AR101483A1 - COMPUESTOS DE TIAZIN-2-AMINA FUSIONADOS CON CICLOPROPILO COMO INHIBIDORES DE b-SECRETASA Y MÉTODOS DE USO - Google Patents

COMPUESTOS DE TIAZIN-2-AMINA FUSIONADOS CON CICLOPROPILO COMO INHIBIDORES DE b-SECRETASA Y MÉTODOS DE USO

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Publication number
AR101483A1
AR101483A1 ARP150102557A ARP150102557A AR101483A1 AR 101483 A1 AR101483 A1 AR 101483A1 AR P150102557 A ARP150102557 A AR P150102557A AR P150102557 A ARP150102557 A AR P150102557A AR 101483 A1 AR101483 A1 AR 101483A1
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Argentina
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alkyl
heterocyclyl
ring
alkenyl
chc
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ARP150102557A
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English (en)
Inventor
Xue Qiufen
D White Ryan
M Stec Markian
C Siegmund Aaron
M Rzasa Robert
Rumfelt Shannon
Qian Wenyuan
J Pickrell Alexander
H Pettus Liping
H Norman Mark
Nishimura Nobuko
T Nguyen Thomas
Elena Minatti Ana
Manning James
Van Ma Vu
D Low Jonathan
Liu Qingyian
Liu Longbin
E Harrington Paul
Guzman-Perez Angel
J Frohn Michael
Cheng Yuan
J Chen Jian
A Brown James
P Bourbeau Matthew
Amegadzie Albert
R Allen Jennifer
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Amgen Inc
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Publication of AR101483A1 publication Critical patent/AR101483A1/es

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    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Reivindicación 1: Un compuesto de la fórmula (1), o un estereoisómero, tautómero, hidrato, solvato o sal farmacéuticamente aceptable del mismo, caracterizado porque A⁴ es CR⁴ o N; A⁵ es CR⁵ o N; A⁶ es CR⁶ o N; A⁸ es CR⁸ o N, con la condición de que no más de dos de A⁴, A⁵, A⁶ y A⁸ es N; cada uno de Rᵃ y Rᵇ, independientemente, es H, F, Cl, alquilo-C₁₋₆, alquenilo-C₂₋₄, alquinilo-C₂₋₄, CN, -CH₂O-alquilo-C₁₋₆, -O-alquilo-C₁₋₆, -S(O)ₒ-alquilo-C₁₋₆, -NH-alquilo-C₁₋₆ o -C(O)alquilo-C₁₋₆, en donde cada uno de la porción alquilo-C₁₋₆, alquenilo-C₂₋₄, alquinilo-C₂₋₄, y alquilo-C₁₋₆ de -CH₂O-alquilo-C₁₋₆, -O-alquilo-C₁₋₆, -S(O)ₒ-alquilo-C₁₋₆, -NH-alquilo-C₁₋₆ y -C(O)alquilo-C₁₋₆ están opcionalmente sustituidas con 1 - 4 sustituyentes de F, oxo u OH; R¹ y cualquiera de Rᵃ o Rᵇ puede unirse opcionalmente para formar un anillo saturado de 5 miembros que incluye un heteroátomo S; R¹ es H, F, Cl, alquilo-C₁₋₆, alquenilo-C₂₋₄, alquinilo-C₂₋₄,CN, -CH₂O-alquilo-C₁₋₆, -O-alquilo-C₁₋₆, -S(O)ₒ-alquilo-C₁₋₆, -NH-alquilo-C₁₋₆, -alquilo-C₁₋₆-NH₂, -alquilo-C₁₋₆-NH-alquilo-C₁₋₆, -alquilo-C₁₋₆-NHC(O)O-alquilo-C₁₋₆, -alquilo-C₁₋₆-NHC(O)NH-alquilo-C₁₋₆, -alquilo-C₁₋₆-NHC(O)alquilo-C₁₋₆, -C(O)NH₂, -CH=CHC(O)NH₂, -CH=CHC(O)NH-alquilo-C₁₋₆, -CH=CHC(O)N(alquilo-C₁₋₆)₂, -CH=CHC(O)NH-alquilo-C₁₋₆-O-alquilo-C₁₋₆, -CH=CHC(O)-heterociclilo, CH=C(CH₃)C(O)-heterociclilo, -CH=CHC(O)₂H, -CH=CHC(O)O-alquilo-C₁₋₆, -CH=CHCH₂OH, alquilo-C₁₋₆-C(O)NH-alquilo-C₁₋₆, alquilo-C₁₋₆-C(O)N(alquilo-C₁₋₆)₂, -C(O)alquilo-C₁₋₆, -C(O)alquenilo-C₁₋₆, -C(O)OH, -C(O)O-alquilo-C₁₋₆, -C(O)NH-alquilo-C₁₋₆, -C(O)N(alquilo-C₁₋₆)₂, -C(O)NH-cicloalquilo-C₃₋₆, -C(O)NHO-alquilo-C₁₋₆, -C(O)N(alquilo-C₁₋₆)O-alquilo-C₁₋₆, -C(O)-heterociclilo, -CH₂-heteroarilo, o heteroarilo, en donde los grupos heterociclilo de los grupos -CH=CHC(O)-heterociclilo, -CH=C(CH₃)C(O)-heterociclilo, y -C(O)-heterociclilo son anillos monocíclicos de 3, 4, 5, 6 ó 7 miembros completamente o parcialmente insaturados que incluye 1 heteroátomo seleccionado de N, O, o S si el anillo es un anillo de 3 miembros, que incluye 1 ó 2 heteroátomos independientemente seleccionados de N, O, o S si el anillo es un anillo de 4 ó 5 miembros, e incluye 1, 2, ó 3 heteroátomos independientemente seleccionados de N, O, o S si el anillo es un anillo de 6 ó 7 miembros, en donde el grupo heteroarilo de los grupos -CH₂-heteroarilo y heteroarilo es un anillo de 5 ó 6 que incluye 1, 2, 3 ó 4 heteroátomos seleccionados de N ,O, o S, en donde cada una de la porción alquilo-C₁₋₆, alquenilo-C₂₋₄, alquinilo-C₂₋₄ y cicloalquilo-C₃₋₆ de los grupos alquilo-C₁₋₆, alquenilo-C₂₋₄, alquinilo-C₂₋₄, -CH₂O-alquilo-C₁₋₆, -O-alquilo-C₁₋₆, -S(O)ₒ-alquilo-C₁₋₆, NH-alquilo-C₁₋₆, C₍O₎ₐₗqᵘⁱₗₒ₋C₁₋₆, -C(O)alquenilo-C₁₋₆, -C(O)NH-alquilo-C₁₋₆, -C(O)N(alquilo-C₁₋₆)₂, -C(O)NH-cicloalquilo-C₃₋₆, -CH=CHC(O)NH-alquilo-C₁₋₆ y alquilo-C₁₋₆-C(O)NH-alquilo-C₁₋₆, están opcionalmente sustituidas con 1 - 4 sustituyentes de F, CN, metilo, oxo u OH, y además en donde cada uno de los grupos heterociclilo de los grupos -CH=CHC(O)-heterociclilo, -CH=C(CH₃)C(O)-heterociclilo, y -C(O)heterociclilo está opcionalmente sustituido con 1 - 4 sustituyentes independientemente seleccionados de F, metilo, OH, o OCH₃ y además en donde cada uno de los grupos heteroarilo de los grupos -CH₂-heteroarilo y heteroarilo está opcionalmente sustituido con 1 - 3 sustituyentes independientemente seleccionados de halo, metilo, u OH; R² es H, F, Cl, alquilo-C₁₋₆, alquenilo-C₂₋₄, alquinilo-C₂₋₄, CN, -CH₂O-alquilo-C₁₋₆, -O-alquilo-C₁₋₆, -S(O)ₒ-alquilo-C₁₋₆, -NH-alquilo-C₁₋₆, -C(O)NH₂, -CH=CHC(O)NH-alquilo-C₁₋₆, -CH=CHC(O)₂H, CH=CHCH₂OH, alquilo-C₁₋₆-C(O)NH-alquilo-C₁₋₆, -C(O)alquilo-C₁₋₆ o -C(O)alquenilo-C₁₋₆, en donde cada una de la porción alquilo-C₁₋₆, alquenilo-C₂₋₄, alquinilo-C₂₋₄, y alquilo-C₁₋₆ de -CH₂O-alquilo-C₁₋₆, -O-alquilo-C₁₋₆, -S(O)ₒ-alquilo-C₁₋₆, -NH-alquilo-C₁₋₆, C₍O₎ₐₗqᵘⁱₗₒ₋C₁₋₆, -C(O)alquenilo-C₁₋₆, -CH=CHC(O)NH-alquilo-C₁₋₆ y alquilo-C₁₋₆-C(O)NH-alquilo-C₁₋₆, está opcionalmente sustituida con 1 - 4 sustituyentes de F, CN, oxo u OH; R³ es alquilo-C₁₋₄, CH₂O-alquilo-C₁₋₄, CH₂OH, haloalquilo-C₁₋₄ o ciclopropilo, en donde cada uno del alquilo-C₁₋₄, CH₂O-alquilo-C₁₋₄, haloalquilo-C₁₋₄ y ciclopropilo está opcionalmente sustituido con 1 - 4 átomos F; cada uno de R⁴, R⁵, R⁶ y R⁸, independientemente, es H halo, haloalquilo, haloalcoxilo, alquilo-C₁₋₄ CN, OH, O-alquilo-C₁₋₄, S(O)ₒ-alquilo-C₁₋₄, NH-alquilo-C₁₋₄, C₍O₎ₐₗqᵘⁱₗₒ₋C₁₋₄, C₍O₎O₋ₐₗqᵘⁱₗₒ₋C₁₋₄, o CH₂OH; R⁷ es -NH-R⁹ o-NH-C(=O)-R⁹; R⁹ es un anillo monocíclico de 3, 4, 5, 6 ó 7 miembros o bicíclico de 8, 9 ó 10 miembros completamente o parcialmente insaturado formado de átomos de carbono, el anillo incluye opcionalmente 1 - 4 heteroátomos si es monocíclico o 1 - 5 heteroátomos si es bicíclico, los heteroátomos seleccionados de O, N o S, en donde el anillo está opcionalmente sustituido, independientemente, con 1 - 5 sustituyentes de R¹⁰; cada R¹⁰, independientemente, es H, halo, haloalquilo, CN, OH, NO₂, NH₂, SF₅, acetilo, -C(O)NH-alquilo-C₁₋₆, -OCH₂C(O)NH-alquilo-C₁₋₆, -OCH₂C(O)N(alquilo-C₁₋₆)₂, -OCH₂CH₂-pirolidinonilo, oxo, ciclopropilmetoxi, 2-propiniloxi, 2-butiniloxi, 3-butiniloxi, 3-pentiniloxi, 2-pentiloxi, alquilo-C₁₋₆, alquenilo-C₂₋₆, alquinilo-C₂₋₆, cicloalquilo-C₃₋₆, alquilamino-C₁₋₆, dialquilamino-C₁₋₆, alcoxilo-C₁₋₆, -O-alquenilo-C₂₋₆, tioalcoxilo-C₁₋₆, -OCH₂-cicloalquilo-C₃₋₆, morfolinilo, pirazolilo, isoxazolilo, dihidropiranilo, pirrolilo, pirrolidinilo, tetrahidropirrolilo, piperazinilo, oxetan-3-ilo, imidazo-piridinilo, dioxolilo, -O-heterociclilo, o -OCH₂-heteroarilo, en donde el heterociclilo del grupo -O-heterociclilo es un anillo saturado monocíclico de 3, 4, 5, 6 ó 7 miembros que incluye 1 heteroátomo seleccionados de N, O, o S si el anillo heterociclilo es un anillo de 3 miembros, que incluye 1 ó 2 heteroátomos independientemente seleccionados de N, O, o S si el anillo heterociclilo es un anillo de 4 ó 5 miembros, e incluye 1, 2, ó 3 heteroátomos independientemente seleccionados de N, O, o S si el anillo heterociclilo es un anillo de 6 ó 7 miembros en donde el grupo heteroarilo del grupo -OCH₂-heteroarilo es un anillo de 5 ó 6 miembros que incluye 1, 2, 3, ó 4 heteroátomos seleccionados de N, O, o S, y además en donde cada uno del ciclopropilmetoxi, 2-propiniloxi, 2-butiniloxi, 2-pentiloxi, alquilo-C₁₋₆, alquenilo-C₂₋₆, alquinilo-C₂₋₆, cicloalquilo-C₃₋₆, alquilamino-C₁₋₆, dialquilamino-C₁₋₆, alcoxilo-C₁₋₆, tioalcoxilo-C₁₋₆, -OCH₂-cicloalquilo-C₃₋₆, morfolinilo, pirazolilo, isoxazolilo, dihidropiranilo, pirrolidinilo, oxetan-3-ilo, dioxolilo o -OCH₂-heteroarilo está opcionalmente sustituido independientemente con 1 - 5 sustituyentes de F, Cl, Br, CN, NO₂, NH₂, OH, oxo, CF₃, CHF₂, CH₂F, metilo, metoxi, etilo, etoxi, CH₂CF₃, CH₂CHF₂, propilo, propoxi, isopropilo, isopropoxi, ciclopropilo, butilo, butoxilo, ciclobutilo, isobutoxi, tert-butoxi, isobutilo, sec-butilo, tert-butilo, ciclopentilo, ciclohexilo, fenilo, alquilamino-C₁₋₃, dialquilamino-C₁₋₃, tioalcoxilo-C₁₋₃, oxazolilo, isoxazolilo, tiazolilo, isotiazolilo, tiadiazolilo, tienilo, furilo, pirrolilo, tetrahidropiranilo, tetrahidropirrolilo, oxetan-2-ilo, u oxetan-3-ilo; y el subíndice o se selecciona de 0, 1, ó 2.
ARP150102557A 2014-08-08 2015-08-07 COMPUESTOS DE TIAZIN-2-AMINA FUSIONADOS CON CICLOPROPILO COMO INHIBIDORES DE b-SECRETASA Y MÉTODOS DE USO AR101483A1 (es)

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