AR115091A1 - MCL-1 INHIBITORS - Google Patents

MCL-1 INHIBITORS

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Publication number
AR115091A1
AR115091A1 ARP190101280A ARP190101280A AR115091A1 AR 115091 A1 AR115091 A1 AR 115091A1 AR P190101280 A ARP190101280 A AR P190101280A AR P190101280 A ARP190101280 A AR P190101280A AR 115091 A1 AR115091 A1 AR 115091A1
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AR
Argentina
Prior art keywords
alkyl
cycloalkyl
heteroalkyl
aryl
membered
Prior art date
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ARP190101280A
Other languages
Spanish (es)
Inventor
Hong Yang
William J Watkins
Chandrasekar Venkataramani
Vickie H Tsui
Neil H Squires
Zachary Newby
Devan Naduthambi
Michael L Mitchell
Jonathan W Medley
David W Lin
Xiaofen Li
Scott E Lazerwith
John E Knox
Tetsuya Kobayashi
Darryl Kato
Lan Jiang
Tae H Hwang
Anna E Hurtley
Juan A Guerrero
Hang Chu
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Gilead Sciences Inc
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Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Publication of AR115091A1 publication Critical patent/AR115091A1/en

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Abstract

Compuestos heterocíclicos condensados como inhibidores de MCL-1, composición farmacéutica que los comprende y su utilización en el tratamiento de diversos tipos de cáncer, incluyendo leucemia. Reivindicación 1: Un compuesto según la fórmula (1), en donde: ⁻ ⁻ ⁻ ⁻ ⁻ es un enlace simple o doble; X es O ó NR⁷; R¹² es hidrógeno o -C(O)R¹; R¹ es alquilo C₁₋₆, halógenoalquilo C₁₋₆, alquenilo C₂₋₆, alquinilo C₂₋₆, cicloalquilo C₃₋₁₀, arilo C₆₋₁₀, heterociclilo de 3 - 12 miembros, heteroarilo de 5 - 10 miembros, -OR⁷, o -NR⁸R⁹, en donde dichos alquilo C₁₋₆, heteroalquilo C₁₋₆, alquinilo C₂₋₆, cicloalquilo C₃₋₁₀, arilo C₆₋₁₀, heterociclilo de 3 - 12 miembros, y heteroarilo de 5 - 10 miembros están opcionalmente sustituidos con 1 - 5 grupos R¹⁰; R² es hidrógeno, alquilo C₁₋₆, heteroalquilo C₁₋₆, cicloalquilo C₃₋₁₀, o heterociclilo de 3 - 12 miembros, en donde dichos alquilo C₁₋₆, heteroalquilo C₁₋₆, cicloalquilo C₃₋₁₀, y heterociclilo de 3 - 12 miembros están opcionalmente sustituidos con 1 - 5 grupos R¹⁰; R³ y R⁴ son independientemente hidrógeno, alquilo C₁₋₆, -OR⁷, heteroalquilo C₁₋₆, -NR⁸R⁹, NR⁸C(O)R⁹, -NR⁸C(O)OR⁹, arilo C₆₋₁₀, cicloalquilo C₃₋₁₀, heteroarilo de 5 - 10 miembros, heterociclilo de 3 - 12 miembros, -C(O)R⁷, -C(O)OR⁷, -C(O)NR⁸R⁹, -OC(O)NR⁸R⁹, -CN, o -SO₂R⁷, en donde dichos alquilo C₁₋₆, heteroalquilo C₁₋₆, arilo C₆₋₁₀, cicloalquilo C₃₋₁₀, heteroarilo de 5 - 10 miembros, y heterociclilo de 3 - 12 miembros están opcionalmente sustituidos con 1 - 5 grupos R¹⁰; R⁵ es hidrógeno, alquilo C₁₋₆, -(CH₂CH₂O)ₚR⁷, heteroalquilo C₆₋₁₀, arilo C₆₋₁₀, cicloalquilo C₃₋₁₀, heteroarilo de 5 - 10 miembros, o heterociclilo de 3 - 12 miembros, en donde dichos alquilo C₁₋₆, heteroalquilo C₁₋₆, arilo C₆₋₁₀, cicloalquilo C₃₋₁₀, heteroarilo de 5 - 10 miembros, y heterociclilo de 3 - 12 miembros están opcionalmente sustituidos con 1 - 5 grupos R¹⁰; R⁶ es hidrógeno o halógeno; cada R⁷ es independientemente hidrógeno, alquilo C₁₋₆, cicloalquilo C₃₋₁₀, heteroalquilo C₁₋₆, heterociclilo de 3 - 12 miembros, arilo C₆₋₁₀, o heteroarilo de 5 - 10 miembros, en donde dichos alquilo C₁₋₆, cicloalquilo C₃₋₁₀, heteroalquilo C₁₋₆, heterociclilo de 3 - 12 miembros, arilo C₆₋₁₀, y heteroarilo de 5 - 10 miembros están opcionalmente sustituidos con de 1 - 5 grupos R¹⁰; cada R⁸ y R⁹ son independientemente hidrógeno, alquilo C₁₋₆, cicloalquilo C₃₋₁₀, heteroalquilo C₁₋₆, heterociclilo de 3 - 12 miembros, arilo C₆₋₁₀, o heteroarilo de 5 - 10 miembros, o R⁸ y R⁹ junto con los átomos a los que están unidos forman un heterociclo de 3 - 12 miembros, en donde dichos alquilo C₁₋₆, cicloalquilo C₃₋₁₀, heteroalquilo C₁₋₆, heterociclilo de 3 - 12 miembros, arilo C₆₋₁₀, y heteroarilo de 5 - 10 miembros están opcionalmente sustituidos con 1 - 5 grupos R¹⁰; cada R¹⁰ es independientemente alquilo C₁₋₆, cicloalquilo C₃₋₁₀, heteroalquilo C₁₋₆, heterociclilo de 3 - 12 miembros, arilo C₆₋₁₀, heteroarilo de 5 - 10 miembros, halógeno, oxo, -ORᵃ, -C(O)Rᵃ, -C(O)ORᵃ, -C(O)NRᵃRᵇ, -OC(O)NRᵃRᵇ, -NRᵃRᵇ, -NRᵃC(O)Rᵇ, -NRᵃC(O)ORᵇ, -S(O)qRᵃ, -S(O)₂NRᵃRᵇ, -NRᵃS(O)₂Rᵇ ,-N₃, -CN, o -NO₂, o dos R¹⁰ los grupos forman un cicloalquilo C₃₋₁₀ fusionado, espiro o con puente o heterociclilo de 3 - 12 miembros, en donde cada alquilo C₁₋₆, heteroalquilo C₁₋₆, alquinilo C₂₋₆, cicloalquilo C₃₋₁₀, arilo C₆₋₁₀, heterociclo de 3 - 12 miembros, y heteroarilo de 5 - 10 miembros está opcionalmente sustituido con 1 - 5 grupos R²⁰; cada Rᵃ y Rᵇ es independientemente hidrógeno, alquilo C₁₋₆, alquenilo C₂₋₆, cicloalquilo C₃₋₁₀, heteroalquilo C₁₋₆, heterociclilo de 3 - 12 miembros, arilo C₆₋₁₀, heteroarilo de 5 - 10 miembros, o Rᵃ y Rᵇ junto con los átomos a los que están unidos forman un heterociclilo de 3 - 12 miembros en donde dichos alquilo C₁₋₆, alquenilo C₂₋₆, cicloalquilo C₃₋₁₀, heteroalquilo C₁₋₆, heterociclilo de 3 - 12 miembros, arilo C₆₋₁₀, heteroarilo de 5 - 10 miembros está opcionalmente sustituido con 1 - 5 grupos R²⁰; cada R²⁰ es independientemente alquilo C₁₋₆, cicloalquilo C₃₋₁₀, heteroalquilo C₁₋₆, heterociclilo de 3 - 12 miembros, arilo C₆₋₁₀, heteroarilo de 5 - 10 miembros, hidroxil, alcoxi C₁₋₆, amino, -CN, -C(O)H, -C(O)NH₂, -C(O)NH(alquilo C₁₋₆), -C(O)N(alquilo C₁₋₆)₂, -COOH, -C(O)alquilo C₁₋₆, -C(O)O-alquilo C₁₋₆, o halógeno; n es 0, 1 ó 2; p es 0, 1 ó 2; y q es 0, 1 ó 2; o una sal farmacéuticamente aceptable del mismo.Heterocyclic compounds condensed as MCL-1 inhibitors, a pharmaceutical composition that comprises them and their use in the treatment of various types of cancer, including leukemia. Claim 1: A compound according to formula (1), wherein: ⁻ ⁻ ⁻ ⁻ ⁻ is a single or double bond; X is O or NR⁷; R¹² is hydrogen or -C (O) R¹; R¹ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, -OR⁷, or -NR⁸R⁹, wherein said C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 3-12 membered heterocyclyl, and 5-10 membered heteroaryl are optionally substituted with 1 - 5 R¹⁰ groups; R² is hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, or 3-12 membered heterocyclyl, wherein said C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, and 3-12 membered heterocyclyl 12 members are optionally substituted with 1-5 R¹⁰ groups; R³ and R⁴ are independently hydrogen, C₁₋₆ alkyl, -OR⁷, C₁₋₆ heteroalkyl, -NR⁸R⁹, NR⁸C (O) R⁹, -NR⁸C (O) OR⁹, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- heteroaryl 10-membered, 3-12-membered heterocyclyl, -C (O) R⁷, -C (O) OR⁷, -C (O) NR⁸R⁹, -OC (O) NR⁸R⁹, -CN, or -SO₂R⁷, wherein said C₁ alkyl ₋₆, C₁₋₆ heteroalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl are optionally substituted with 1-5 R¹⁰ groups; R⁵ is hydrogen, C₁₋₆ alkyl, - (CH₂CH₂O) ₚR⁷, C₆₋₁₀ heteroalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, wherein said C₁ alkyl ₋₆, C₁₋₆ heteroalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl are optionally substituted with 1-5 R¹⁰ groups; R⁶ is hydrogen or halogen; each R⁷ is independently hydrogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀ aryl, or 5-10 membered heteroaryl, wherein said C₁₋₆ alkyl, cycloalkyl C₃₋₁₀, C₁₋₆ heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R¹⁰ groups; each R⁸ and R⁹ are independently hydrogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀ aryl, or 5-10 membered heteroaryl, or R⁸ and R⁹ together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀ aryl, and 5- 10 members are optionally substituted with 1-5 R¹⁰ groups; each R¹⁰ is independently C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halogen, oxo, -ORᵃ, -C (O) Rᵃ, -C (O) ORᵃ, -C (O) NRᵃRᵇ, -OC (O) NRᵃRᵇ, -NRᵃRᵇ, -NRᵃC (O) Rᵇ, -NRᵃC (O) ORᵇ, -S (O) qRᵃ, -S ( O) ₂NRᵃRᵇ, -NRᵃS (O) ₂Rᵇ, -N₃, -CN, or -NO₂, or two R¹⁰ groups form a fused, spiro or bridged C₃₋₁₀ cycloalkyl or 3-12 membered heterocyclyl, where each alkyl C₁₋₆, C₁₋₆ heteroalkyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 3-12 membered heterocycle, and 5-10 membered heteroaryl is optionally substituted with 1-5 R²⁰ groups; each Rᵃ and Rᵇ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₁₀ cycloalkyl, C₁₋₆ heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or Rᵃ and Rᵇ together with the atoms to which they are attached form a 3-12 membered heterocyclyl wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₁₀ cycloalkyl, C₁₋₆ heteroalkyl, 3-12 membered heterocyclyl, C₆ aryl ₋₁₀, 5-10 membered heteroaryl is optionally substituted with 1-5 R²⁰ groups; each R²⁰ is independently C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, hydroxyl, C₁₋₆ alkoxy, amino, -CN, -C (O) H, -C (O) NH₂, -C (O) NH (C₁₋₆ alkyl), -C (O) N (C₁₋₆ alkyl) ₂, -COOH, -C (O) alkyl C₁₋₆, -C (O) O-C₁₋₆ alkyl, or halogen; n is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

ARP190101280A 2018-05-14 2019-05-14 MCL-1 INHIBITORS AR115091A1 (en)

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