WO2017100726A1 - Methods for treatng huntington's disease - Google Patents

Methods for treatng huntington's disease Download PDF

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Publication number
WO2017100726A1
WO2017100726A1 PCT/US2016/066042 US2016066042W WO2017100726A1 WO 2017100726 A1 WO2017100726 A1 WO 2017100726A1 US 2016066042 W US2016066042 W US 2016066042W WO 2017100726 A1 WO2017100726 A1 WO 2017100726A1
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WO
WIPO (PCT)
Prior art keywords
amino
methyl
tetramethylpiperidin
pyridazin
pyrazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2016/066042
Other languages
English (en)
French (fr)
Other versions
WO2017100726A8 (en
Inventor
Suresh Babu
Anuradha Bhattacharyya
Seongwoo Hwang
Minakshi JANI
Young-Choon Moon
Nadiya Sydorenko
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PTC Therapeutics Inc
Original Assignee
PTC Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=59013375&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2017100726(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to NZ743147A priority Critical patent/NZ743147B2/en
Priority to SI201631243T priority patent/SI3386511T1/sl
Priority to IL294124A priority patent/IL294124B2/en
Priority to SG11201804915RA priority patent/SG11201804915RA/en
Priority to CN201680081666.1A priority patent/CN108697709A/zh
Priority to CN201911286032.1A priority patent/CN110946865B/zh
Priority to EP21158464.4A priority patent/EP3848035B1/en
Priority to JP2018529967A priority patent/JP2019500352A/ja
Priority to AU2016366694A priority patent/AU2016366694C1/en
Priority to PL16874024T priority patent/PL3386511T3/pl
Priority to IL281633A priority patent/IL281633B/en
Priority to KR1020227021757A priority patent/KR20220100719A/ko
Priority to US15/781,303 priority patent/US10874672B2/en
Priority to LTEP16874024.9T priority patent/LT3386511T/lt
Priority to EP16874024.9A priority patent/EP3386511B2/en
Application filed by PTC Therapeutics Inc filed Critical PTC Therapeutics Inc
Priority to DK16874024.9T priority patent/DK3386511T3/da
Priority to KR1020187016467A priority patent/KR102488323B1/ko
Priority to CN202110932557.9A priority patent/CN113717154B/zh
Priority to EA201800367A priority patent/EA201800367A1/ru
Priority to CA3007412A priority patent/CA3007412C/en
Priority to MX2018007022A priority patent/MX382671B/es
Priority to ES16874024T priority patent/ES2879995T3/es
Priority to MX2021001091A priority patent/MX391850B/es
Publication of WO2017100726A1 publication Critical patent/WO2017100726A1/en
Priority to IL259843A priority patent/IL259843B/en
Priority to PH12018501226A priority patent/PH12018501226A1/en
Anticipated expiration legal-status Critical
Publication of WO2017100726A8 publication Critical patent/WO2017100726A8/en
Priority to US16/710,515 priority patent/US10881658B2/en
Priority to AU2020201380A priority patent/AU2020201380B2/en
Priority to US17/093,194 priority patent/US11638706B2/en
Priority to US18/111,421 priority patent/US20230201200A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2835—Movement disorders, e.g. Parkinson, Huntington, Tourette

Definitions

  • 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.
  • the present description relates to substituted monocyclic heteroaryl compounds, forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease.
  • Huntington's disease is a progressive, autosomal dominant neurodegenerative disorder of the brain, having symptoms characterized by involuntary movements, cognitive impairment, and mental deterioration. Death, typically caused by pneumonia or coronary artery disease, usually occurs 13 to 15 years after the onset of symptoms. The prevalence of HD is between three and seven individuals per 100,000 in populations of western European descent. In North America, an estimated 30,000 people have HD, while an additional 200,000 people are at risk of inheriting the disease from an affected parent.
  • the disease is caused by an expansion of uninterrupted trinucleotide CAG repeats in the "mutant" huntingtin (Htt) gene, leading to production of HTT (Htt protein) with an expanded poly-glutamine (polyQ) stretch, also known as a "CAG repeat” sequence.
  • Htt huntingtin
  • polyQ poly-glutamine
  • the present description relates to methods for treating or ameliorating HD in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I): N— N
  • W, X, A and B are as defined herein, or forms and compositions thereof.
  • the present description relates to a use of a compound of Formula (I) or a form or composition thereof in a method for treating or ameliorating HD in a subject in need thereof comprising, administering an effective amount of the compound or a form or
  • composition thereof, to the subject is
  • the present description further relates to the use of a compound of Formula (I) or a form thereof in combination with agents having additive or synergistic activity, thus providing a combination product for the treatment of HD.
  • the present description relates to a method or use of a compound for treating or ameliorating HD in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I :
  • A is aryl, heteroaryl, heterocyclyl, or C9_iocycloalkyl
  • aryl is selected from phenyl and naphthyl, each optionally substituted with 1, 2, 3, or 4 substituents each selected from Ri,
  • heteroaryl is a saturated monocyclic, bicyclic or tricyclic 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 Ri
  • heterocyclyl is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic 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 2
  • C9_iocycloalkyl is a saturated or partially unsaturated bicyclic ring system optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R 2 ;
  • heterocyclyl is a saturated or partially unsaturated monocyclic, bicyclic or polycyclic 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 ;
  • Ri is halogen, hydroxyl, cyano, Ci_ 4 alkyl, halo-Ci_ 4 alkyl, amino, Ci_ 4 alkyl- amino,
  • heteroaryl-C i_ 4 alkyl-amino heteroaryl-C i_ 4 alkyl-amino, heteroaryl-C i_ 4 alkyl-amino-carbonyl,
  • heteroaryl-C i_ 4 alkyl-carbonyl-amino heteroaryl-C i_ 4 alkyl-amino-carbonyl-C i_ 4 alkyl, heteroaryl-C i_ 4 alkyl-carbonyl-amino-C i_ 4 alkyl, heterocyclyl, heterocyclyl-C i- 4 alkyl, heterocyclyl-Ci- 4 alkoxy, phenyl, or phenyl-Ci_ 4 alkoxy,
  • heteroaryl is a saturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S,
  • 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
  • R 2 is halogen, hydroxyl, cyano, oxo, hydroxyl-imino, Ci- 4 alkyl, halo-Ci- 4 alkyl, amino, Ci- 4 alkyl-amino, (Ci_ 4 alkyl) 2 -amino, amino-Ci- 4 alkyl, Ci- 4 alkyl-amino-Ci- 4 alkyl,
  • 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
  • heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R 3 ;
  • R 3 is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, Ci- 4 alkyl, halo-Ci- 4 alkyl, amino,
  • Ci_ 4 alkyl 2 -amino-carbonyl, Ci_ 4 alkyl-amino-carbonyl-Ci_ 4 alkyl, (Ci_ 4 alkyl) 2 -amino- carbonyl-Ci- 4 alkyl, Ci- 4 alkyl-carbonyl-amino, Ci- 4 alkyl-carbonyl-amino-Ci- 4 alkyl, hydroxyl-Ci_ 4 alkyl, Ci- 4 alkyl-carbonyl, Ci- 4 alkoxy, halo-Ci- 4 alkoxy, amino-Ci- 4 alkoxy, hydroxyl-C i_ 4 alkoxy, C i_ 4 alkyl-C i- 4 alkoxy, C i_ 4 alkyl-amino-C i_ 4 alkoxy,
  • heteroaryl-C i_ 4 alkyl-amino heteroaryl-C i_ 4 alkyl-amino, heteroaryl-C i_ 4 alkyl-amino-carbonyl,
  • heteroaryl-C i_ 4 alkyl-carbonyl-amino heteroaryl-C i_ 4 alkyl-amino-carbonyl-C i- 4 alkyl, heteroaryl-C i_ 4 alkyl-carbonyl-amino-C i- 4 alkyl, heterocyclyl, heterocyclyl-C i- 4 alkyl, phenyl, or phenyl-Ci- 4 alkoxy;
  • R4 is independently selected from halogen, Ci_ 4 alkyl, hydroxyl-C i_ 4 alkyl, amino, Ci ⁇ alkyl- amino, (Ci_ 4 alkyl) 2 -amino or hydroxyl-C i_ 4 alkyl-amino; and
  • R5 is hydrogen, Ci- 4 alkyl, or hydroxyl-C i- 4 alkyl
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • An embodiment of the present description further relates to a method or use of a compound for treating or ameliorating HD in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) selected from a compound of Formula (la) and Formula (lb :
  • A is aryl, heteroaryl, heterocyclyl, or C9_iocycloalkyl
  • aryl is selected from phenyl and naphthyl, each optionally substituted with 1, 2, 3, or 4 substituents each selected from Ri,
  • heteroaryl is a saturated monocyclic, bicyclic or tricyclic 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 Ri,
  • heterocyclyl is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic 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 2
  • C9_iocycloalkyl is a saturated or partially unsaturated bicyclic ring system optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R 2 ;
  • heterocyclyl is a saturated or partially unsaturated monocyclic, bicyclic or polycyclic 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 ;
  • Ri is halogen, hydroxyl, cyano, Ci_ 4 alkyl, halo-Ci_ 4 alkyl, amino, Ci_ 4 alkyl- amino,
  • heteroaryl-C i_ 4 alkyl-amino heteroaryl-C i_ 4 alkyl-amino, heteroaryl-C i_ 4 alkyl-amino-carbonyl,
  • heteroaryl-C i_ 4 alkyl-carbonyl-amino heteroaryl-C i_ 4 alkyl-amino-carbonyl-C i- 4 alkyl, heteroaryl-C i_ 4 alkyl-carbonyl-amino-C i- 4 alkyl, heterocyclyl, heterocyclyl-C i- 4 alkyl, heterocyclyl-Ci- 4 alkoxy, phenyl, or phenyl-Ci_ 4 alkoxy,
  • heteroaryl is a saturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S,
  • 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
  • R 2 is halogen, hydroxyl, cyano, oxo, hydroxyl-imino, Ci- 4 alkyl, halo-Ci- 4 alkyl, amino,
  • R 3 is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, Ci- 4 alkyl, amino, Ci- 4 alkyl-amino,
  • heteroaryl-C i_ 4 alkyl-amino heteroaryl-C i_ 4 alkyl-amino, heteroaryl-C i_ 4 alkyl-amino-carbonyl,
  • R 4 is independently selected from halogen, Ci_ 4 alkyl, hydroxyl-Ci_ 4 alkyl, amino, Ci ⁇ alkyl- amino, (Ci_ 4 alkyl)2-amino or hydroxyl-Ci_ 4 alkyl-amino;
  • R5 is hydrogen, Ci_ 4 alkyl, or hydroxyl-Ci_ 4 alkyl
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • Another embodiment of the present description further relates to methods for treating or ameliorating HD in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) selected from a compound of Formula (la) and Formula (lb):
  • X is O, NH, N(CH 3 ) or a bond
  • A is aryl, heteroaryl or heterocyclyl
  • aryl is selected from the group consisting of:
  • heteroar l is selected from the group consisting of
  • Ri a , Ri b and Ri c are each, where allowed by available valences, one or more substituents each selected from halogen, hydroxyl, cyano, Ci- 4 alkyl, halo-Ci- 4 alkyl, amino,
  • Ci_ 4 alkyl 2 -amino-carbonyl, Ci_ 4 alkyl-amino-carbonyl-Ci_ 4 alkyl, (Ci_ 4 alkyl) 2 -amino- carbonyl-Ci- 4 alkyl, Ci- 4 alkyl-carbonyl-amino, Ci- 4 alkyl-carbonyl-amino-Ci- 4 alkyl, hydroxyl-Ci_ 4 alkyl, Ci- 4 alkyl-carbonyl, Ci- 4 alkoxy, halo-Ci- 4 alkoxy, amino-Ci- 4 alkoxy, hydroxyl-C i_ 4 alkoxy, C i_ 4 alkyl-C i_ 4 alkoxy, C i_ 4 alkyl-amino-C i_ 4 alkoxy,
  • heteroaryl-C i_ 4 alkyl-carbonyl-amino heteroaryl-C i_ 4 alkyl-amino-carbonyl-C i- 4 alkyl, heteroaryl-C i_ 4 alkyl-carbonyl-amino-C i- 4 alkyl, heterocyclyl, heterocyclyl-C i- 4 alkyl, heterocyclyl-Ci- 4 alkoxy, phenyl, or phenyl-Ci_ 4 alkoxy,
  • heteroaryl is a saturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S,
  • 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
  • R 2a , R 2b and R 2C are each, where allowed by available valences, one or more substituents each selected from halogen, hydroxyl, cyano, oxo, hydroxyl-imino, Ci_ 4 alkyl, halo-Ci_ 4 alkyl, amino, Ci_ 4 alkyl-amino, (Ci_ 4 alkyl) 2 -amino, amino-Ci_ 4 alkyl, Ci_ 4 alkyl-amino-Ci_ 4 alkyl, (Ci- 4 alkyl) 2 -amino-Ci_ 4 alkyl, amino-carbonyl, hydroxyl-Ci- 4 alkyl, Ci- 4 alkoxy,
  • Ci- 4 alkoxy-carbonyl C 2 - 4 alkenyl, C3_ 7 cycloalkyl, or heterocyclyl-Ci- 4 alkyl
  • 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
  • heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R 3 ;
  • R 3 is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, Ci_ 4 alkyl, amino, Ci_ 4 alkyl-amino,
  • heteroaryl-C i_ 4 alkyl-amino heteroaryl-C i_ 4 alkyl-amino, heteroaryl-C i_ 4 alkyl-amino-carbonyl,
  • heteroaryl-C i_ 4 alkyl-carbonyl-amino heteroaryl-C i_ 4 alkyl-amino-carbonyl-C i_ 4 alkyl, heteroaryl-C i_ 4 alkyl-carbonyl-amino-C i_ 4 alkyl, heterocyclyl, heterocyclyl-C i_ 4 alkyl, phenyl, or phenyl-Ci- 4 alkoxy;
  • R4a, R4b, R4c, R4d, R4e, 3 ⁇ 44f and R4 g are independently selected from halogen, Ci-4alkyl,
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • a compound of Formula (I) selected from a com ound of Formula (lal 1), Formula (Ial5), Formula (Ial8) or Formula (Ibl):
  • X is selected from O, NR 5 , or a bond
  • A is selected from phenyl, thiophenyl, indazolyl, pyridinyl, pyrimidinyl or phenoxy, wherein phenyl and phenoxy are each optionally substituted with 1, 2 or 3 substituents each selected from Ri a ,
  • thiophenyl, indazolyl, pyridinyl, pyrimidinyl are each optionally substituted with 1 or 2 substituents each selected from Ri a ,
  • B is selected from lH-pyrazolyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, ( IR,5S)-S- azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, 2,6-diazaspiro[3.4]octyl or 2,7- diazaspiro[3.5]nonyl, each optionally substituted with 1 or 2 substituents each selected from R 4a ;
  • Ri a is selected from halogen, hydroxyl, Ci_ 4 alkyl, halo-Ci_ 4 alkyl, amino, Ci_ 4 alkoxy, or
  • heteroaryl is a saturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S optionally substituted with 1 or 2 substituents each selected from R 3a ;
  • R 3a is selected from nitro or Ci_ 4 alkyl
  • R 4a is Ci- 4 alkyl
  • R5 a is hydrogen, Ci_ 4 alkyl, or hydroxyl-Ci_ 4 alkyl; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • Another aspect of the present description relates to a compound of Formula (I) selected from a compound of Formula (lal 1), Formula (Ial5), Formula (Ial8) or Formula (Ibl):
  • Ri a is selected from fluoro, chloro, hydroxyl, methyl, difluoromethyl, amino, methoxy or 1H- pyrazolyl or lH-imidazol-l-yl,
  • lH-pyrazolyl is optionally substituted with 1 or 2 substituents each selected from R 3a ;
  • R 3a is selected from nitro or methyl or amino;
  • R 4a is methyl or ethyl
  • Rs a is hydrogen or methyl
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (lal) or a form thereof, wherein substituents Ri a , Ri b , and X, when present, are indicated in the table below with multiple substituents separated by a comma; and, "— " indicates that one or more Ri a , R ⁇ , and X substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ia2) or a form thereof, wherein substituents Ri a , Ri b , and R 4a , when present, are indicated in the table below with multiple substituents separated by a comma; and, "— " indicates that one or more Ri a , Ri , and R 4a substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ia3) or a form thereof, wherein substituents Ri a , and X, when present, are indicated in the table below with multiple substituents separated by a comma; and, "— " indicates that one or more Ri a , and X substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ia4) or a form thereof, wherein substituents X, Ri a , Ri b and R 4a , when present, are indicated in the table below; and, "— " indicates that one or more X, Ri a , Ri b and R 4a substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ia5) or a form thereof, wherein substituents Ri a and Ri b , when present, are indicated in the table below with multiple substituents separated by a comma; and, "— " indicates that one or more Ri a and substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ia6) or a form thereof, wherein substituents Ri a , when present, are indicated in the table below; and, "— indicates that one or more Ri a substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ia7) or a form thereof, wherein substituents Ri a , when present, are indicated in the table below; and, "— indicates that one or more Ri a substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ia8) or a form thereof, wherein substituents Ri a and B, when present, are indicated in the table below; and, "— " indicates that one or more Ri a and B substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ia9) or a form thereof, wherein substituents Ri a and B, when present, are indicated in the table below; and, "— " indicates that one or more Ri a and B substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (la 10) or a form thereof, wherein substituents Ri a and B, when present, are indicated in the table below; and, "— " indicates that one or more Ri a and B substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (lal 1) or a form thereof, wherein substituents A, X and R 4a , when present, are indicated in the table below; and, "— " indicates that one or more A, X and R 4a substituents are not present:
  • Another embodiment of the present description includes a compound of Formula (la) or a form thereof selected from a compound of Formula (lal 1) or a form thereof, wherein
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (lal 1) or a form thereof, wherein substituents A, X and R 4a , when present, are indicated in the table below; and, "— " indicates that one or more A, X and R 4a substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (la 12) or a form thereof, wherein substituents X, Ri a and B, when present, are indicated in the table below; and, "— " indicates that one or more X, Ri a and B substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ial3) or a form thereof, wherein substituents X, Ri a and R 4a , when present, are indicated in the table below; and, "— " indicates that one or more X, Ri a and R 4a substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (la 14) or a form thereof, wherein substituents X and B, when present, are indicated in the table below; and, "— " indicates that one or more X and B substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ial5) or a form thereof, wherein substituents X, Ri a and R 4a , when present, are indicated in the table below; and, "— " indicates that one or more X, Ri a and R 4a substituents are not present:
  • Another embodiment of the present description includes a compound of Formula (la) or a form thereof selected from a compound of Formula (Ial5) or a form thereof, wherein
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ial5) or a form thereof, wherein substituents X, Ri a and R 4a , when present, are indicated in the table below; and, "— " indicates that one or more X, Ri a and R 4a substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (la 16) or a form thereof, wherein substituents Ri a and R4 a , when present, are indicated in the table below; and, "— " indicates that one or more Ri a and R 4a substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ial7) o form thereof, wherein substituent Ri a , when present, is indicated in the table below; and, "— indicates that one or more Ri a substituents are not present:
  • Another embodiment of the present description includes a compound of Formula (la) or a form thereof selected from a compound of Formula (Ial8) or a form thereof, wherein
  • Another embodiment of the method of the present description includes the use of a compound of Formula (la) or a form thereof selected from a compound of Formula (Ial8) or a form thereof, wherein substituents X, Ri a and B, when present, are indicated in the table below; and, "— " indicates that one or more X, Ri a and B substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ibl) or a form thereof, wherein substituent A is indicated in the table below:
  • Another embodiment of the present description includes a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ibl) or a form thereof, wherein substituent A is indicated in the table below
  • Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ibl) or a form thereof, wherein substituent A is indicated in the table below:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib2) or a form thereof, wherein substituent A is indicated in the table below:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib3) or a form thereof, wherein substituents Ri a , and B, when present, are indicated in the table below; and, "— " indicates that one or more Ri a , and B substituents are not present:
  • Another embodiment of the ccpresent description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib4) or a form thereof, wherein substituents Ri a , R ⁇ , Ri c , Ri d (each representative of the scope of Ri) and X, when present, are indicated in the table below; and, "— " indicates that one or more Ri a , R ⁇ , Ri c , Ri d and X substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib5) or a form thereof, wherein substituents Ri a , R ⁇ , Ri c , Ri d (each representative of the scope of Ri) and R 4a , when present, are indicated in the table below; and, "— " indicates that one or more Ri a , R ⁇ , Ri c , Ri d and R4 a substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib6) or a form thereof, wherein substituents Ri a , R ⁇ , Ri c and R ⁇ (each representative of the scope of Ri), when present, are indicated in the table below; and, "— " indicates that one or more Ri a , Ri b , Ri c and Ri d substituents are not present:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib7) or a form thereof, wherein substituent Ri b , when present, is indicated in the table below:
  • Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib8) or a form thereof, wherein substituent Rib, when present, is indicated in the table below:
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject, selected from the group consisting of:
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • the compound of Formula (I) or a form thereof includes a compound selected from the group consisting of:
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • Another embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof (wherein compound number (#*) indicates that the salt form was isolated) to the subject, selected from the group consisting of:

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CN201680081666.1A CN108697709A (zh) 2015-12-10 2016-12-11 用于治疗亨廷顿病的方法
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KR1020187016467A KR102488323B1 (ko) 2015-12-10 2016-12-11 헌팅턴병 치료 또는 개선을 위한 조성물
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