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AR119156A1 - COMBINATION OF AN MCL-1 INHIBITOR AND A STANDARD MEDICAL CARE TREATMENT FOR BREAST CANCER, USES AND PHARMACEUTICAL COMPOSITIONS THEREOF - Google Patents

COMBINATION OF AN MCL-1 INHIBITOR AND A STANDARD MEDICAL CARE TREATMENT FOR BREAST CANCER, USES AND PHARMACEUTICAL COMPOSITIONS THEREOF

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AR119156A1
AR119156A1 ARP200101679A ARP200101679A AR119156A1 AR 119156 A1 AR119156 A1 AR 119156A1 AR P200101679 A ARP200101679 A AR P200101679A AR P200101679 A ARP200101679 A AR P200101679A AR 119156 A1 AR119156 A1 AR 119156A1
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Argentina
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group
alkyl
branched
straight
hydrogen atom
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ARP200101679A
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Spanish (es)
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Ensar Halilovic
Dale Porter
Florence Binlich
Alix Derreal
Sbastien Banquet
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Servier Lab
Novartis Ag
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Publication of AR119156A1 publication Critical patent/AR119156A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Una combinación que comprende un inhibidor de Mcl-1 y un segundo agente anticanceroso, en donde el segundo agente anticanceroso se selecciona de eribulina y fulvestrant, y composiciones y usos de la misma. Reivindicación 1: Una combinación que comprende: (a) un inhibidor de Mcl-1 de fórmula (1), en donde: D representa un grupo cicloalquilo, un grupo heterocicloalquilo, un grupo arilo o un grupo heteroarilo, E representa un anillo furilo, tienilo o pirrolilo, X¹, X³, X⁴ y X⁵, independientemente uno de otro, representan un átomo de carbono o un átomo de nitrógeno, X² representa un grupo C-R²⁶ o un átomo de nitrógeno, el “anillo punteado” significa que el anillo es aromático, Y representa un átomo de nitrógeno o un grupo C-R³, Z representa un átomo de nitrógeno o un grupo C-R⁴, R¹ representa un átomo de halógeno, un grupo alquilo C₁₋₆ lineal o ramificado, un grupo alquenilo C₂₋₆ lineal o ramificado, un grupo alquinilo C₂₋₆ lineal o ramificado, un grupo haloalquilo C₁₋₆ lineal o ramificado, un grupo hidroxi, un grupo hidroxialquilo C₁₋₆, un grupo alcoxi C₁₋₆ lineal o ramificado, grupo -S-alquilo C₁₋₆, un grupo ciano, un grupo nitro, -Cy⁸, -alquilo C₀₋₆-NR¹¹R¹¹’, -O-alquilo C₁₋₆-NR¹¹R¹¹’, -O-alquilo C₁₋₆-R¹², -C(O)-OR¹¹, -O-C(O)-R¹¹, -C(O)-NR¹¹R¹¹’, -NR¹¹-C(O)-R¹¹’, -NR¹¹-C(O)-OR¹¹’, -alquilo C₁₋₆-NR¹¹-C(O)-R¹¹’, -SO₂-NR¹¹R¹¹’, o-SO₂-alquilo C₁₋₆, R², R³, R⁴ y R⁵, independientemente uno de otro, representan un átomo de hidrógeno, un átomo de halógeno, un grupo alquilo C₁₋₆ lineal o ramificado, un grupo alquenilo C₂₋₆ lineal o ramificado, un grupo alquinilo C₂₋₆ lineal o ramificado, un haloalquilo C₁₋₆ lineal o ramificado, un grupo hidroxi, un grupo hidroxialquilo C₁₋₆, un grupo alcoxi C₁₋₆ lineal o ramificado, un grupo -S-alquilo C₁₋₆, un grupo ciano, un grupo nitro, -alquilo C₀₋₆-NR¹¹R¹¹’, -OCy¹, -alquilo C₀₋₆-Cy¹, -alquenilo C₂₋₆-Cy¹, -alquinilo C₂₋₆-Cy¹, -O-alquilo C₁₋₆-NR¹¹R¹¹’, -O-alquilo C₁₋₆-R¹², -C(O)-OR¹¹, -O-C(O)-R¹¹, -C(O)-NR¹¹R¹¹’, -NR¹¹-C(O)-R¹¹’, -NR¹¹-C(O)-OR¹¹’, -alquilo C₁₋₆-NR¹¹-C(O)-R¹¹’, -SO₂-NR¹¹R¹¹’, o -SO₂-alquilo C₁₋₆, o la pareja (R¹, R²), (R², R³), (R³, R⁴), o (R⁴, R⁵) junto con los átomos de carbono a los que están unidas forman un anillo aromático o no aromático compuesto por de 5 a 7 miembros en el anillo, que puede contener de 1 a 3 heteroátomos seleccionados de oxígeno, azufre y nitrógeno, entendiéndose que el anillo resultante puede estar sustituido con de 1 a 2 grupos seleccionados de halógeno, alquilo C₁₋₆ lineal o ramificado, -alquilo C₀₋₆-NR¹¹R¹¹’, -NR¹³R¹³’, -alquilo C₀₋₆-Cy¹ u oxo, R⁶ y R⁷, independientemente uno de otro, representan un átomo de hidrógeno, un átomo de halógeno, un grupo alquilo C₁₋₆ lineal o ramificado, un grupo alquenilo C₂₋₆ lineal o ramificado, un grupo alquinilo C₂₋₆ lineal o ramificado, un haloalquilo C₁₋₆ lineal o ramificado, un grupo hidroxi, un grupo alcoxi C₁₋₆ lineal o ramificado, un grupo -S-alquilo C₁₋₆, un grupo ciano, un grupo nitro, -alquilo C₀₋₆-NR¹¹R¹¹’, -O-alquilo C₁₋₆-NR¹¹R¹¹’, -O-Cy¹, -alquilo C₀₋₆-Cy¹, -alquenilo C₂₋₆-Cy¹, -alquinilo C₂₋₆-Cy¹, -O-alquilo C₁₋₆-R¹², -C(O)-OR¹¹, -O-C(O)-R¹¹, -C(O)-NR¹¹R¹¹’, -NR¹¹-C(O)-R¹¹’, -NR¹¹-C(O)-OR¹¹’, -alquilo C₁₋₆-NR¹¹-C(O)-R¹¹’, -SO₂-NR¹¹R¹¹’, o -SO₂-alquilo C₁₋₆, o la pareja (R⁶, R⁷), cuando está fusionada con los dos átomos de carbono adyacentes, junto con los átomos de carbono a los que está unida forman un anillo aromático o no aromático compuesto por de 5 a 7 miembros en el anillo, que puede contener de 1 a 3 heteroátomos seleccionados de oxígeno, azufre y nitrógeno, entendiéndose que el anillo resultante puede estar sustituido con un grupo seleccionado de un grupo alquilo C₁₋₆ lineal o ramificado, -NR¹³R¹³’, -alquilo C₀₋₆-Cy¹ o un oxo, W representa un grupo -CH₂-, un grupo -NH- o un átomo de oxígeno, R⁸ representa un átomo de hidrógeno, un grupo alquilo C₁₋₈ lineal o ramificado, un grupo -CHRᵃRᵇ, un grupo arilo, un grupo heteroarilo, un grupo arilalquilo C₁₋₆, o un grupo heteroarilalquilo C₁₋₆, R⁹ representa un átomo de hidrógeno, un grupo alquilo C₁₋₆ lineal o ramificado, un grupo alquenilo C₂₋₆ lineal o ramificado, un grupo alquinilo C₂₋₆ lineal o ramificado, -Cy², -alquilo C₁₋₆-Cy², -alquenilo C₂₋₆-Cy², -alquinilo C₂₋₆-Cy², -Cy²-Cy³, -alquinilo C₂₋₆-O-Cy², -Cy²-alquilo C₀₋₆-O-alquilo C₀₋₆-Cy³, un átomo de halógeno, un grupo ciano, -C(O)-R¹⁴, o -C(O)-NR¹⁴R¹⁴’, R¹⁰ representa un átomo de hidrógeno, un grupo alquilo C₁₋₆ lineal o ramificado, un grupo alquenilo C₂₋₆ lineal o ramificado, un grupo alquinilo C₂₋₆ lineal o ramificado, un grupo arilalquilo C₁₋₆, un grupo cicloalquilalquilo C₁₋₆, un haloalquilo C₁₋₆ lineal o ramificado, o -alquilo C₁₋₆-O-Cy⁴, o la pareja (R⁹, R¹⁰), cuando está fusionada con los dos átomos de carbono adyacentes, junto con los átomos de carbono a los que está unida forman un anillo aromático o no aromático compuesto por de 5 a 7 miembros en el anillo, que puede contener de 1 a 3 heteroátomos seleccionados de oxígeno, azufre y nitrógeno, R¹¹ y R¹¹’, independientemente uno de otro, representan un átomo de hidrógeno, un grupo alquilo C₁₋₆ lineal o ramificado sustituido opcionalmente, o -alquilo C₀₋₆-Cy¹, o la pareja (R¹¹, R¹¹’) junto con el átomo de nitrógeno al que está unida forman un anillo aromático o no aromático compuesto por de 5 a 7 miembros en el anillo, que puede contener, además del átomo de nitrógeno, de 1 a 3 heteroátomos seleccionados de oxígeno, azufre y nitrógeno, entendiéndose que el nitrógeno en cuestión puede estar sustituido con de 1 a 2 grupos que representan un átomo de hidrógeno, o un grupo alquilo C₁₋₆ lineal o ramificado y entendiéndose que uno o más de los átomos de carbono de los posibles sustituyentes, pueden estar deuterados, R¹² representa -Cy⁵, -Cy⁵-alquilo C₀₋₆-O-alquilo C₀₋₆-Cy⁶, -Cy⁵-alquilo C₀₋₆-Cy⁶, -Cy⁵-alquilo C₀₋₆-NR¹¹-alquilo C₀₋₆-Cy⁶, -Cy⁵-Cy⁶-O-alquilo C₀₋₆-Cy⁷, -Cy⁵-alquilo C₀₋₆-O-alquilo C₀₋₆-Cy⁹, -Cy⁵-alquilo C₀₋₆-Cy⁹, -NH-C(O)-NH-R¹¹, -Cy⁵-alquilo C₀₋₆-NR¹¹-alquilo C₀₋₆-Cy⁹, -C(O)-NR¹¹R¹¹’, -NR¹¹R¹¹’, -OR¹¹, -NR¹¹-C(O)-R¹¹’, -O-alquilo C₁₋₆-OR¹¹, -SO₂-R¹¹, -C(O)-OR¹¹, R¹³, R¹³’, R¹⁴ y R¹⁴’, independientemente uno de otro, representan un átomo de hidrógeno, o un grupo alquilo C₁₋₆ lineal o ramificado sustituido opcionalmente, Rᵃ representa un átomo de hidrógeno o un grupo alquilo C₁₋₆ lineal o ramificado, Rᵇ representa un grupo -O-C(O)-O-Rᶜ, un grupo -O-C(O)-NRᶜRᶜ’, o un grupo -O-P(O)(ORᶜ)₂, Rᶜ y Rᶜ’, independientemente uno de otro, representan un átomo de hidrógeno, un grupo alquilo C₁₋₈ lineal o ramificado, un grupo cicloalquilo, un grupo alcoxi C₁₋₆alquilo C₁₋₆, o un grupo alcoxicarbonil C₁₋₆alquilo C₁₋₆, o la pareja (Rᶜ, Rᶜ’) junto con el átomo de nitrógeno al que está unida forman un anillo no aromático compuesto por de 5 a 7 miembros en el anillo, que puede contener, además del átomo de nitrógeno, de 1 a 3 heteroátomos seleccionados de oxígeno y nitrógeno, entendiéndose que el nitrógeno en cuestión puede estar sustituido con un grupo que representa un grupo alquilo C₁₋₆ lineal o ramificado, Cy¹, Cy², Cy³, Cy⁴, Cy⁵, Cy⁶, Cy⁷, Cy⁸ y Cy¹⁰, independientemente uno de otro, representan un grupo cicloalquilo, un grupo heterocicloalquilo, un grupo arilo o un grupo heteroarilo, Cy⁹ representa un resto de fórmula (2), o Cy⁹ representa un grupo heteroarilo que está sustituido con un grupo seleccionado de -O-P(O)(OR²⁰)₂; -O-P(O)(O-M⁺)₂; -(CH₂)ₚ-O-(CHR¹⁸-CHR¹⁹-O)q-R²⁰; hidroxi; hidroxialquilo C₁₋₆; -(CH₂)ʳ-U-(CH₂)ₛ-heterocicloalquilo; o -U-(CH₂)q-NR²¹R²¹, R¹⁵ representa un átomo de hidrógeno; un grupo -(CH₂)ₚ-O-(CHR¹⁸-CHR¹⁹-O)q-R²⁰; un grupo alcoxi C₁₋₆alquilo C₁₋₆ lineal o ramificado; un grupo -U-(CH₂)q-NR²¹R²¹’; o un grupo -(CH₂)ʳ-U-(CH₂)ₛ-heterocicloalquilo, R¹⁶ representa un átomo de hidrógeno; un grupo hidroxi; un grupo hidroxialquilo C₁₋₆; un grupo -(CH₂)ʳ-U-(CH₂)ₛ-heterocicloalquilo; un grupo (CH₂)ʳ-U-V-O-P(O)(OR²⁰)₂; un grupo -O-P(O)(O-M⁺)₂; un grupo -O-S(O)₂OR²⁰; un grupo -S(O)₂OR²⁰; un grupo -(CH₂)ₚ-O-(CHR¹⁸-CHR¹⁹-O)q-R²⁰; un grupo -(CH₂)ₚ-O-C(O)-NR²²R²³; o un grupo -U-(CH₂)q-NR²¹R²¹’, R¹⁷ representa un átomo de hidrógeno; un grupo -(CH₂)ₚ-O-(CHR¹⁸-CHR¹⁹-O)q-R²⁰; un grupo -CH₂-O-P(O)(OR²⁰)₂; un grupo -O-P(O)(OR²⁰)₂; un grupo -O-P(O)(O-M⁺)₂; un grupo hidroxi; un grupo hidroxialquilo C₁₋₆; un grupo -(CH₂)ʳ-U-(CH₂)ₛ-heterocicloalquilo; un grupo -U-(CH₂)q-NR²¹R²¹’; o un ácido aldónico, M⁺ representa un catión monovalente farmacéuticamente aceptable, U representa un enlace o un átomo de oxígeno, V representa un grupo -(CH₂)ₛ- o un grupo -C(O)-, R¹⁸ representa un átomo de hidrógeno o un grupo alcoxi C₁₋₆alquilo C₁₋₆, R¹⁹ representa un átomo de hidrógeno o un grupo hidroxialquilo C₁₋₆, R²⁰ representa un átomo de hidrógeno o un grupo alquilo C₁₋₆ lineal o ramificado, R²¹ y R²¹’, independientemente uno de otro, representan un átomo de hidrógeno, un grupo alquilo C₁₋₆ lineal o ramificado, o un grupo hidroxialquilo C₁₋₆, o la pareja (R²¹, R²¹’) junto con el átomo de nitrógeno al que está unida forman un anillo aromático o no aromático compuesto por de 5 a 7 miembros en el anillo, que puede contener, además del átomo de nitrógeno, de 1 a 3 heteroátomos seleccionados de oxígeno, azufre y nitrógeno, entendiéndose que el anillo resultante puede estar sustituido con un grupo que representa un átomo de hidrógeno o un grupo alquilo C₁₋₆ lineal o ramificado, R²² representa un grupo alcoxi C₁₋₆alquilo C₁₋₆, un grupo -(CH₂)ₚ-NR²⁴R²⁴’, o un grupo -(CH₂)ₚ-O-(CHR¹⁸-CHR¹⁹-O)q-R²⁰, R²³ representa un átomo de hidrógeno o un grupo alcoxi C₁₋₆alquilo C₁₋₆, o la pareja (R²², R²³) junto con el átomo de nitrógeno al que está unida forman un anillo aromático o no aromático compuesto por de 5 a 18 miembros en el anillo, que puede contener, además del átomo de nitrógeno, de 1 a 5 heteroátomos seleccionados de oxígeno, azufre y nitrógeno, entendiéndose que el anillo resultante puede estar sustituido con un grupo que representa un átomo de hidrógeno, un grupo alquilo C₁₋₆ lineal o ramificado o un grupo heterocicloalquilo, R²⁴ y R²⁴’, independientemente uno de otro, representan un átomo de hidrógeno o un grupo alquilo C₁₋₆ lineal o ramificado, o la pareja (R²⁴, R²⁴’) junto con el átomo de nitrógeno al que está unida forman un anillo aromático o no aromático compuesto por de 5 a 7 miembros en el anillo, que puede contener, además del átomo de nitrógeno, de 1 a 3 heteroátomos seleccionados de oxígeno, azufre y nitrógeno, entendiéndose que el anillo resultante puede estar sustituido con un grupo que representa un átomo de hidrógeno o un grupo alquilo C₁₋₆ lineal o ramificado, R²⁵ representa un átomo de hidrógeno, un grupo hidroxi, o un grupo hidroxialquilo C₁₋₆, R²⁶ representa un átomo de hidrógeno, un átomo de halógeno, un grupo alquilo C₁₋₆ lineal o ramificado, o un grupo ciano, R²⁷ representa un átomo de hidrógeno o un grupo alquilo C₁₋₆ lineal o ramificado, R²⁸ representa un grupo -O-P(O)(O)(O-), un grupo -O-P(O)(O-)(OR³⁰), un grupo -O-P(O)(OR³⁰)(OR³⁰’), un grupo -(CH₂)ₚ-O-S(O)₂O-; un grupo -(CH₂)ₚ-S(O)₂O-; un grupo -(CH₂)ₚ-O-S(O)₂OR³⁰; -Cy¹⁰, un grupo -O-C(O)-R²⁹, un grupo -O-C(O)-OR²⁹ o un grupo -O-C(O)-NR²⁹R²⁹’; R²⁹ y R²⁹’, independientemente uno de otro, representan un átomo de hidrógeno, un grupo alquilo C₁₋₆ lineal o ramificado o un grupo aminoalquilo C₁₋₆ lineal o ramificado, R³⁰ y R³⁰’, independientemente uno de otro, representan un átomo de hidrógeno, un grupo alquilo C₁₋₆ lineal o ramificado o un grupo arilalquilo C₁₋₆, R³¹ representa los grupos: del grupo de fórmulas (3), en donde el ion amonio existe opcionalmente como una forma zwiteriónica o tiene un contraión aniónico monovalente, n es un número entero igual a 0 ó 1, p es un número entero igual a 0, 1, 2, ó 3, q es un número entero igual a 1, 2, 3 ó 4, r y s son independientemente un número entero igual a 0 ó 1, entendiéndose que: “arilo” significa un grupo fenilo, naftilo, bifenilo, indanilo o indenilo, “heteroarilo” significa cualquier grupo mono o bicíclico compuesto por de 5 a 10 miembros en el anillo, que tiene al menos un resto aromático y que contiene de 1 a 3 heteroátomos seleccionados de oxígeno, azufre y nitrógeno, “cicloalquilo” significa cualquier grupo carbocíclico no aromático mono o bicíclico que contiene de 3 a 10 miembros en el anillo, “heterocicloalquilo” significa cualquier grupo carbocíclico no aromático mono o bicíclico que contiene de 3 a 10 miembros en el anillo, y que contiene de 1 a 3 heteroátomos seleccionados de oxígeno, azufre y nitrógeno, que puede incluir sistemas de anillos fusionados, con puente o espiro, siendo posible para los grupos arilo, heteroarilo, cicloalquilo y heterocicloalquilo así definidos y el alquilo, alquenilo, alquinilo, alcoxi, estar sustituidos con de 1 a 4 grupos seleccionados de alquilo C₁₋₆ lineal o ramificado sustituido opcionalmente, grupo alquenilo C₂₋₆ lineal o ramificado sustituido opcionalmente, grupo alquinilo C₂₋₆ lineal o ramificado sustituido opcionalmente, alcoxi C₁₋₆ lineal o ramificado sustituido opcionalmente, alquilo C₁₋₆-S- sustituido opcionalmente, hidroxi, oxo (o N-óxido cuando sea apropiado), nitro, ciano, -C(O)-OR’, -O-C(O)-R’, -C(O)-NR’R’’, -NR’R’’, -(C=NR’)-OR’’, haloalquilo C₁₋₆ lineal o ramificado, trifluorometoxi, o halógeno, entendiéndose que R’ y R’’, independientemente uno de otro, representan un átomo de hidrógeno o un grupo alquilo C₁₋₆ lineal o ramificado sustituido opcionalmente, y entendiéndose que uno o más de los átomos de carbono de los posibles sustituyentes anteriores, pueden estar deuterados, o sus enantiómeros, diastereoisómeros, atropisómeros, o sales de adición de los mismos con un ácido o base farmacéuticamente aceptable, y (b) un segundo agente anticanceroso, en donde el segundo agente anticanceroso se selecciona de eribulina y fulvestrant, para uso simultáneo, secuencial o separado.A combination comprising a Mcl-1 inhibitor and a second anticancer agent, wherein the second anticancer agent is selected from eribulin and fulvestrant, and compositions and uses thereof. Claim 1: A combination comprising: (a) an inhibitor of Mcl-1 of formula (1), wherein: D represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, E represents a furyl ring, thienyl or pyrrolyl, X¹, X³, X⁴ and X⁵, independently of one another, represent a carbon atom or a nitrogen atom, X² represents a C-R²⁶ group or a nitrogen atom, the “dotted ring” means that the ring is aromatic, Y represents a nitrogen atom or a C-R³ group, Z represents a nitrogen atom or a C-R⁴ group, R¹ represents a halogen atom, a linear or branched C₁₋₆ alkyl group, a C₂ alkenyl group ₋₆ linear or branched, a C₂₋₆ alkynyl group linear or branched, a C₁₋₆ haloalkyl group linear or branched, a hydroxy group, a hydroxyalkyl C₁₋₆ group, a C₁₋₆ alkoxy group linear or branched, -S group -C₁₋₆-alkyl, a cyano group, a nitro group, -Cy⁸, -C₀₋₆-alkyl-NR¹¹R¹¹’, -O-C₁₋₆-alkyl-NR¹¹R¹¹’, -O- C₁₋₆-R¹²-alkyl, -C(O)-OR¹¹, -OC(O)-R¹¹, -C(O)-NR¹¹R¹¹’, -NR¹¹-C(O)-R¹¹’, -NR¹¹-C(O) -OR¹¹’, -C₁₋₆-alkyl-NR¹¹-C(O)-R¹¹’, -SO₂-NR¹¹R¹¹’, o-SO₂-C₁₋₆-alkyl, R², R³, R⁴ and R⁵, independently of one another, represent a hydrogen atom, a halogen atom, a straight or branched C₁₋₆ alkyl group, a straight or branched C₂₋₆ alkenyl group, a straight or branched C₂₋₆ alkynyl group, a straight or branched C₁₋₆ haloalkyl, a hydroxy, a C₁₋₆ hydroxyalkyl group, a linear or branched C₁₋₆ alkoxy group, a -S-C₁₋₆ alkyl group, a cyano group, a nitro group, -C₀₋₆ alkyl-NR¹¹R¹¹’, -OCy¹, - C₀₋₆-Cy¹-alkyl, -C₂₋₆-Cy¹-alkenyl, -C₂₋₆-Cy¹-alkynyl, -O-C₁₋₆-alkyl-NR¹¹R¹¹’, -O-C₁₋₆-R¹²-alkyl, -C(O)- OR¹¹, -OC(O)-R¹¹, -C(O)-NR¹¹R¹¹’, -NR¹¹-C(O)-R¹¹’, -NR¹¹-C(O)-OR¹¹’, -C₁₋₆-alkyl-NR¹¹-C (O)-R¹¹’, -SO₂-NR¹¹R¹¹’, or -SO₂-C₁₋₆ alkyl, or the pair (R¹, R²), (R², R³), (R³, R⁴), or (R⁴, R⁵) together with the carbon atoms to which they are attached they form an aromatic ring. co or non-aromatic composed of 5 to 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted with 1 to 2 groups selected from halogen, alkyl C₁₋₆ linear or branched, -C₀₋₆-alkyl-NR¹¹R¹¹’, -NR¹³R¹³’, -C₀₋₆-Cy¹-alkyl or oxo, R⁶ and R⁷, independently of one another, represent a hydrogen atom, a halogen atom, a straight or branched C₁₋₆ alkyl group, a straight or branched C₂₋₆ alkenyl group, a straight or branched C₂₋₆ alkynyl group, a straight or branched C₁₋₆ haloalkyl, a hydroxy group, a straight or branched C₁₋₆ alkoxy group or branched, -S-C₁₋₆-alkyl group, cyano group, nitro group, -C₀₋₆-alkyl-NR¹¹R¹¹’, -O-C₁₋₆-alkyl-NR¹¹R¹¹’, -O-Cy¹, -C₀₋-alkyl ₆-Cy¹, -C₂₋₆-Cy¹ alkenyl, -C₂₋₆-Cy¹ alkynyl, -O-C₁₋₆-R¹² alkyl, -C(O)-OR¹¹, -OC(O)-R¹¹, -C(O )-NR¹¹R¹¹’, -NR¹¹-C(O)-R¹¹’, -NR¹¹-C(O)-OR¹¹’, -C₁₋₆-alkyl-NR¹¹-C(O)-R¹¹’, -SO₂-NR¹¹R ¹¹’, or -SO₂-C₁₋₆ alkyl, or the pair (R⁶, R⁷), when fused to the two adjacent carbon atoms, together with the carbon atoms to which it is attached form an aromatic or non-aromatic ring composed of from 5 to 7 members in the ring, which may contain from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted with a group selected from a straight or branched C₁₋₆ alkyl group, -NR¹³R¹³', -C₀₋₆-Cy¹ alkyl or an oxo, W represents a -CH₂- group, an -NH- group or an oxygen atom, R⁸ represents a hydrogen atom, a linear or branched C₁₋₈ alkyl group , a -CHRᵃRᵇ group, an aryl group, a heteroaryl group, a C₁₋₆ arylalkyl group, or a C₁₋₆ heteroarylalkyl group, R⁹ represents a hydrogen atom, a straight or branched C₁₋₆ alkyl group, a C₂ alkenyl group ₋₆ straight or branched, a C₂₋₆ straight or branched alkynyl group, -Cy², -C₁₋₆-Cy²-alkyl, -C₂₋₆-Cy²-alkenyl, -alkyn C₂₋₆-Cy²-yl, -Cy²-Cy³, -C₂₋₆-alkynyl-O-Cy², -Cy²-C₀₋₆-alkyl-O-C₀₋₆-Cy³-alkyl, a halogen atom, a cyano group, -C (O)-R¹⁴, or -C(O)-NR¹⁴R¹⁴’, R¹⁰ represents a hydrogen atom, a linear or branched C₁₋₆ alkyl group, a linear or branched C₂₋₆ alkenyl group, a linear C₂₋₆ alkynyl group or branched, a C₁₋₆ arylalkyl group, a C₁₋₆ cycloalkylalkyl group, a straight or branched C₁₋₆ haloalkyl, or -C₁₋₆-O-Cy⁴-alkyl, or the couple (R⁹, R¹⁰), when fused with the two adjacent carbon atoms, together with the carbon atoms to which it is attached, form an aromatic or non-aromatic ring composed of 5 to 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, R¹¹ and R¹¹’, independently of one another, represent a hydrogen atom, an optionally substituted linear or branched C₁₋₆ alkyl group, or -C₀₋₆-Cy¹-alkyl, or the pair (R¹¹, R¹¹’) together with the nitrogen atom to which u is nida form an aromatic or non-aromatic ring composed of 5 to 7 ring members, which may contain, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the nitrogen in question may be substituted with 1 to 2 groups representing a hydrogen atom, or a linear or branched C₁₋₆ alkyl group and it being understood that one or more of the carbon atoms of the possible substituents may be deuterated, R¹² represents -Cy⁵, - Cy⁵-C₀₋₆-alkyl-O-C₀₋₆-alkyl-Cy⁶, -Cy⁵-C₀₋₆-alkyl-Cy⁶, -Cy⁵-C₀₋₆-alkyl-NR¹¹-C₀₋₆-Cy⁶-alkyl, -Cy⁵-Cy⁶-O- alkyl C₀₋₆-NR¹¹-C₀₋₆-Cy⁹-alkyl, -C(O)-NR¹¹R¹¹’, -NR¹¹R¹¹’, -OR¹¹, -NR¹¹-C(O)-R¹¹’, -O-C₁₋₆-OR¹¹-OR, -SO₂-R¹¹, -C(O)-OR¹¹, R¹³, R¹³', R¹⁴ and R¹⁴', independently of one another, represent a hydrogen atom, or a linear or branched substituted C₁₋₆ alkyl group. optionally, Rᵃ represents a hydrogen atom or a linear or branched C₁₋₆ alkyl group, Rᵇ represents an -OC(O)-O-Rᶜ group, an -OC(O)-NRᶜRᶜ’ group, or an -OP group (O)(ORᶜ)₂, Rᶜ and Rᶜ', independently of one another, represent a hydrogen atom, a linear or branched C₁₋₈ alkyl group, a cycloalkyl group, a C₁₋₆alkoxy-C₁₋₆alkyl group, or a C₁₋₆C₁₋₆alkyl alkoxycarbonyl group, or the couple (Rᶜ, Rᶜ’) together with the nitrogen atom to which it is attached form a non-aromatic ring composed of 5 to 7 members in the ring, which may contain, in addition to the nitrogen atom, from 1 to 3 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be substituted with a group representing a straight or branched C₁₋₆ alkyl group, Cy¹, Cy², Cy³, Cy⁴, Cy⁵, Cy⁶ , Cy⁷, Cy⁸ and Cy¹⁰, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, Cy⁹ represents a moiety of formula (2), or Cy⁹ represents a heteroaryl group which is substituted with a group selected from -O-P(O)(OR²⁰)₂; -O-P(O)(O-M⁺)₂; -(CH₂)ₚ-O-(CHR¹⁸-CHR¹⁹-O)q-R²⁰; hydroxy; C₁₋₆ hydroxyalkyl; -(CH₂)ʳ-U-(CH₂)ₛ-heterocycloalkyl; or -U-(CH₂)q-NR²¹R²¹, R¹⁵ represents a hydrogen atom; a -(CH₂)ₚ-O-(CHR¹⁸-CHR¹⁹-O)q-R²⁰ group; a linear or branched C₁₋₆C₁₋₆alkyl alkoxy group; a group -U-(CH₂)q-NR²¹R²¹'; or a -(CH₂)ʳ-U-(CH₂)ₛ-heterocycloalkyl group, R¹⁶ represents a hydrogen atom; a hydroxy group; a C₁₋₆ hydroxyalkyl group; a -(CH₂)ʳ-U-(CH₂)ₛ-heterocycloalkyl group; a (CH₂)ʳ-U-V-O-P(O)(OR²⁰)₂ group; an -O-P(O)(O-M⁺)₂ group; an -O-S(O)₂OR²⁰ group; a -S(O)₂OR²⁰ group; a -(CH₂)ₚ-O-(CHR¹⁸-CHR¹⁹-O)q-R²⁰ group; a -(CH₂)ₚ-O-C(O)-NR²²R²³ group; or a group -U-(CH₂)q-NR²¹R²¹', R¹⁷ represents a hydrogen atom; a -(CH₂)ₚ-O-(CHR¹⁸-CHR¹⁹-O)q-R²⁰ group; a -CH₂-O-P(O)(OR²⁰)₂ group; an -O-P(O)(OR²⁰)₂ group; an -O-P(O)(O-M⁺)₂ group; a hydroxy group; a C₁₋₆ hydroxyalkyl group; a -(CH₂)ʳ-U-(CH₂)ₛ-heterocycloalkyl group; a group -U-(CH₂)q-NR²¹R²¹'; or an aldonic acid, M⁺ represents a pharmaceutically acceptable monovalent cation, U represents a bond or an oxygen atom, V represents a -(CH₂)ₛ- group or a -C(O)- group, R¹⁸ represents a hydrogen atom or a C₁₋₆-C₁₋₆-alkyl alkoxy group, R¹⁹ represents a hydrogen atom or a C₁₋₆-hydroxyalkyl group, R²⁰ represents a hydrogen atom or a straight or branched C₁₋₆-alkyl group, R²¹ and R²¹’, independently one of another, represent a hydrogen atom, a linear or branched C₁₋₆ alkyl group, or a C₁₋₆ hydroxyalkyl group, or the pair (R²¹, R²¹’) together with the nitrogen atom to which it is attached form an aromatic ring or non-aromatic composed of from 5 to 7 members in the ring, which may contain, in addition to the nitrogen atom, from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted with a group representing a hydrogen atom or a straight or branched C₁₋₆ alkyl group, R² ² represents a C₁₋₆C₁₋₆ alkyl group, a -(CH₂)ₚ-NR²⁴R²⁴’ group, or a -(CH₂)ₚ-O-(CHR¹⁸-CHR¹⁹-O)q-R²⁰ group, R²³ represents an atom of hydrogen or a C₁₋₆C₁₋₆alkyl alkoxy group, or the couple (R²², R²³) together with the nitrogen atom to which it is attached form an aromatic or non-aromatic ring composed of 5 to 18 ring members, which can contain, in addition to the nitrogen atom, from 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted with a group representing a hydrogen atom, a linear or branched C₁₋₆ alkyl group or a heterocycloalkyl group, R²⁴ and R²⁴', independently of one another, represent a hydrogen atom or a linear or branched C₁₋₆ alkyl group, or the couple (R²⁴, R²⁴') together with the nitrogen atom to which it is attached form a aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain, in addition to the nitrogen atom, from 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, it being understood that the resulting ring may be substituted with a group representing a hydrogen atom or a linear or branched C₁₋₆ alkyl group, R²⁵ represents a hydrogen atom, a hydroxy group, or a C₁₋₆ hydroxyalkyl group, R²⁶ represents a hydrogen atom, a halogen atom, a straight or branched C₁₋₆ alkyl group, or a cyano group, R²⁷ represents a hydrogen atom or a straight or branched C₁₋₆ alkyl group , R²⁸ represents a group -OP(O)(O)(O-), a group -OP(O)(O-)(OR³⁰), a group -OP(O)(OR³⁰)(OR³⁰’), a group -(CH₂)ₚ-OS(O)₂O-; a -(CH₂)ₚ-S(O)₂O- group; a -(CH₂)ₚ-O-S(O)₂OR³⁰ group; -Cy¹⁰, a group -O-C(O)-R²⁹, a group -O-C(O)-OR²⁹ or a group -O-C(O)-NR²⁹R²⁹’; R²⁹ and R²⁹', independently of one another, represent a hydrogen atom, a straight or branched C₁₋₆ alkyl group or a straight or branched C₁₋₆ aminoalkyl group, R³⁰ and R³⁰', independently of one another, represent a hydrogen atom hydrogen, a straight or branched C₁₋₆ alkyl group or a C₁₋₆ arylalkyl group, R³¹ represents the groups: from the group of formulas (3), wherein the ammonium ion optionally exists as a zwitterionic form or has a monovalent anionic counterion, n is an integer equal to 0 or 1, p is an integer equal to 0, 1, 2, or 3, q is an integer equal to 1, 2, 3, or 4, r and s are independently an integer equal to 0 or 1, it being understood that: "aryl" means a phenyl, naphthyl, biphenyl, indanyl or indenyl group, "heteroaryl" means any mono or bicyclic group composed of 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, “cyclo "alkyl" means any non-aromatic mono or bicyclic carbocyclic group containing from 3 to 10 ring members, "heterocycloalkyl" means any non-aromatic mono or bicyclic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which may include fused, bridged or spiro ring systems, it being possible for aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and alkyl, alkenyl, alkynyl, alkoxy, to be substituted with 1 to 4 groups selected from optionally substituted straight or branched C₁₋₆ alkyl, optionally substituted straight or branched C₂₋₆ alkenyl group, optionally substituted straight or branched C₂₋₆ alkynyl group, optionally substituted straight or branched C₁₋₆ alkoxy, optionally substituted C₁₋₆-S-alkyl, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, -C(O)-OR', -OC(O)-R', -C(O) -NR'R' ’, -NR’R’’, -(C=NR’)-OR’’, linear or branched C₁₋₆ haloalkyl, trifluoromethoxy, or halogen, it being understood that R’ and R’’, independently of each other, represent a hydrogen atom or an optionally substituted linear or branched C₁₋₆ alkyl group, and it being understood that one or more of the carbon atoms of the above possible substituents may be deuterated, or their enantiomers, diastereomers, atropisomers, or addition salts of the same with a pharmaceutically acceptable acid or base, and (b) a second anticancer agent, wherein the second anticancer agent is selected from eribulin and fulvestrant, for simultaneous, sequential or separate use.

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