Compounds for treating spinal muscular atrophy

Patent metadata

Field	Value
Publication number	US-10851101-B2
Application number	US-201916541401-A
Country	US
Kind code	B2
Filing date	Aug 15, 2019
Priority date	Feb 10, 2012
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

Abstract

Provided herein are compounds of Formula (I):

and forms thereof, including compositions thereof and uses therewith for treating spinal muscular atrophy.

First claim

What is claimed is:

1. A method for enhancing the inclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene, comprising contacting a human cell with a compound of Formula (IIa1):

or a free acid, free base, salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof, wherein:
R 1 is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl and 6,9-diazaspiro[4.5]decyl;
wherein, each instance of heterocyclyl is optionally substituted with one, two or three R 3 substituents and optionally, with one additional R 4 substituent;
R 2 is phenyl or heteroaryl;
wherein, R 2 is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R 7 substituent;
R a is, in each instance, independently selected from hydrogen, halogen or C 1-8 alkyl;
R b is hydrogen, halogen, C 1-8 alkyl or C 1-8 alkoxy;
R c is hydrogen, halogen or C 1-8 alkyl;
R 3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkoxy-carbonyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl] 2 -amino, (C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, C 1-8 alkoxy-C 1-8 alkyl-amino, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino, C 1-8 alkyl-carbonyl-amino, C 1-8 alkoxy-carbonyl-amino, hydroxy-C 1-8 alkyl, hydroxy-C 1-8 alkoxy-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl) 2 -amino or (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino;
R 4 is C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, C 3-14 cycloalkyl-amino, aryl-C 1-8 alkyl, aryl-C 1-8 alkoxy-carbonyl, aryl-sulfonyloxy-C 1-8 alkyl, heterocyclyl or heterocyclyl-C 1-8 alkyl; wherein, each instance of C 3-14 cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R 5 substituents;
R 5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino or C 1-8 alkyl-thio;
R 6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, halo-C 1-8 alkyl, hydroxy-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino or C 1-8 alkyl-thio; and,
R 7 is C 3-14 cycloalkyl, C 3-14 cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

2. The method of claim 1 , wherein R 2 is heteroaryl selected from furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl and quinoxalinyl; wherein, each instance of heteroaryl is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R 7 substituent.

3. The method of claim 1 , wherein R 3 is C 1-8 alkyl selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

4. The method of claim 1 , wherein R 6 is C 1-8 alkyl selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

5. The method of claim 1 , wherein R a is, in each instance, hydrogen.

6. The method of claim 1 , wherein R b is C 1-8 alkyl.

7. The method of claim 1 , wherein R c is hydrogen or C 1-8 alkyl.

8. The method of claim 1 , wherein the salt form is a chloride, hydrobromide, hydrochloride, dihydrochloride, acetate, trifluoroacetate or trifluoroacetic acid salt.

9. The method of claim 1 , wherein the compound is selected from the group consisting of:
2-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(5-fluoropyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(5-fluoropyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(5-chloropyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(5-chloropyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(5-chloro-6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(1H-indol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(1H-indol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(imidazo[1,2-a]pyridin-7-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(imidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one,
7-(1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,
2-(6,8-dimethylimidazo[1,2-a]py

Assignees

• Ptc Therapeutics Inc
• F Hoffmann—La Roche Ag
• Hoffmann La Roche

Inventors

• Qi Hongyan
• Choi Soongyu
• Dakka Amal
• Karp Gary Mitchell
• Narasimhan Jana
• Naryshkin Nikolai
• Turpoff Anthony A
• Weetall Marla L
• Welch Ellen
• Woll Matthew G
• Yang Tianle
• Zhang Nanjing
• Zhang Xiaoyan
• Zhao Xin
• Green Luke
• Pinard Emmanuel
• Ratni Hasane

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title