Compounds for treating spinal muscular atrophy

Patent metadata

Field	Value
Publication number	US-9617268-B2
Application number	US-201214369294-A
Country	US
Kind code	B2
Filing date	Dec 28, 2012
Priority date	Dec 30, 2011
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

Provided herein are compounds, compositions thereof and uses therewith for treating spinal muscular atrophy. In a specific embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene. In another specific embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN1 into mRNA that is transcribed from the SMN1 gene. In yet another embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN1 and SMN2 into mRNA that is transcribed from the SMN1 and SMN2 genes, respectively.

First claim

What is claimed is:

1. A compound selected from Formula (Ia) :

or a free acid, free base, salt, stereoisomer, racemate, enantiomer, diastereomer or tautomer form thereof, wherein:
R 1 is heterocyclyl selected from azetidin-1-yl, tetrahydrofuran-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, piperazin-1-yl, 1,4-diazepan-1-yl, 1,2,5,6-tetrahydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl, octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazin-2-yl, 3-azabicyclo[3.1.0]hex-3-yl, 8-azabicyclo[3.2.1]oct-3-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-2-en-3-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl, 9-azabicyclo[3.3.1]non-3-yl, (1R,5S)-9-azabicyclo[3.3.1]non-3-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.2]oct-2-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, (1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl, 1,4-diazabicyclo[3.2.2]non-4-yl, azaspiro[3.3]hept-2-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2,7-diazaspiro[3.5]non-7-yl, 5,8-diazaspiro[3.5]non-8-yl, 2,7-diazaspiro[4.4]non-2-yl and 6,9-diazaspiro[4.5]dec-9-yl optionally substituted with one, two or three R 3 substituents and one additional, optional R 4 substituent;
R 2 is heteroaryl selected from thien-2-yl, thien-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1,2,4-oxadiazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, pyrimidin-4-yl, 1H-indol-3-yl, 1H-indol-4-yl, indol-5-yl, indol-6-yl, 1H-indazol-5-yl, 2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl, benzothien-2-yl, benzothien-3-yl, 1H-benzimidazol-6-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 9H-purin-8-yl, furo[3,2-b]pyridine-2-yl, furo[3,2-c]pyridine-2-yl, furo[2,3-c]pyridin-2-yl, thieno[3,2-c]pyridin-2-yl, thieno[2,3-d]pyrimidin-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl, pyrrolo[1,2-a]pyrimidin-7-yl, pyrrolo[1,2-a]pyrazin-7-yl, pyrrolo[1,2-b]pyridazin-2-yl, pyrrolo[1,2-b]pyridazin-6-yl, pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyrazin-2-yl, imidazo[2,1-b][1,3]thiazol-6-yl, imidazo[2,1-b][1,3,4]thiadiazol-6-yl, [1,3]oxazolo[4,5-b]pyridin-2-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-a]pyrazin-2-yl and quinoxalin-2-yl;
wherein, each 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 1-8 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 alkoxy-C 1-8 alkyl-amino, C 1-8 alkyl-carbonyl-amino, C 1-8 - 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, 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, halo-C 1-8 alkyl, hydroxy-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; 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 salt form is a chloride, hydrochloride, dihydrochloride, hydrobromide, acetate or trifluoroacetate salt.

3. A compound, wherein the compound is selected from:
7-(piperazin-1-yl)-3-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2H-chromen-2-one;
7-(piperazin-1-yl)-3-[7-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2H-chromen-2-one;
2-oxo-N-phenyl-7-(piperazin-1-yl)-2H-chromene-3-carboxamide;
3-(1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;
3-(4-chloro-1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;
3-(7-chloro-1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;
3-(4-chloro-1,3-benzothiazol-2-yl)-7-(piperazin-1-ylmethyl)-2H-chromen-2-one;
3-(1,3-benzothiazol-2-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one;
7-[(propan-2-ylamino)methyl]-3-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]-2H-chromen-2-one;
3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one;
7-(4-methylpiperazin-1-yl)-3-[3-(trifluoromethyl)phenyl]-2H-chromen-2-one;
7-(piperazin-1-yl)-3-(pyridin-3-yl)-2H-chromen-2-one;
3-(1,3-benzothiazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-one;
3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-one;
3-(1,3-benzothiazol-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;
3-(1,3-benzothiazol-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;
3-(4-chloro-1,3-benzothiazol-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;
3-(4-chloro-1,3-benzothiazol-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one;
3-(5-fluoro-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;
3-(1,3-benzoxazol-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one;
3-(4-methyl-1,3-benzoxazol-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;
3-(4-methyl-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;
3-(1,3-benzoxazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;
3-(1,3-benzothiazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;
3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;
3-(3-fluorophenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;
7-(piperazin-1-yl)-3-(pyridin-4-yl)-2H-chromen-2-one;
3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(4-methylpiperazin-1-yl)carbonyl]-2H-chromen-2-one;
7-(piperazin-1-yl)-3-(1H-pyrazol-5-yl)-2H-chromen-2-one;
7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-oxo-N-phenyl-2H-chromene-3-carboxamide;
7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(4-methyl-1,3-benzoxazol-2-yl)-2H-chromen-2-one;
7-(piperazin-1-yl)-3-(pyridin-2-ylamino)-2H-chromen-2-one;
7-(piperazin-1-yl)-3-(pyrimidin-2-ylamino)-2H-chromen-2-one;
3-(imidazo[1,2-a]pyridin-2-yl)-

Assignees

• Ptc Therapeutics Inc
• Hoffmann La Roche
• Ptc Therapeutics Inc

Inventors

• Woll Matthew G
• Chen Guangming
• Choi Soongyu
• Dakka Amal
• Huang Song
• Karp Gary Mitchell
• Lee Chang-Sun
• Li Chunshi
• Narasimhan Jana
• Naryshkin Nikolai
• Paushkin Sergey
• Qi Hongyan
• Turpoff Anthony A
• Weetall Marla L
• Welch Ellen
• Yang Tianle
• Zhang Nanjing
• Zhang Xiaoyan
• Zhao Xin
• Pinard Emmanuel
• Ratni Hasane

Classifications

• A61P21/00

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

• A61P21/02

  Muscle relaxants, e.g. for tetanus or cramps · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D413/04

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

• C07D311/18

  substituted otherwise than in position 3 or 7 · CPC title