Compounds for treating spinal muscular atrophy

Patent metadata

Field	Value
Publication number	US-9399649-B2
Application number	US-201314373937-A
Country	US
Kind code	B2
Filing date	Jan 25, 2013
Priority date	Jan 26, 2012
Publication date	Jul 26, 2016
Grant date	Jul 26, 2016

Abstract

Provided herein are compounds, compositions thereof and uses therewith for treating spinal muscular atrophy.

First claim

What is claimed is:

1. A compound of Formula (I):

or a form thereof, wherein:
w 1 is C—R b ;
w 2 and w 6 are C—R 1 or C—R 2 ;
w 3 , w 4 and w 5 are C—R a ;
wherein one of w 2 and w 6 is C—R 1 and the other is C—R 2 , provided that, when w 2 is C—R 1 , then w 6 is C—R 2 ; or, when w 2 is C—R 2 , then w 6 is C—R 1 ;
R 1 is C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -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, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, (amino-C 1-8 alkyl) 2 -amino, (amino-C 1-8 alkyl)(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-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, 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 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkoxy, amino-C 2-8 alkenyl, C 1-8 alkyl-amino-C 2-8 alkenyl, (C 1-8 alkyl) 2 -amino-C 2-8 alkenyl, amino-C 2-8 alkynyl, C 1-8 alkyl-amino-C 2-8 alkynyl, (C 1-8 alkyl) 2 -amino-C 2-8 alkynyl, halo-C 1-8 alkyl-amino, (halo-C 1-8 alkyl) 2 -amino, (halo-C 1-8 alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 alkoxy-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl) 2 -amino, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino-C 1-8 alkoxy, (hydroxy-C 1-8 alkyl) 2 -amino-C 1 -alkoxy, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkoxy, hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl-amino, [(hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, [(hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl](C 1-8 alkyl)amino, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-C 1-8 alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 alkyl, heterocyclyl-C 1-8 alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2 -amino, (heterocyclyl-C 1-8 alkyl)(C 1-8 alkyl)amino, heterocyclyl-C 1-8 alkyl-amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-C 1-8 alkyl-amino, (aryl-C 1-8 alkyl) 2 -amino, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl, (aryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-C 1-8 alkoxy, heteroaryl-amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl) 2 -amino, (heteroaryl-C 1-8 alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl, (heteroaryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl or (heteroaryl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl;
wherein, each instance of heterocyclyl and heteroaryl is optionally substituted with one, two or three R 3 substituents and one additional, optional R 4 substituent; and,
wherein, alternatively, each instance of heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R 3 substituents;
R 2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;
wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6 substituents and one additional, optional 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 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 -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 compound of claim 1 , wherein the form is selected from a free acid, free base, salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

3. The compound of claim 1 , wherein the salt form is a chloride, hydrochloride, dihydrochloride, hydrobromide, acetate or trifluoroacetate salt.

4. The compound of claim 1 , wherein the compound is selected from:
7-(piperazin-1-yl)-3-(pyridin-2-yl)-1H-isochromen-1-one;
7-(piperazin-1-yl)-3-(thiophen-3-yl)-1H-isochromen-1-one;
3-(3,4-dimethoxyphenyl)-7-(piperazin-1-yl)-1H-isochromen-1-one;
7-(4-methylpiperazin-1-yl)-3-(pyridin-2-yl)-1H-isochromen-1-one;
7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(pyridin-2-yl)-1H-isochromen-1-one;
3-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;
3-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(4-methyl-1,4-diazepan-1-yl)-1H-isochromen-1-one;
3-(1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;
3-(1,3-benzothiazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-isochromen-1-one;
3-(1,3-benzothiazol-2-yl)-7-(1,4-diazepan-1-yl)-1H-isochromen-1-one;
3-(1,3-benzothiazol-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-1H-isochromen-1-one;
3-(1,3-benzodioxol-5-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;
3-(3,5-difluorophenyl)-7-(piperazin-1-yl)-1H-isochromen-1-one;
3-(1,3-benzodioxol-5-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;
3-(3,4-dimethoxyphenyl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;
3-(3,4-dime

Assignees

• Ptc Therapeutics Inc
• Ptc Therapeutics Inc

Inventors

• Chen Guangming
• Dakka Amal
• Karp Gary Mitchell
• Li Chunshi
• Narasimhan Jana
• Naryshkin Nikolai
• Weetall Marla L
• Welch Ellen
• Zhao Xin

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P21/04

  for myasthenia gravis · CPC title

• A61P21/00

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

• C07D407/04

  directly linked by a ring-member-to-ring-member bond · CPC title