IP Library Granted Patent US 9,399,649
Granted Patent B2
US 9,399,649 · App. 14/373,937 · Granted Jul 26, 2016

Compounds for treating spinal muscular atrophy

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Quick Facts
Patent No.
US 9,399,649
App. No.
14/373,937
Granted
Jul 26, 2016
Kind
B2
Abstract

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

Claims (188)

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-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-isochromen-1-one;

3-(3-methoxyphenyl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(3-methoxyphenyl)-1H-isochromen-1-one;

7-(1,4-diazepan-1-yl)-3-(3-methoxyphenyl)-1H-isochromen-1-one;

3-(2-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(2-methoxyphenyl)-1H-isochromen-1-one;

3-(4-methoxyphenyl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(imidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(imidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(4-methoxyphenyl)-1H-isochromen-1-one;

3-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(2-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

7-[(3S)-3-methylpiperazin-1-yl]-3-(pyridin-2-yl)-1H-isochromen-1-one;

3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(1,3-benzothiazol-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-isochromen-1-one;

3-(1,3-benzodioxol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(3,4-dihydroxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(4-ethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(3-hydroxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(2-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(3-chloro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(4-fluoro-3-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(5-fluoro-2-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(3,5-difluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(2,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(4-ethoxyphenyl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(2-methyl-1-benzofuran-5-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-[3-(difluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-[4-(difluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-1H-isochromen-1-one;

3-(3,4-dimethoxyphenyl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-1H-isochromen-1-one;

7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-1H-isochromen-1-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(4-ethylpiperazin-1-yl)-1H-isochromen-1-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-1H-isochromen-1-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-1H-isochromen-1-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1H-isochromen-1-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(4-propylpiperazin-1-yl)-1H-isochromen-1-one;

7-(4-tert-butylpiperazin-1-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

7-(4-cyclopropylpiperazin-1-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(2-methoxyethyl)piperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(2-methylpropyl)piperazin-1-yl]-1H-isochromen-1-one;

7-(4-cyclobutylpiperazin-1-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(2-methoxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-isochromen-1-one;

7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperidin-4-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(oxetan-3-yl)piperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-isochromen-1-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-1H-isochromen-1-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-1H-isochromen-1-one;

3-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(2-methyl-1,3-benzothiazol-6-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(2-methyl-1,3-benzothiazol-6-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-1H-isochromen-1-one;

3-(2-methyl-1,3-benzothiazol-5-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(2-methyl-1,3-benzothiazol-6-yl)-7-[4-(oxetan-3-yl)piperazin-1-yl]-1H-isochromen-1-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-1H-isochromen-1-one;

7-(1-cyclobutylpiperidin-4-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)piperidin-4-yl]-1H-isochromen-1-one;

7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

7-[(3S)-3,4-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(4-hydroxypiperidin-1-yl)-1H-isochromen-1-one;

7-[4-(dimethylamino)piperidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

7-[(3R)-3,4-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-1H-isochromen-1-one;

7-[(3R,5S)-4-ethyl-3,5-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

7-[(3R,5S)-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-1H-isochromen-1-one;

7-[(3R,5S)-4-cyclobutyl-3,5-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

7-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methyl-4-propylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-propylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

7-[(3R)-4-cyclobutyl-3-methylpiperazin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-4-(2-methoxyethyl)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-4-(2-methoxyethyl)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R,5S)-4-ethyl-3,5-dimethylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,5-dimethyl-4-propylpiperazin-1-yl]-1H-isochromen-1-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-1H-isochromen-1-one;

3-(8-ethyl-6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(8-ethyl-6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(8-ethyl-6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

3-(8-ethyl-6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-1H-isochromen-1-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(8-ethyl-6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

7-[(3S)-3,4-dimethylpiperazin-1-yl]-3-(8-ethyl-6-methylimidazo[1,2-a]pyrazin-2-yl)-1H-isochromen-1-one;

3-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-1H-isochromen-1-one;

3-(2-methyl-2H-indazol-5-yl)-7-(4-methylpiperazin-1-yl)-1H-isochromen-1-one;

3-(8-ethyl-6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-1H-isochromen-1-one; or

3-(8-ethyl-6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one,

or a salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

5. A pharmaceutical composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.

6. The pharmaceutical composition of claim 5 for use in the treatment of spinal muscular atrophy (SMA).

7. 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 the compound of claim 1 .

8. A method for increasing the amount of Smn protein, comprising contacting a human cell with the compound of claim 1 .

9. The method of claim 7 or 8 , wherein the human cell is a human cell from a human SMA patient.

10. A method for treating SMA in a human subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 .

11. A method for treating SMA in a human subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 5 .

Assignments (4)
RELEASE OF SECURITY INTEREST Recorded Jul 14, 2020
From: MIDCAP FINANCIAL TRUST, AS AGENT
To: PTC THERAPEUTICS, INC.
Reel/Frame 053209/0872 →
CORRECTIVE ASSIGNMENT TO CORRECT THE INCLUSION OF 6420591,6583309,6503713, 5843995,7029846,7056656, 6468969,6486305,6630294, 6989256,6627398,8247167, 9017935 PREVIOUSLY RECORDED ON REEL 042418 FRAME 0774. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY INTEREST. Recorded Aug 24, 2017
From: PTC THERAPEUTICS, INC.
To: MIDCAP FINANCIAL TRUST, AS AGENT
Reel/Frame 043672/0096 →
SECURITY INTEREST Recorded May 8, 2017
From: PTC THERAPEUTICS, INC.
To: MIDCAP FINANCIAL TRUST, AS AGENT
Reel/Frame 042418/0774 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 8, 2015
From: CHEN, GUANGMING; DAKKA, AMAL; KARP, GARY MITCHELL; NARASIMHAN, JANA; NARYSHKIN, NIKOLAI; WEETALL, MARLA L.; WELCH, ELLEN; ZHAO, XIN; LI, CHUNSHI
To: PTC THERAPEUTICS, INC.
Reel/Frame 034668/0141 →