ES2860299T3 - Inhibidores de DNA-PK - Google Patents

Inhibidores de DNA-PK Download PDF

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Publication number
ES2860299T3
ES2860299T3 ES18186230T ES18186230T ES2860299T3 ES 2860299 T3 ES2860299 T3 ES 2860299T3 ES 18186230 T ES18186230 T ES 18186230T ES 18186230 T ES18186230 T ES 18186230T ES 2860299 T3 ES2860299 T3 ES 2860299T3
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alkyl
group
ra1b
groups
hydrogen
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ES18186230T
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Inventor
Paul S Charifson
Kevin Michael Cottrell
Hongbo Deng
John P Duffy
Huai Gao
Simon Giroux
Jeremy Green
Katrina Lee Jackson
John Patrick Maxwell
Mark A Morris
Albert Charles Pierce
Nathan D Waal
Joseph M Kennedy
David J Lauffer
Mark Willem Ledeboer
Pan Li
Jinwang Xu
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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    • 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
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Abstract

Una cantidad farmacéuticamente aceptable de un compuesto representado por la fórmula estructural (I) o una sal farmacéuticamente aceptable del mismo: para su uso en el tratamiento de un cáncer seleccionado entre el grupo que consiste en: cáncer de mama, cáncer colorrectal, cáncer gástrico-esofágico, fibrosarcoma, glioblastoma, carcinoma hepatocelular, carcinoma de células escamosas de cabeza y cuello, melanoma, cáncer de pulmón, cáncer de páncreas o cáncer de próstata, en donde Q es N o CH; R1 es hidrógeno, CH3 o CH2CH3, o R1 y el carbono al cual está unido forman un grupo C= CH2; el anillo A es un sistema de anillo seleccionado entre **(Ver fórmula)** y RA1 es hidrógeno, halógeno, alquilo C1-4, alquil C0-4-cicloalquilo C3-6, alquil C0-4-ORA1a, alquil C0-4-SRA1a, alquil C0-4- C(O)N(RA1a)2, alquil C0-4-CN, alquil C0-4-S(O)-alquilo C1-4, alquil C0-4-S(O)2-alquilo C1-4, alquil C0-4-C(O)ORA1b, alquil C0-4-C(O)alquilo C1-4, alquil C0-4-N(RA1b)C(O)RA1a, alquil C0-4-N(RA1b)S(O)2RA1a, alquil C0-4-N(RA1a)2, alquil C0-4- N(RA1b)(cicloalquilo de 3-6 miembros), alquil C0-4-N(RA1b)(heterociclilo de 4-6 miembros), N(RA1b)alquil C2-4-N(RA1a)2, N(RA1b)alquil C2-4-ORA1a, N(RA1b)alquil C1-4-(heteroarilo de 5-10 miembros), N(RA1b)alquil C1-4-(heterociclilo de 4-6 miembros), N(RA1b)alquil C2-4-N(RA1b)C(O)RA1a, alquil C0-4-N(RA1b)C(O)alquilo C1-4, alquil C0-4-N(RA1b)C(O)Oalquilo C1-4, alquil C0-4-(fenilo),alquil C0-4-(heterociclilo de 3-10 miembros), alquil C0-4-C(O)-(heterociclilo de 4-6 miembros), alquil C0-4-O-alquil C0-4-(heterociclilo de 4-6 miembros), alquil C0-4-(heteroarilo de 5-6 miembros), alquil C0-4-C(O)- (heteroarilo de 5-6 miembros), alquil C0-4-O-alquil C0-4-(heteroarilo de 5-6 miembros), alquil C0-4-N(RA1a)(heterociclilo de 4-6 miembros) o alquil C0-4-N(RA1b)(heteroarilo de 5-6 miembros), donde cada uno de dicho heterociclilo RA1 es un sistema de anillo seleccionado entre aziridinilo, oxetanilo, tetrahidrofuranilo, tetrahidropiranilo, dioxanilo, dioxolanilo, azetidinilo, pirrolidinilo, pirrolidinonilo, pirrolidinadionilo, morfolinilo, piperidinilo, piperazinilo, piperazinonilo, tetrahidrotiofenodioxidilo, 1,1-dioxotietanilo, 2-oxa-6-azaespiro[3.4]octanilo e isoindolinonilo, donde cada uno de dicho heteroarilo RA1 es un sistema de anillo seleccionado entre furanilo, tiofenilo, imidazolilo, benzoimidazolilo, oxazolilo, oxadiazolilo, tiazolilo, pirazolilo, tiadiazolilo, piridinilo, pirimidinilo, pirazinilo, triazolilo y tetrazolilo y donde cada uno de dichos grupos alquilo, cicloalquilo, fenilo, heterociclilo y heteroarilo RA1 está opcionalmente sustituido con hasta tres átomos F, hasta dos grupos alquilo C1-2, un grupo cicloalquilo C3-6, un grupo fenilo, un grupo bencilo, un grupo alquenil-alquilo C0-2, un grupo alquinil-alquilo C0-2, hasta dos grupos alquil C0-2-ORA1b, un grupo alquil C0-2- N(RA1b)2, un grupo Salquilo C1-4, un grupo S(O)2alquilo C1-4, un grupo C(O)RA1b, un grupo C(O)ORA1b, un grupo C(O)N(RA1b)2, un grupo -CN o un sistema de anillo heterocíclico C4-6 seleccionado entre oxetanilo, tetrahidrofuranilo, tetrahidropiranilo, piperidinilo y morfolinilo; cada RA1a es, independientemente, hidrógeno, alquilo C1-4, cicloalquilo C3-6, heterociclilo C4-6 seleccionado entre oxetanilo, tetrahidrofuranilo, tetrahidropiranilo, pirrolidinilo y piperidinilo, heteroarilo C5-6 seleccionado entre imidazolilo, triazolilo, tetrazolilo, pirazolilo, tiofenilo, tiazolilo, piridinilo, pirimidinilo y pirazinilo o dos RA1a y un átomo de nitrógeno intermedio forman un anillo heterocíclico de 3-6 miembros seleccionado entre aziridinilo, azetidinilo, pirrolidinilo, pirrolidinonilo, piperidinilo, piperidinonilo, tetrahidropiridinilo, piperazinilo y morfolinilo, donde cada uno de dichos grupos alquilo, cicloalquilo, heterociclilo y heteroarilo RA1a está opcionalmente sustituido con hasta tres átomos F, hasta dos grupos alquilo C1-2, un grupo cicloalquilo C3-6, hasta dos grupos alquil C0-2-ORA1b, un grupo alquil C0-2-N(RA1b)2, un grupo Salquilo C1-4, un grupo C(O)RA1b, un grupo C(O)ORA1b, un grupo C(O)N(RA1b)2 o un grupo -CN; cada RA1b es, independientemente, hidrógeno, alquilo C1-2 o cicloalquilo C3-4; RA2 es hidrógeno, alquilo C1-4, alquil C0-4-cicloalquilo C3-6, alquil C0-2-heterociclilo (4-6 miembros), alquil C2-4-ORA2a, alquil C0-2-C(O)N(RA2a)2, alquil C0-2-S(O)2-alquilo C1-4, alquil C0-2-C(O)Oalquilo C1-4 o alquil C0-2-C(O)-heterociclilo (4-6 miembros), donde cada uno de dicho heterociclilo se selecciona entre oxetanilo, tetrahidropiranilo, tetrahidrofuranilo, dioxanilo, dioxolanilo, azetidinilo, pirrolidinilo, pirrolidinonilo, pirrolidinadionilo, morfolinilo, piperidinilo, piperazinilo, piperazinonilo y 1,1-dioxotietanilo y cada uno de dichos grupos RA2, excepto hidrógeno, está opcionalmente sustituido con hasta tres átomos F, hasta dos grupos alquilo C1-2, un grupo cicloalquilo C3-6, un grupo alquenil-alquilo C0-2, un grupo alquinil-alquilo C0-2, hasta dos grupos ORA2b, un grupo alquil C0-2-N(RA2b)2, un grupo Salquilo C1-4, un grupo S(O)2alquilo C1-4, un grupo C(O)RA2b, un grupo C(O)ORA2b, un grupo C(O)N(RA2b)2 o un grupo -CN; cada RA2a es, independientemente, hidrógeno, alquilo C1-4, un heteroarilo C5-6 seleccionado entre imidazolilo, triazolilo, tetrazolilo, pirazolilo, tiofenilo, tiazolilo, piridinilo, pirimidinilo y pirazinilo o dos RA2a y un átomo de nitrógeno intermedio forman un anillo heterocíclico de 3-6 miembros seleccionado entre aziridinilo, azetidinilo, pirrolidinilo, pirrolidinonilo, piperidinilo, piperidinonilo, tetrahidropiridinilo, piperazinilo y morfolinilo; cada RA2b es, independientemente, hidrógeno, alquilo C1-4 o cicloalquilo C3-4; RA3 es hidrógeno o alquilo C1-2; cada RA4 es, independientemente, deuterio, halógeno, CN, alquilo C1-4 u Oalquilo C1-4, donde cada alquilo RA4 está opcionalmente sustituido con hasta 3 átomos F, dos grupos OH no geminales o un Oalquilo C1-2, o dos RA4 junto con un átomo de carbono saturado intermedio forman un anillo ciclobutilo o ciclopropilo espiral; n es 0-3; el anillo B es un sistema de anillo seleccionado entre **(Ver fórmula)** y RB1 es hidrógeno, alquilo C1-4, (CH2)0-1cicloalquilo C3-6, C(O)alquilo C1-2, (CH2)0-1-anillo heterociclilo (4-6 miembros) donde dicho anillo heterocíclico se selecciona entre oxetanilo, tetrahidrofuranilo, tetrahidropiranilo, dioxanilo, dioxolanilo y pirrolidinonilo, fenilo, bencilo o (CH2)1-2anillo heteroarilo (5-6 miembros) donde dicho anillo heteroarilo se selecciona entre piridinilo, imidazolilo y pirazolilo y donde cada uno de dichos grupos alquilo, cicloalquilo, fenilo, bencilo, heterociclilo y heteroarilo RB1 está opcionalmente sustituido con hasta 3 átomos F, hasta dos grupos alquilo C1-2, dos grupos OH no geminales o un Oalquilo C1-2; RB2 es hidrógeno, alquilo C1-4 u Oalquilo C1-4; cada RB3 es, independientemente, hidrógeno, halógeno, alquilo C1-4, alquenilo C2-4, alquinilo C2-4, CN, C(O)H, C(O)alquilo C1-4, C(O)Oalquilo C1-4, C(O)alquilo C1-4, C(O)NH2, C(O)NHalquilo C1-4, C(O)NH(CH2)0-1cicloalquilo C3-6, C(O)NHCH2oxetanilo, C(O)NHCH2tetrahidrofuranilo, C(O)NHCH2tetrahidropiranilo, C(O)NHfenilo, C(O)NHbencilo, C(O)NHOH, C(O)NHOalquilo C1-4, C(O)NHO(CH2)0-1cicloalquilo C3-6, C(O)NHO(CH2)0-1oxetanilo, C(O)NHO(CH2)0- 1tetrahidrofuranilo, C(O)NHO(CH2)0-1tetrahidropiranilo, C(O)NHOfenilo, C(O)NHObencilo, NH2, NHC(O)alquilo C1-4, Oalquilo C1-4, Salquilo C1-4, S(O)alquilo C1-4 o un sistema de anillo heteroarilo de 5 miembros seleccionado entre furanilo, tiofenilo, imidazolilo, pirrol, pirazolilo y oxadiazolilo, donde cada grupo RB3, excepto hidrógeno o halógeno, está opcionalmente sustituido con Cl, hasta tres átomos F, hasta dos grupos OH no geminales, hasta dos Oalquilo C1-2, un NH2, un NHalquilo C1-2, un NHC(O)alquilo C1-2 o un N(alquilo C1-2)2; cada RB4 es, independientemente, hidrógeno, halógeno, alquilo C1-4, Oalquilo C1-4, Salquilo C1-4, NH2, NH(alquilo C1- 4), N(alquilo C1-4)2, NHC(O)alquilo C1-4, C(O)OH, C(O)Oalquilo C1-4, C(O)NH2, C(O)NHalquilo C1-4, C(O)N(alquilo C1- 4)2, CN, un anillo morfolinilo o un anillo imidazolilo, donde cada alquilo RB4 está opcionalmente sustituido con hasta 3 átomos F, dos grupos OH no geminales o un Oalquilo C1-2; RB5 es hidrógeno, alquilo C1-4, C(O)alquilo C1-4, C(O)Oalquilo C1-4, C(O)NH2, C(O)NHalquilo C1-4 o C(O)N(alquilo C1- 4)2, donde dicho alquilo R B5 está opcionalmente sustituido con hasta 3 átomos F, dos grupos OH no geminales o un Oalquilo C1-2 y RB6 es F o alquilo C1-2 o dos RB6 y un átomo de carbono intermedio forman un anillo espirociclopropilo o espirociclobutilo; donde además "alquilo" o "grupo alquilo" significa una cadena de hidrocarburo de cadena lineal o ramificado, sustituido o sin sustituir, que está completamente saturado; y "alcoxi" o "tioalquilo" se refiere a un grupo alquilo unido a la cadena de carbono principal a través de un átomo de oxígeno ("alcoxi") o de azufre ("tioalquilo").
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