US 12,723,049 B2Granted

Methods for treating spinocerebellar ataxia type 3

AssigneePTC Therapeutics, Inc.

InventorsGayan Mirihana Arachchilage, Michael A. Arnold, Scott Barraza, Anuradha Bhattacharyya, Gary Mitchell Karp

Life of this patent

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Abstract

The present description relates to methods of treating spinocerebellar ataxia type 3 (SCA3) using substituted thieno[3,2-d]pyrimidine compounds, forms, and pharmaceutical compositions thereof.

Claims16

Dependent claims

A method for inhibiting or ameliorating spinocerebellar ataxia type 3 (SCA3) in a subject in need thereof, comprising administering to said subject an effective amount of a compound of Formula (I):

or a form thereof, wherein
R1 is selected from the group consisting of tetrazolyl, phenyl and heteroaryl,
wherein the heteroaryl is a bicyclic aromatic carbon atom ring structure or a 5-8 membered monocyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S, and
wherein phenyl or heteroaryl is optionally substituted with one, two, three, or four, independently selected R1a substituents;
R1a is independently selected from the group consisting of cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, deutero-C1-6alkyl, and C1-6alkoxy;
R2 is selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, phenyl, heterocyclyl, and heteroaryl,
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S,
wherein the heteroaryl is a bicyclic aromatic carbon atom ring structure or a 5-8 membered monocyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S,
wherein C1-6alkyl, C2-6alkenyl, and C2-6alkynyl optionally contain a chiral carbon having an (R) or (S) configuration, and
wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, phenyl, heterocyclyl, or heteroaryl are optionally substituted with one, two, three, or four independently selected R2a substituents;
R2a is independently selected from the group consisting of cyano, halo, hydroxy, oxo, C1-6alkyl, halo-C1-6alkyl, deutero-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, halo-C1-6alkoxy, carboxyl, amino, C1-6alkyl-amino, halo-C1-6alkyl-amino, deutero-C1-6alkyl-amino, (C1-6alkyl)2-amino, C3-10cycloalkyl-amino, phenyl-amino, heterocyclyl-amino, heteroaryl-amino, C1-6alkyl-thio, C1-6alkyl-sulfonyl, C3-10cycloalkyl, phenyl, heterocyclyl, and heteroaryl,
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S,
wherein the heteroaryl is a bicyclic aromatic carbon atom ring structure or a 5-8 membered monocyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S, and
wherein each instance of C3-10cycloalkyl, phenyl, heterocyclyl or heteroaryl is optionally substituted with one, two, three or four independently selected R2a′ substituents;
R2a′ is independently selected from the group consisting of cyano, halo, hydroxy, oxo, C1-6alkyl, halo-C1-6alkyl, deutero-C1-6alkyl, and C1-6alkoxy;
R3 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, amino, C1-6alkyl-amino, (C1-6alkyl)2-amino, C3-10cycloalkyl, phenyl, heterocyclyl, and heteroaryl,
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S, and
wherein the heteroaryl is a bicyclic aromatic carbon atom ring structure or a 5-8 membered monocyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S, and
wherein C1-6alkyl, C3-10cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one, two, three, or four independently selected R3a substituents;
R3a is independently selected from the group consisting of cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, and C1-6alkoxy;
R4 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, carbamoyl, C3-10cycloalkyl, phenyl, and heterocyclyl, and
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S;
and
wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, and tautomer form thereof.

21 more elements

A method for inhibiting or ameliorating spinocerebellar ataxia type 3 (SCA3) in a subject in need thereof, comprising administering to said subject an effective amount of a compound or a form thereof wherein the compound is selected from the group consisting of;

2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2R,3S)-2-amino-3-methylpentyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2R)-2-amino-3,3-dimethylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-ethyl-N-[(furan-2-ylI)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-cyclopropyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
(2R)-2-amino-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)propan-1-ol;
6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carboxamide;
6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carbonitrile;
(2R)-2-amino-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol;
2-chloro-7-methyl-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
N-[(furan-2-yl)methyl]-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-V-[(3-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrazin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine
6-[(2S)-2-aminopropyl]-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2,S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-bromo-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-(azetidin-3-yl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
7-bromo-2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluorophenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(IS)-1-aminoethyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(1S)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(1R)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-amino-4-fluorobutyl]-2-chloro-V-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
(4S)-4-[(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)methyl]-1,3-oxazinan-2-one;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
(2R)-2-amino-3-(2-chloro-7-methyl-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol;
2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-(pyrrolidin-3-yl)thieno[3,2-d]pyrimidin-4-amine;
6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-phenylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluoropyridin-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(1S)-1-aminoethyl]-N-[(furan-2-yl)methyl]-2,7-diphenylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,2-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)propan-I-ol;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(3,5-difluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-amine;
(2S)-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-1-ol;
6-(3-aminopropyl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-V-[(3-fluoropyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-oxazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
(2R)-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-1-ol;
6-[(2R)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(1H-imidazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2R)-2-amino-3-methoxypropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-[(2S)-2-(methylamino)propyl]thieno[3,2-d]pyrimidin-4-amine;
7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine:
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-pyrazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[((2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-7-bromo-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2-carbonitrile;
2-chloro-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-7-carbonitrile;
6-[(2S)-2-aminopropyl]-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2,7-dicarbonitrile;
6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-V-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-phenyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-7-(4-chlorophenyl)-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
6-[(1R)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine;
2-chloro-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
2-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine;
(3S)-3-amino-4-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)butan-1-ol;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoropyrimidin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine, and
(2R)-2-amino-3-(2-chloro-7-methoxy-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol;
and
wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, and tautomer form thereof.

98 more elements

A method for inhibiting or ameliorating spinocerebellar ataxia type 3 (SCA3) in a subject in need thereof, comprising administering to said subject an effective amount of a compound salt or form thereof wherein the compound salt is selected from the group consisting of;

6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2R,3S)-2-amino-3-methylpentyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2R)-2-amino-3,3-dimethylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-ethyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-cyclopropyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride;
(2R)-2-amino-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride;
6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carboxamide trifluoroacetate;
6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carbonitrile trifluoroacetate;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-1[(4-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-1[(3-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrazin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-anine trifluoroacetate;
6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-bromo-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine trifluoroacetate;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-(azetidin-3-yl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine trifluoroacetate;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluorophenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(1S)-1-aminoethyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(1S)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(1R)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-amino-4-fluorobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
(2R)-2-amino-3-(2-chloro-7-methyl-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride;
2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-(pyrrolidin-3-yl)thieno[3,2-d]pyrimidin-4-amine formate;
6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-phenylthieno[3,2-d]pyrimidin-4-amine formate;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluoropyridin-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(1S)-1-aminoethyl]-N-[(furan-2-yl)methyl]-2,7-diphenylthieno[3,2-d]pyrimidin-4-amine formate;
6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,2-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine formate;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(3,5-difluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-amine formate;
6-(3-aminopropyl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-oxazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(2R)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(1H-imidazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-V-[(1,3-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2R)-2-amino-3-methoxypropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride;
2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine formate;
2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-[(2S)-2-(methylamino)propyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-pyrazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(2S)-2-aminopropyl]-7-bromo-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2-carbonitrile formate;
6-[(2S)-2-aminopropyl]-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2,7-dicarbonitrile hydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine formate;
6-[(2S)-2-aminopropyl]-2-chloro-7-phenyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-7-(4-chlorophenyl)-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride;
6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride;
6-[(1R)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride;
(3S)-3-amino-4-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)butan-1-ol dihydrochloride;
6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoropyrimidin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine formate, and (2R)-2-amino-3-(2-chloro-7-methoxy-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride;
and
wherein the form of the compound salt is selected from the group consisting of a hydrate, solvate, and tautomer form thereof.

82 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/264,189Filed 2 Feb 2022 · us provisional application
Priority: 5 Feb 2021
Published: US 2024/0043444 A18 Feb 2024
Granted: 1 Sep 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
C07D 495/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 21/00
Drugs for disorders of the muscular or neuromuscular system
A61K 2121/00
Preparations for use in therapy

Family

Application63/146,151Us provisional application · filed 5 Feb 2021
US 2024/0043444 A1Pre-grant publication · published 8 Feb 2024
US 12,723,049 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

The present description relates to methods of treating spinocerebellar ataxia type 3 (SCA3) using substituted thieno[3,2-d]pyrimidine compounds, forms, and pharmaceutical compositions thereof.

A method for inhibiting or ameliorating spinocerebellar ataxia type 3 (SCA3) in a subject in need thereof, comprising administering to said subject an effective amount of a compound of Formula (I):

or a form thereof, wherein
R1 is selected from the group consisting of tetrazolyl, phenyl and heteroaryl,
wherein the heteroaryl is a bicyclic aromatic carbon atom ring structure or a 5-8 membered monocyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S, and
wherein phenyl or heteroaryl is optionally substituted with one, two, three, or four, independently selected R1a substituents;
R1a is independently selected from the group consisting of cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, deutero-C1-6alkyl, and C1-6alkoxy;
R2 is selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, phenyl, heterocyclyl, and heteroaryl,
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S,
wherein the heteroaryl is a bicyclic aromatic carbon atom ring structure or a 5-8 membered monocyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S,
wherein C1-6alkyl, C2-6alkenyl, and C2-6alkynyl optionally contain a chiral carbon having an (R) or (S) configuration, and
wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, phenyl, heterocyclyl, or heteroaryl are optionally substituted with one, two, three, or four independently selected R2a substituents;
R2a is independently selected from the group consisting of cyano, halo, hydroxy, oxo, C1-6alkyl, halo-C1-6alkyl, deutero-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, halo-C1-6alkoxy, carboxyl, amino, C1-6alkyl-amino, halo-C1-6alkyl-amino, deutero-C1-6alkyl-amino, (C1-6alkyl)2-amino, C3-10cycloalkyl-amino, phenyl-amino, heterocyclyl-amino, heteroaryl-amino, C1-6alkyl-thio, C1-6alkyl-sulfonyl, C3-10cycloalkyl, phenyl, heterocyclyl, and heteroaryl,
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S,
wherein the heteroaryl is a bicyclic aromatic carbon atom ring structure or a 5-8 membered monocyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S, and
wherein each instance of C3-10cycloalkyl, phenyl, heterocyclyl or heteroaryl is optionally substituted with one, two, three or four independently selected R2a′ substituents;
R2a′ is independently selected from the group consisting of cyano, halo, hydroxy, oxo, C1-6alkyl, halo-C1-6alkyl, deutero-C1-6alkyl, and C1-6alkoxy;
R3 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, amino, C1-6alkyl-amino, (C1-6alkyl)2-amino, C3-10cycloalkyl, phenyl, heterocyclyl, and heteroaryl,
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S, and
wherein the heteroaryl is a bicyclic aromatic carbon atom ring structure or a 5-8 membered monocyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S, and
wherein C1-6alkyl, C3-10cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one, two, three, or four independently selected R3a substituents;
R3a is independently selected from the group consisting of cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, and C1-6alkoxy;
R4 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, carbamoyl, C3-10cycloalkyl, phenyl, and heterocyclyl, and
wherein heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S;
and
wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, and tautomer form thereof.

21 more elements

Facts

Application

18/264,189Filed 2 Feb 2022 · us provisional application

Priority

5 Feb 2021

Published

US 2024/0043444 A18 Feb 2024

Granted

1 Sep 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
C07D 495/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 21/00
Drugs for disorders of the muscular or neuromuscular system
A61K 2121/00
Preparations for use in therapy