Methods for treating Huntington's disease

Patent metadata

Field	Value
Publication number	US-10874672-B2
Application number	US-201615781303-A
Country	US
Kind code	B2
Filing date	Dec 11, 2016
Priority date	Dec 10, 2015
Publication date	Dec 29, 2020
Grant date	Dec 29, 2020

Abstract

In particular, the present description relates to substituted monocyclic 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 method for treating or ameliorating HD in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (Ia):

or a form thereof, wherein
X is CH 2 , O, NR 5 , or a bond;
A is aryl, heteroaryl, heterocyclyl, or C 9-10 cycloalkyl, wherein:
aryl is selected from phenyl substituted with hydroxyl and optionlly with 1, 2, or 3, or 4 additional substituents each selected from R 1 and hydroxyl, and naphthyl optionally substituted with hydroxyl and optionally with 1, 2, or 3 additional substituents each selected from R 1 and hydroxyl,
heteroaryl is a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical having one or more heteroatoms selected from O, S, and N, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R 1 , wherein heteroaryl is not pyridine,
heterocyclyl is selected from the group consisting of oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl, pyrazolinyl, pyrazolidinyl, dihydroimidazolyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, dihydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydro-pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1,4,5,6-tetrahydropyrimidinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl, tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl, dihydro-benzooxazolyl, 2,3-dihydrobenzo[d]oxazolyl, tetrahydro-benzooxazolyl, dihydro-benzooxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, tetrahydro-benzooxazinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxanyl, dihydro-purinyl, tetrahydro-purinyl, dihydro-quinolinyl, tetrahydro-quinolinyl, 1,2,3,4-tetrahydroquinolinyl, dihydro-isoquinolinyl, 3,4-dihydroisoquinolin-(1H)-yl, tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, dihydro-quinazolinyl, tetrahydro-quinazolinyl, dihydro-quinoxalinyl, tetrahydro-quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-imidazolyl, tetrahydro-2H-pyranyl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, (4aR,7aS)- hexahydropyrrolo[3,4-b][1,4]oxazin-(4aH)-yl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, (cis)-octahydrocyclopenta[clpyrrolyl, hexahydropyrrolo[3,4-blpyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4]-pyridinyl, tetrahydro-1H-pyrrolo[3,4-b]pyridin-(2H,7H, 7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9-tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3-dihydro-1H-pyrrolo[1,2-a]indolyl, (3aR,6aR)- hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4S,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, 1,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-1H-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptenyl, 3- azabicyclo[3.1.0]anyl, 3,6-diazabicyclo[3.1.0]hexanyl, (1R,5S)-3-azabicyclo[3.1.0]hexanyl, (1S,5R)-3-azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4loctanyl, 2,6-diazaspiro[3.4]loctanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 3,6-diazabicyclo[3.2.1]loctyl, 1,4-dihydroindeno[1,2-c]pyrazolyl, dihydropyranyl, dihydropyridinyl, dihydroquinolinyl, 8H-indeno[1,2]-dithiazolyl, tetrahydroimidazo[1,2]-alpyridinyl, pyridin-2(1H)-one, (1R,5S)-8-azabicyclo[3.2.1]loctyl, and 8-azabicyclo[3.2.1oct-2-enyl, wherein heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R 2 , and
C 9-10 cycloalkyl is a saturated or partially unsaturated bicyclic ring system optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R 2 ;

B is monocyclic heterocyclyl, wherein heterocyclyl is a saturated or partially unsaturated ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R 4 ;
R 1 is halogen, cyano, C 1-4 alkyl, halo-C 1-4 alkyl, amino, C 1-4 alkyl-amino, (C 1-4 alkyl) 2 -amino, amino-C 1-4 alkyl, C 1-4 alkyl-amino-C 1-4 alkyl, (C 1-4 alkyl) 2 -amino-C 1-4 alkyl, amino-carbonyl, C 1-4 alkyl-amino-carbonyl, (C 1-4 alkyl) 2 -amino-carbonyl, C 1-4 alkyl-amino-carbonyl-C 1-4 alkyl, (C 1-4 alkyl) 2 -amino-carbonyl-C 1-4 alkyl, C 1-4 alkyl-carbonyl-amino, C 1-4 alkyl-carbonyl-amino-C 1-4 alkyl, hydroxyl-C 1-4 alkyl, C 1-4 alkyl-carbonyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, amino-C 1-4 alkoxy, hydroxyl-C 1-4 alkoxy, C 1-4 alkyl-C 1-4 alkoxy, C 1-4 alkyl-amino-C 1-4 alkoxy, (C 1-4 alkyl) 2 -amino-C 1-4 alkoxy, C 1-4 alkyl-carbonyl-amino-C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkoxy-carbonyl, C 1-4 alkoxy-carbonyl-amino, C 1-4 alkoxy-carbonyl-amino-C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkenyl-amino-carbonyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkoxy, C 3-7 cycloalkenyl, heteroaryl, heteroaryl-C 1-4 alkyl, heteroaryl-C 1-4 alkyl-amino, heteroaryl-C 1-4 alkyl-amino-carbonyl, heteroaryl-C 1-4 alkyl-carbonyl-amino, heteroaryl-C 1-4 alkyl-amino-carbonyl-C 1-4 alkyl, heteroaryl-C 1-4 alkyl-carbonyl-amino-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, heterocyclyl-C 1-4 alkoxy, phenyl, or phenyl, C 1-4 alkoxy, wherein:
heteroaryl is a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical having one or more heteroatoms selected from O, S, and N,
heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and
each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R 3 ;

R 2 is halogen, cyano, oxo, hydroxyl-imino, C 1-4 alkyl, halo-C 1-4 alkyl, amino, C 1-4 alkyl-amino, (C 1-4 alkyl) 2 -amino, amino-C 1-4 alkyl, C 1-4 alkyl-amino-C 1-4 alkyl, (C 1-4 alkyl) 2 -amino-C 1-4 alkyl, amino-carbonyl, hydroxyl-C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-carbonyl, C 2-4 alkenyl, C 3-7 cycloalkyl, or heterocyclyl-C 1-4 alkyl, wherein:
heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and
each instance of heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R 3 ;

R 3 is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, C 1-4 alkyl, amino, C 1-4 alkyl-amino, (C 1-4 alkyl) 2 -amino, amino-C 1-4 alkyl, C 1-4 alkyl-amino-C 1-4 alkyl, (C 1-4 alkyl) 2 -amino-C 1-4 alkyl, amino-carbonyl, C 1-4 alkyl-amino-carbonyl, (C 1-4 alkyl) 2 -amino-carbonyl, C 1-4 alkyl-amino-carbonyl-C 1-4 alkyl, (C 1-4 alkyl) 2 -amino-carbonyl-C 1-4 alkyl, C 1-4 alkyl-carbonyl-amino, C 1-4 alkyl-car

Assignees

• Ptc Therapeutics Inc

Inventors

• Babu Suresh
• Bhattacharyya Anuradha
• Hwang Seongwoo
• Jani Minakshi
• Moon Young-Choon
• Sydorenko Nadiya

Classifications

• A61P25/14

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

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/501 Primary

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title