AR092491A1 - Derivados de imidazolin-5-ona utiles como inhibidores de fasn para el tratamiento contra el cancer - Google Patents

Derivados de imidazolin-5-ona utiles como inhibidores de fasn para el tratamiento contra el cancer

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AR092491A1
AR092491A1 ARP130103205A ARP130103205A AR092491A1 AR 092491 A1 AR092491 A1 AR 092491A1 AR P130103205 A ARP130103205 A AR P130103205A AR P130103205 A ARP130103205 A AR P130103205A AR 092491 A1 AR092491 A1 AR 092491A1
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Abstract

Se dan a conocer compuestos, composiciones y métodos para el tratamiento de varios trastornos, síndromes, enfermedades y afecciones, que incluyen aquellos mediados por la inhibición de la enzima ácido graso sintasa (FASN), tales como cáncer, obesidad y trastornos relacionados, y trastornos relacionados con el hígado. Reivindicación 1: Un compuesto de la fórmula (1) en donde R¹ y R² se toman junto con el átomo de carbono al que están ligados para formar una estructura de anillos opcionalmente sustituida seleccionada del grupo que consiste en (a) cicloalquilo C₃₋₈; en donde el cicloalquilo C₃₋₈ se sustituye opcionalmente con uno a dos grupos R¹¹; (b) cicloalquilo C₅₋₆ fusionado con benzo; en donde el cicloalquilo C₅₋₆ fusionado con benzo está ligado a través de un átomo de carbono de la porción de cicloalquilo C₅₋₆ de la estructura de anillos; en donde el cicloalquilo C₅₋₆ fusionado con benzo se sustituye opcionalmente con uno a dos grupos R¹¹; y (c) heterociclilo saturado de 4 a 8 miembros; en donde el heterociclilo saturado de 4 a 8 miembros contiene un heteroátomo seleccionado del grupo que consiste en O, S y N; en donde el S se sustituye opcionalmente con uno a dos oxo; en donde el N se sustituye con R¹⁰; siempre que el heteroátomo no esté presente en la posición 2 con relación al átomo de carbono de la imidazolin-5-ona; y en donde el heterociclilo saturado de 4 a 8 miembros se sustituye opcionalmente con un grupo R¹¹ y, además se sustituye opcionalmente con un grupo R¹²; en donde R¹⁰ se selecciona del grupo que consiste en hidrógeno, alquilo C₁₋₄, alquilo C₁₋₄ fluorizado, -CH₂-(alquilo C₁₋₄ sustituido con hidroxilo), alquilo C₂₋₄-O-alquilo C₁₋₄, -(alquenilo C₂₋₄), -(alquil C₁₋₄)-fenilo, -C(O)-NRARB, -C(O)-(alquil C₁₋₃)-NRARB, -C(O)-(alquilo C₁₋₄), -C(O)-(alquilo C₁₋₂ fluorizado), -C(O)-(cicloalquilo C₃₋₆), -C(O)-fenilo, -C(O)-(heteroarilo de 5 a 6 miembros), un resto de fórmula (2) ó (3), -C(O)O-(alquilo C₁₋₄), -SO₂-(alquilo C₁₋₄), SO₂-NRARB, fenilo, y heteroarilo de 5 a 6 miembros; en donde Z¹ se selecciona del grupo que consiste en -CH₂-, -O-, -N(RC)-, -S-, -S(O)- y -SO₂-; en donde RA, RB y RC se seleccionan independientemente del grupo que consiste en hidrógeno y alquilo C₁₋₄; y en donde el fenilo o heteroarilo de 5 a 6 miembros ya sea solo o como parte de un grupo sustituyente, se sustituye, además, opcionalmente con uno a dos sustituyentes independientemente seleccionados del grupo que consiste en halógeno, hidroxilo, ciano, NRARB, alquilo C₁₋₄, alquilo C₁₋₄ fluorizado, alcoxi C₁₋₄, y alcoxi C₁₋₄ fluorizado; en donde cada R¹¹ se selecciona independientemente del grupo que consiste en hidroxi, oxo, halógeno, alquilo C₁₋₄, alquilo C₁₋₄ fluorizado, alcoxi C₁₋₄, alcoxi C₁₋₄ fluorizado, alquilo C₁₋₄ sustituido con hidroxi, -(alquilo C₁₋₄)-O-(alquilo C₁₋₄), -(alquilo C₁₋₄)-fenilo, -ciano, -NRDRE, -C(O)-NRDRE, -C(O)-(alquilo C₁₋₄), -C(O)-fenilo, -C(O)-(heteroarilo de 5 a 6 miembros), un resto de fórmula (2) ó (4), -C(O)OH, -C(O)O-(alquilo C₁₋₄), -SO₂-(alquilo C₁₋₄), SO₂-NRDRE, fenilo y heteroarilo de 5 a 6 miembros; en donde Z² se selecciona del grupo que consiste en -CH₂-, -O-, -N(RC)-, -S-, -S(O)- y -SO₂-; en donde RD, RE y RF se seleccionan independientemente del grupo que consiste en hidrógeno y alquilo C₁₋₄; y en donde el fenilo o heteroarilo de 5 a 6 miembros ya sea solo o como parte de un grupo sustituyente, se sustituye, además, opcionalmente con uno a dos sustituyentes independientemente seleccionados del grupo que consiste en halógeno, hidroxi, ciano, NRDRE, alquilo C₁₋₄, alquilo C₁₋₄ fluorizado, alcoxi C₁₋₄ y alcoxi C₁₋₄ fluorizado; y en donde R¹² se selecciona del grupo que consiste en hidroxi, oxo, halógeno, alquilo C₁₋₄, alquilo C₁₋₄ fluorizado, alcoxi C₁₋₄, alcoxi C₁₋₄ fluorizado, y alquilo C₁₋₄ sustituido con hidroxi; m es un entero de 0 a 1; y n es un entero de 0 a 2; siempre que, cuando n es 2, entonces m es 1; el resto de fórmula (5) selecciona del grupo que consiste en azetidin-3-ilo, pirrolidin-3-ilo, pirrolidin-3R-ilo, pirrolidin-3S-ilo, piperidin-3-ilo, piperidin-3R-ilo, piperidin-2S-ilo, y piperidin-4-ilo; a es un entero de 0 a 1; L¹ se selecciona del grupo que consiste en -C(O)-, -C(O)O-, -C(O)-NRL-, -C(S)-, -SO₂-, y -SO₂-NRL; en donde RL se selecciona de grupo que consiste en hidrógeno y alquilo C₁₋₄; R³ se selecciona del grupo que consiste en alquilo C₁₋₄, alquilo C₁₋₄ fluorizado, alquilo C₁₋₄ sustituido con hidroxi, alquenilo C₂₋₄, cicloalquilo C₃₋₆, -(alquilo C₁₋₄)-(cicloalquilo C₃₋₆), heterociclilo saturado de 4 a 6 miembros, -(alquilo C₁₋₄)-(heterociclilo saturado de 4 a 6 miembros), -(alquenilo C₂₋₄)-(heterociclilo saturado de 5 a 6 miembros), heteroarilo de 5 a 6 miembros, -(alquilo C₁₋₄)-(heteroarilo de 5 a 6 miembros), -(alquenilo C₂₋₄)-(heteroarilo de 5 a 6 miembros), y NRVRW; en donde RV y RW se seleccionan independientemente del grupo que consiste en hidrógeno y alquilo C₁₋₄; en donde cicloalquilo C₃₋₆, heterociclilo saturado de 4 a 6 miembros o heteroarilo de 5 a 6 miembros, ya sea solo o como parte de un grupo sustituyente, se sustituyen opcionalmente con uno a dos sustituyentes independientemente seleccionados del grupo que consiste en halógeno, hidroxilo, ciano, alquilo C₁₋₄, alquilo C₁₋₄ fluorizado, -(alquilo C₁₋₄)-OH, alcoxi C₁₋₄, alcoxi C₁₋₄ fluorizado, y NRGRH; en donde RG y RH se seleccionan independientemente del grupo que consiste en hidrógeno y alquilo C₁₋₄; el resto de fórmula (6) se selecciona del grupo que consiste en el grupo de formulas (7); b es un entero de 0 a 2; cada R⁴ se selecciona independientemente del grupo que consiste en hidroxi, halógeno, alquilo C₁₋₄, alquilo C₁₋₄ fluorizado, alcoxi C₁₋₄, alcoxi C₁₋₄ fluorizado, ciano, y NRJRK; en donde RJ y RK se seleccionan independientemente del grupo que consiste en hidrógeno y alquilo C₁₋₄; siempre que cada grupo R⁴ esté ligado a un átomo de carbono; siempre que, cuando el resto de fórmula (6) se selecciona del grupo que consiste en el grupo de formulas (8), y esté sustituido con -(R⁴)ᵇ, entonces b es un entero de 0 a 1; R⁵ se selecciona del grupo que consiste en (a) el compuesto de formula (9)y (b) el compuesto de fórmula (10); en donde el anillo A¹ se selecciona del grupo que consiste en arilo, heteroarilo y heterociclilo parcialmente insaturado; c es un entero de 0 a 2; cada R⁶ se selecciona independientemente del grupo que consiste en hidroxi, oxo, halógeno, ciano, nitro, alquilo C₁₋₄, alquilo C₁₋₄ fluorizado, alquilo C₁₋₄ sustituido con hidroxi, -(alquilo C₁₋₄)-CN, -(alquilo C₁₋₄)-O-(alquilo C₁₋₄, alcoxi C₁₋₄, alcoxi C₁₋₄ fluorizado, -SO₂-(alquilo C₁₋₄), -NRMRN, -(alquilo C₁₋₄)-NRPRQ, -C(O)-(alquilo C₁₋₄), -C(O)-(alquilo C₁₋₂ fluorizado), -C(O)-NRMRN, -C(O)OH, -C(O)O-(alquilo C₁₋₄), -NRM-C(O)H, -NRM-C(O)-(alquilo C₁₋₄), -NRM-SO₂-(alquilo C₁₋₄), cicloalquilo C₃₋₆, -ciano-(cicloalquilo C₃₋₆), -(alquilo C₁₋₄)-(cicloalquilo C₃₋₆), -S-(cicloalquilo C₃₋₆), -SO-(cicloalquilo C₃₋₆), -SO₂-(cicloalquilo C₃₋₆), -NH-(cicloalquilo C₃₋₆), -NH-SO₂-(cicloalquilo C₃₋₆), oxetanilo, -(alquilo C₁₋₂)-oxetanilo, tetrahidrofuranilo, -(alquilo C₁₋₂)-tetrahidro-furanilo, tetrahidropiranilo, y -(alquilo C₁₋₂)-tetrahidro-piranilo; en donde RM y RN se seleccionan independientemente del grupo que consiste en hidrógeno y alquilo C₁₋₄; en donde RP y RQ se seleccionan independientemente del grupo que consiste en hidrógeno y alquilo C₁₋₄; alternativamente RP y RQ se toman junto con el átomo de nitrógeno al que están ligados para formar un heterociclilo saturado de 5 a 6 miembros; tal heterociclilo saturado de 5 a 6 miembros se sustituye opcionalmente con un sustituyente seleccionado del grupo que consiste en halógeno, alquilo C₁₋₄, y alquilo C₁₋₄ fluorizado; en donde el anillo A² se selecciona
ARP130103205A 2012-09-07 2013-09-09 Derivados de imidazolin-5-ona utiles como inhibidores de fasn para el tratamiento contra el cancer AR092491A1 (es)

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US20150099730A1 (en) 2015-04-09
WO2014039769A1 (en) 2014-03-13
US10077261B2 (en) 2018-09-18
US20160002219A1 (en) 2016-01-07
US20180327401A1 (en) 2018-11-15
EP2892892B1 (en) 2017-05-31
EP2892892A1 (en) 2015-07-15
JP2015527397A (ja) 2015-09-17
CA2884355A1 (en) 2014-03-13
JP6285442B2 (ja) 2018-02-28

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