AR094116A1 - Imidazopiridinas sustituidas como inhibidores de hdm2 - Google Patents

Imidazopiridinas sustituidas como inhibidores de hdm2

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Publication number
AR094116A1
AR094116A1 ARP130104855A ARP130104855A AR094116A1 AR 094116 A1 AR094116 A1 AR 094116A1 AR P130104855 A ARP130104855 A AR P130104855A AR P130104855 A ARP130104855 A AR P130104855A AR 094116 A1 AR094116 A1 AR 094116A1
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Argentina
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cra2
alkyl
cycloalkyl
heteroaryl
heterocyclic
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ARP130104855A
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Merck Sharp & Dohme
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Los compuestos representativos son útiles como inhibidores de la proteína HDM2. También se desvelan composiciones farmacéuticas que comprenden los compuestos anteriores y métodos potenciales para el tratamiento del cáncer que usan los mismos. Reivindicación 1: Compuesto representado por la fórmula (1), en la que R¹ se selecciona entre el grupo que consiste en H, alquilo C₁₋₆, -(CRᵃ₂)ₙCOOR¹¹, -T-NHR⁵, -(CRᵃ₂)ₙNR⁵SO₂R⁶, -(CRᵃ₂)ₙSO₂NR⁵R⁶, -(CRᵃ₂)ₙC(O)NRᶜSO₂N(Rᶜ)₂, -(CRᵃ₂)ₙC(O)NRᶜSO₂Rᶜ, -(CRᵃ₂)ₙC(O)R⁵, -(CRᵃ₂)ₙCONR⁵R⁶, -(CRᵃ₂)ₙCONR⁵OR⁶, -(CRᵃ₂)ₙNR⁵C(O)R⁶, -(CRᵃ₂)ₙOR⁵, -(CRᵃ₂)ₙS(O)Rᶜ, -(CRᵃ₂)ₙS(O)₂Rᶜ, y anillo de heterocíclico, heteroarilo o heterociclenilo de 5 ó 6 miembros que contiene nitrógeno, en el que el alquilo y el anillo de 5 ó 6 miembros pueden estar opcionalmente sustituidos con ORᶜ, SRᶜ, NH₂, nitro, CN, amida, COOR¹¹, alquilo C₁₋₆, haloalquilo C₁₋₆, haloalcoxi C₁₋₆, hidroxialquilo C₁₋₆, alquenilo C₂₋₆, alquil C₁₋₆-C(=O)O-, alquil C₁₋₆-C(=O)-, alquinilo C₂₋₆, grupo halo, hidroxialcoxi, -SO₂NRᶜRᶜ, -NRᶜSO₂Rᶜ, alquilsulfonilo C₁₋₆, alquilamino C₁₋₆ o dialquil C₁₋₆amino; R² se selecciona entre el grupo que consiste en arilo, heteroarilo, cicloalquilo C₃₋₈, -W(CRᵃR⁹)ₜR⁷, y heterocíclico, en el que W es NRᶜ u O, en el que el arilo, heteroarilo, o heterocíclico está opcionalmente sustituido con R¹² seleccionado entre el grupo que consiste en halo, CN, haloalquilo C₁₋₆, alquilo C₁₋₆, -(CRᵃ₂)ᶻORᶜ, -(CRᵃ₂)ᶻNHR⁸, -(CRᵃ₂)ᶻC(O)NRᶜRᶜ, -(CRᵃ₂)ᶻCOOR¹⁰, -(CRᵃ₂)ᶻ-arilo, -(CRᵃ₂)ᶻ-heteroarilo, -(CRᵃ₂)ᶻ-heterocíclico, -(CRᵃ₂)ᶻ-cicloalquilo C₃₋₈, -(CRᵃ₂)ᶻ-ciclenilo, y -(CRᵃ₂)ᶻ-heterocicleniIo, en el que el alquilo, arilo, heteroarilo, heterocíclico, cicloalquilo, ciclenilo y heterociclenilo de R¹² pueden estar opcionalmente sustituidos con OH, NH₂, nitro, CN, CON(Rᶜ)₂, -(CRᵃ₂)ᶻCOOR¹⁰, alcoxi C₁₋₆, alquilo C₁₋₆, haloalquilo C₁₋₆, haloalcoxi C₁₋₆, hidroxialquilo C₁₋₆, alquenilo C₂₋₆, alquil C₁₋₆-C(=O)O-, alquil C₁₋₆-C(=O)-, alquinilo C₂₋₆, grupo halo, hidroxi-alcoxi, -SO₂NRᶜRᶜ, -NRᶜSO₂Rᶜ, alquilsulfonilo C₁₋₆, alquilamino C₁₋₆ o dialquil C₁₋₆amino; R³ se selecciona entre el grupo que consiste en H, -(CRᵃ₂)qNRᶜR⁸, -(CRᵃ₂)qOR⁸, -(CRᵃ₂)qSR⁸, -(CRᵃ₂)qC(O)R⁸, -(CRᵃ₂)qS(O)R⁸, -(CRᵃ₂)qS(O)₂R⁸, -(CRᵃ₂)qCONRᶜR⁸, (CRᵃ₂)qNRᶜC(O)R⁸, -T-alquilo, alquenilo C₂₋₆, -T-arilo, -T-heteroarilo, -T-heterocíclico, -T-cicloalquilo C₃₋₇, -T-ciclenilo, y -T-heterociclenilo, en el que el alquilo, alquenilo, arilo, heteroarilo, heterocíclico, cicloalquilo, ciclenilo y heterociclenilo pueden estar opcionalmente sustituidos con halo, SRᶜ, ORᶜ, haloalquilo C₁₋₆, haloalcoxi C₁₋₆, -(CRᵃ₂)ᶻCN, alquilo C₁₋₆, alquenilo C₂₋₆, alquinilo C₂₋₆, -(CRᵃ₂)ᶻC(O)OR¹¹, -(CRᵃ₂)ᶻC(O)R⁸, -(CRᵃ₂)ᶻOR⁸, -(CRᵃ₂)ᶻNRᶜR⁸, -(CRᵃ₂)ᶻS(O)₂R⁸, -(CRᵃ₂)ᶻC(O)NRᶜR⁸, -(CRᵃ₂)ᶻ-arilo, -(CRᵃ₂)ᶻ-heteroarilo, -(CRᵃ₂)ᶻ-cicloalquilo C₃₋₈, -(CRᵃ₂)ᶻ-heterocíclico, -(CRᵃ₂)ᶻ-heterociclenilo, -(CRᵃ₂)ᶻ-ciclenilo, -(CRᵃ₂)ᶻSO₂NRᶜR⁸, o -(CRᵃ₂)ᶻO(CRᵃ₂)ᶻY(CRᵃ₂)ᵛU, dichos alquilo, alquenilo, alquinilo, arilo, heteroarilo, cicloalquilo, heterocíclico, heterociclenilo y ciclenilo pueden estar sustituidos además con OH, SH, NH₂, nitro, CN, CON(Rᶜ)₂, COOR¹⁰, alcoxi C₁₋₆, alquilo C₁₋₆, alquenilo C₂₋₆, haloalquilo C₁₋₆, haloalcoxi C₁₋₆, hidroxialquilo C₁₋₆, alquil C₁₋₆-C(=O)O-, alquil C₁₋₆-, C(=O)-, alquinilo C₂₋₆, grupo halo, hidroxialcoxi, -SO₂NRᶜRᶜ, -SO₂Rᶜ, -NRᶜSO₂Rᶜ, alquilsulfonilo C₁₋₆, alquilamino C₁₋₆ o dialquil C₁₋₆amino; R⁴ se selecciona entre el grupo que consiste en alquilo C₁₋₆, -(CRᵃ₂)ₘ-arilo, -(CRᵃ₂)ₘ-heteroarilo, -(CRᵃ₂)ₘ-heterocíclico, -(CRᵃ₂)ₘ-cicloalquilo C₃₋₈, -(CRᵃ₂)ₘ-ciclenilo, y -(CRᵃ₂)ₘ-heterociclenilo, en el que el alquilo, arilo, heteroarilo, heterocíclico, cicloalquilo, ciclenilo, y heterociclenilo pueden estar opcionalmente sustituidos con OH, SH, NH₂, nitro, CN, CON(Rᶜ)₂, COOR¹¹, alcoxi C₁₋₆, alquilo C₁₋₆, cicloalquilo C₃₋₆, haloalquenilo C₂₋₆, alquenilo C₂₋₆, alquenoxi C₂₋₆, haloalquilo C₁₋₆, haloalcoxi C₁₋₆, hidroxialquilo C₁₋₆, alquil C₁₋₆-C(=O)O-, alquil C₁₋₆-C(=O)-, alquinilo C₂₋₆, grupo halo, hidroxialcoxi, -SO₂NRᶜRᶜ, -NRᶜSO₂Rᶜ, alquilsulfonilo C₁₋₆, alquilamino C₁₋₆ o dialquil C₁₋₆amino; R⁵ se selecciona independientemente entre el grupo que consiste en H, alquilo C₁₋₆, -alquil C₀₋₆-cicloalquilo C₃₋₈, -alquil C₀₋₆-heteroarilo, -alquil C₀₋₆-arilo, y -alquilheterocíclico C₀₋₆, en el que el alquilo, cicloalquilo, heteroarilo, arilo, y heterocíclico pueden estar opcionalmente sustituidos con alquenilo C₂₋₃, cicloalquilo C₃₋₆, alcoxi C₁₋₃, OH, halo, NH₂, alquilamino C₁₋₃, dialquilamino C₁₋₃ o COOR¹¹; R⁶ se selecciona independientemente entre el grupo que consiste en H, alquilo C₁₋₆, -alquil C₀₋₆-cicloalquilo C₃₋₈, -alquil C₀₋₆-heteroarilo, -alquil C₀₋₆-arilo, y -alquilheterocíclico C₀₋₆, en el que el alquilo, cicloalquilo, heteroarilo, arilo, y heterocíclico pueden estar opcionalmente sustituidos con alquenilo C₂₋₃, cicloalquilo C₃₋₆, alcoxi C₁₋₃, OH, halo, NH₂, alquilamino C₁₋₃, dialquilamino C₁₋₃ o COOR¹¹; R⁷ se selecciona entre el grupo que consiste en H, alquilo C₁₋₆, alquenilo C₂₋₆, cicloalquilo C₃₋₈, arilo, heteroarilo, heterocíclico, en el que el alquilo, alquenilo, cicloalquilo, arilo, heteroarilo o heterocíclico puede estar opcionalmente sustituido con halo, nitro, CN, haloalquilo C₁₋₆, haloalcoxi C₁₋₆, alquenilo C₂₋₆, alquinilo C₂₋₆, alquilo C₁₋₆, -alquil C₀₋₆-cicloalquilo C₃₋₈, -alquil C₀₋₆-heteroarilo, -alquilo C₀₋₆-arilo, -alquiIheterocíclico C₀₋₆, -alquilheterociclenilo C₀₋₆, -alquilciclenilo C₀₋₆, -(CRᵃ₂)ᶻNR⁵R⁶, -(CRᵃ₂)ᶻNR⁵SO₂R⁶, -(CRᵃ₂)ᶻSO₂NR⁵R⁶, -(CRᵃ₂)ᶻC(O)R⁵, -(CRᵃ₂)ᶻC(O)OR¹⁰, -(CRᵃ₂)ᶻCONR⁵R⁶, -(CRᵃ₂)ᶻCONR⁵OR⁶, -(CRᵃ₂)ᶻNR⁵C(O)R⁶, -(CRᵃ₂)ᶻOR⁵, -(CRᵃ₂)ᶻS(O)Rᶜ, y -(CRᵃ₂)ᶻS(O)₂Rᶜ; R⁸ se selecciona independientemente
ARP130104855A 2012-12-20 2013-12-18 Imidazopiridinas sustituidas como inhibidores de hdm2 AR094116A1 (es)

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US201261740232P 2012-12-20 2012-12-20
US201361777472P 2013-03-12 2013-03-12

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US (2) US8846657B2 (es)
EP (1) EP2935263B1 (es)
JP (1) JP6387013B2 (es)
KR (1) KR102196882B1 (es)
CN (1) CN105073746B (es)
AR (1) AR094116A1 (es)
AU (1) AU2013361694B2 (es)
BR (1) BR112015013611A2 (es)
CA (1) CA2895504A1 (es)
ES (1) ES2707305T3 (es)
MX (1) MX2015008196A (es)
RU (1) RU2690663C2 (es)
TW (1) TW201429969A (es)
WO (1) WO2014100065A1 (es)

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