selected from the group consisting of furanyl, thiophenyl, 1,3-thiazolyl, and pyridinyl.

4. The compound of claim 1 wherein R 3 is C 1-6 alkyl containing a chiral carbon having the(S) configuration.

5. The compound of claim 1 wherein R 3 is C 1-6 alkyl containing a chiral carbon having the (R) configuration.

6. A compound, or a form thereof, wherein the compound is selected from the group consisting of:
5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine;
1-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)ethan-1-ol;
1-(5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)ethan-1-ol;
(5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)methanol;
3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
3-chloro-5-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
3-bromo-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile;
7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-3,5-dicarbonitrile;
5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-3-carbonitrile;
5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-3-carbonitrile;
7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-3,5-dicarbonitrile;
2-[(2S)-2-aminopropyl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
(2R)-2-amino-3-(5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)propan-1-ol;
2-[(2S)-2-aminopropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine;
2-[(2S)-2-aminobutyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine;
2-[(2S)-2-aminopropyl]-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridine-5-carbonitrile;
2-[(1S)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine;
2-[(1R)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine;
2-[(1R)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
2-[(1S)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
5-chloro-N-[(furan-2-yl)methyl]-2-[(methylamino)methyl]thieno[3,2-b]pyridin-7-amine;
5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(1S)-1-(methylamino)ethyl]thieno[3,2-b]pyridin-7-amine;
5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(methylamino)methyl]thieno[3,2-b]pyridin-7-amine;
2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
2-[(2S)-2-aminopropyl]-5-chloro-N-[(2-fluorophenyl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine;
2-[(1S)-1-amino-2-methylpropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine;
2-[(1R)-1-amino-2-methylpropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine;
5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(1S)-2-methyl-1-(methylamino)propyl]thieno[3,2-b]pyridin-7-amine;
2-[(2S)-2-aminobutyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
2-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine;
2-[(2S)-2-aminopropyl]-5-chloro-N-[(3-fluoropyridin-4-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine;
2-[(2S)-2-aminopropyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
2-[(2S)-2-aminopropyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
2-[(2S)-2-aminopropyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine;
(2R)-2-amino-3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)prop

Assignees

• Ptc Therapeutics Inc

Inventors

• Zhang Nanjing
• Arnold Michael A
• Dakka Amal
• Karp Gary Mitchell
• Luong Tom Tuan
• Narasimhan Jana
• Naryshkin Nikolai A
• Wang Jiashi
• Zhang Xiaoyan

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/4365

  the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title