Substituted pyrrolo [2,3-d]pyrimidines for treating familial dysautonomia

Patent metadata

Field	Value
Publication number	US-12398140-B2
Application number	US-202017430566-A
Country	US
Kind code	B2
Filing date	Feb 10, 2020
Priority date	Feb 13, 2019
Publication date	Aug 26, 2025
Grant date	Aug 26, 2025

Abstract

The present description relates to compounds of formula (I) useful for improving pre-mRNA splicing in a cell. In particular, another aspect described herein relates to substituted pyrrolo[2,3-d]pyrimidine 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 pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
R 1 is phenyl or heteroaryl;
wherein the heteroaryl is a monocyclic or bicyclic 5-8 membered aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and
wherein the phenyl or heteroaryl is optionally substituted with one, two, three, or four Independently selected R 1a substituents;

each R 1a is independently halo, cyano, C 1-6 alkyl, deutero-C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, or C 1-6 alkoxy;
R 2 is hydrogen, halo, or C 1-6 alkyl;
R 3 is C 2-6 alkyl;
wherein the C 2-6 alkyl optionally contains a chiral carbon having an (R) configuration or (S) configuration; and
wherein the C 2-6 alkyl is optionally substituted with one, two, three, or four independently selected R 3a substituents;

each R 3a is independently halo, cyano, C 1-6 alkyl, deutero-C 1-6 alkyl, halo-C 1-6 alkyl, amino, C 1-6 alkyl-amino, deutero-C 1-6 alkyl-amino, (C 1-6 alkyl) 2 -amino, hydroxy, or C 1-6 alkoxy;
R 4 is hydrogen, C 1-6 alkyl, or phenyl, wherein the C 1-6 alkyl or phenyl is optionally substituted with one, two, three, or four independently selected R 4a substituents;
each R 4a is independently halo, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, or C 1-6 alkoxy; and
R 5 is hydrogen, halo, or C 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 is phenyl, furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, isoxazolyl, 1,3-oxazolyl, 1,3-thiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 is furanyl, thiophenyl, 1,3-oxazolyl, 1,3-thiazolyl, or pyridinyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 is C 2-6 alkyl containing a chiral carbon having an (R) configuration.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 is C 2-6 alkyl containing a chiral carbon having an (S) configuration.

6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient in admixture with a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

7. A method for treating familial dysautonomia in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

8. A compound selected from the group consisting of:
6-(3-aminopropyl)-2-chloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-(3-aminopropyl)-2-chloro-5-fluoro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
2-chloro-N-[(furan-2-yl)methyl]-6-[2-(methylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
2-chloro-N-[(furan-2-yl)methyl]-6-[2-(methylamino)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
2-chloro-6-[2-(methylamino)ethyl]-N-[(1,3-thiazol-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
2-chloro-5-fluoro-N-[(furan-2-yl)methyl]-6-[2-(methylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
2-chloro-6-[2-(dimethylamino)ethyl]-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-(2-aminoethyl)-2-chloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
2-chloro-N-[(furan-2-yl)methyl]-6-{2-[( 2 H 3 )methylamino]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-5-fluoro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(pyridin-4-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2,5-dichloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2R)-2-amino-3-methylbutyl]-2-chloro-5-fluoro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2R)-2-amino-3-methylbutyl]-2-chloro-5-fluoro-N-[(pyridin-4-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
2,5-dichloro-N-[(furan-2-yl)methyl]-6-[2-(methylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
5-bromo-2-chloro-N-[(furan-2-yl)methyl]-6-[2-(methylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-5-bromo-2-chloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(pyridin-4-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2,5-dichloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(1,3-thiazol-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2,5-dichloro-N-[(furan-2-yl)methyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-5-fluoro-N-[(furan-2-yl)methyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(thiophen-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(1,3-oxazol-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-5-butyl-2-chloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2R)-2-amino-3,3-dimethylbutyl]-2-chloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-3-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2R,3S)-2-amino-3-methylpentyl]-2-chloro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-5-fluoro-N-[(furan-2-yl)methyl]-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-5,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-5-fluoro-N-[(1,3-thiazol-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2R)-2-amino-3-methoxypropyl]-2-chloro-5-fluoro-N-[(furan-2-yl)methyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-5-fluoro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
(2R)-2-amino-3-(2-chloro-5-fluoro-4-{[(furan-2-yl)methyl]amino}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)propan-1-ol;
6-[(2S)-2-aminopropyl]-2-chloro-5-fluoro-N-[(thiophen-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-5-fluoro-N-[(3-fluoropyridin-4-yl)methyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-5-fluoro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-5-fluoro-7-methyl-N-[(pyridin-4-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-5-fluoro-N-[(furan-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-5-fluoro-N-[(furan-2-yl)methyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-5-fluoro-N-[(furan-2-yl)methyl]-7-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
6-[(2S)-2-amino

Assignees

• Ptc Therapeutics Inc

Inventors

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

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/00 Primary

  Drugs for disorders of the nervous system · CPC title