Compounds for treating Huntington's disease

Patent metadata

Field	Value
Publication number	US-12384789-B2
Application number	US-202217723163-A
Country	US
Kind code	B2
Filing date	Apr 18, 2022
Priority date	Jun 5, 2017
Publication date	Aug 12, 2025
Grant date	Aug 12, 2025

Abstract

The present description relates to compounds, forms, and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease. In particular, the present description relates to substituted bicyclic heteroaryl compounds of Formula (I), forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease.

First claim

What is claimed is:

1. A compound of Formula (Ig1), Formula (Ii1), or Formula (Im1):

or a form thereof, wherein:
R 1 is heterocyclyl or heterocyclyl-amino, wherein heterocyclyl is selected from the group consisting of azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 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, hexahydro-1H-cyclobuta[1,2-c:1,4-c′]dipyrrol-(3H)-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, 1,4-diazabicyclo[3.1.1]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 1,4-diazabicyclo[3.2.1]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, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octanyl, 1,7-diazaspiro[4.4]nonyl, 2,6-diazaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]non yl, 2,7-diazaspiro[4.4]nonyl, 2,7-diazaspiro[4.5]decanyl and 6,9-diazaspiro[4.5]decyl,
wherein, each instance of heterocyclyl is optionally substituted with one, two or three R 3 substituents and optionally, with one additional R 4 substituent, or,
wherein, alternatively, each instance of heterocyclyl is optionally substituted with one, two, three or four R 3 substituents;

R 2 is heteroaryl, selected from the group consisting of thienyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, 2H-pyrazolo[3,4-c]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,3]oxazolo[4,5-c]pyridinyl, [1,3]thiazolo[4,5-c]pyridinyl, [1,3]thiazolo[5,4-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl and quinoxalinyl,
wherein, each instance of heteroaryl is optionally substituted with one, two or three R 6 substituents and optionally, with one additional R 7 substituent;

R a is, in each instance, independently selected from the group consisting of hydrogen and C 1-8 alkyl;
R b is, in each instance, independently selected from the group consisting of hydrogen and halogen;
R 3 is, in each instance, independently selected from the group consisting of cyano, halogen, hydroxy, 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-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 and (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino,
R 4 is C 3-14 cycloalkyl, C 3-4 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, heterocyclyl-C 1-8 alkyl, heteroaryl or heteroaryl-C 1-8 alkyl;
wherein, each instance of C 3-14 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 5 substituents;

R 5 is, in each instance, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, hydroxy-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, C 1-8 alkyl-thio and heteroaryl-C 1-8 alkyl;
R 6 is, in each instance, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, cyano-C 1-8 alkyl, halo-C 1-8 alkyl, hydroxy-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, (C 1-8 alkyl) 2 -amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkoxy, 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, C 1-8 alkyl)amino and C 1-8 alkyl-thio; and,
R 7 is C 3-14 cycloalkyl, C 3-14 cycloalkyl-oxy, aryl, heterocyclyl, heteroaryl or heteroaryl-C 1-8 alkoxy, wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

2. A compound of claim 1 , wherein the form of the compound is a compound salt selected from the group consisting of hydrochloride, hydrobromide, trifluoroacetate, formate, dihydrochloride, dihydrobromide, ditrifluoracetate, diformate, trihydrochloride, trihydrobromide, tritrifluororacetate and triformate.

Assignees

• Ptc Therapeutics Inc

Inventors

• Woll Matthew G
• Amedzo Lukiana
• Babu Suresh
• Barraza Scott J
• Bhattacharyya Anuradha
• Karp Gary Mitchell
• Mazzotti Anthony R
• Narasimhan Jana
• Patel Jigar
• Turpoff Anthony
• Xu Zhenrong

Classifications

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title