Compounds for treating spinal muscular atrophy

摘要

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.

主权项

1. A compound selected from Formula (Ia) : or a free acid, free base, salt, stereoisomer, racemate, enantiomer, diastereomer or tautomer form thereof, wherein: R1 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 R3 substituents and one additional, optional R4 substituent; R2 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 R6 substituents and one additional, optional R7 substituent; Ra is, in each instance, independently selected from hydrogen, halogen or C1-8alkyl; Rb is hydrogen, halogen, C1-8alkyl or C1-8alkoxy; R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C1-8alkyl, halo-C1-8alkyl, C1-8alkyl-carbonyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkoxy-C1-8alkyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino, C1-8alkyl-amino-C1-8alkyl-amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, C1-8alkoxy-C1-8alkyl-amino, C1-8alkyl-carbonyl-amino, C1-8-8 alkoxy-carbonyl-amino, hydroxy-C 1-8 alkyl, hydroxy-C1-8alkoxy-C1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl)2-amino or (hydroxy-C1-8alkyl)(C1-8alkyl)amino; R4 is C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl, C3-14cycloalkyl-amino, aryl-C1-8alkyl, aryl-C1-8alkoxy-carbonyl, heterocyclyl or heterocyclyl-C 1-8 alkyl; wherein, each instance of C3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents; R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino or C1-8alkyl-thio; R6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C1-8alkyl, halo-C1-8alkyl, hydroxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino or C1-8alkyl-thio; and, R7 is C3-14cycloalkyl, C3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.