Compounds for treating spinal muscular atrophy

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 (IIa1l):

• or a free acid, free base, salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof, wherein:
• R1 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 R3 substituents and optionally, with one additional R4 substituent;
• R2 is phenyl or heteroaryl;
• wherein, R2 is optionally substituted with one, two or three R6 substituents and optionally, with one additional R7 substituent;
• Ra is, in each instance, independently selected from hydrogen, halogen or C1-8alkyl;
• Rb is hydrogen, halogen, C1-8alkyl or C1-8alkoxy;
• Rc is hydrogen, halogen or C1-8alkyl;
• 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-amino-C1-8alkyl)2-amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl]2-amino, (C1-8alkyl-amino-C1-8alkyl)(C1-8alkyl)amino, [(C1-8alkyl)2-amino-C1-8alkyl](C1-8alkyl)amino, C1-8alkoxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl)2-amino, (C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino, C1-8alkyl-carbonyl-amino, C1-8alkoxy-carbonyl-amino, hydroxy-C1-8alkyl, hydroxy-C1-8alkoxy-C1-8alkyl, hydroxy-C1-8alkyl-amino, (hydroxy-C1-8alkyl)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, aryl-sulfonyloxy-C1-8alkyl, heterocyclyl or heterocyclyl-C1-8alkyl;
• 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, C2-8alkenyl, halo-C1-8alkyl, hydroxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkoxy-C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino or C1-8alkyl-thio;
• and,
• R7 is C3-14cycloalkyl, C3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.