AR072201A1 - 2-arilaminoquinazolinas para el tratamiento de enfermedades proliferativas - Google Patents

2-arilaminoquinazolinas para el tratamiento de enfermedades proliferativas

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AR072201A1
AR072201A1 ARP090102241A ARP090102241A AR072201A1 AR 072201 A1 AR072201 A1 AR 072201A1 AR P090102241 A ARP090102241 A AR P090102241A AR P090102241 A ARP090102241 A AR P090102241A AR 072201 A1 AR072201 A1 AR 072201A1
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Argentina
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alkyl
amino
ring
phenyl
methyl
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ARP090102241A
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Novartis Ag
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Abstract

Estos compuestos son inhibidores de PDK1. Tambien se proporcionan composiciones farmaceuticas que incluyen a los compuestos, y metodos para el tratamiento de enfermedades proliferativas, tales como c nceres, con los compuestos o composiciones. Reivindicacion 1: Un compuesto de la formula (1) o una sal farmaceuticamente aceptable del mismo, en donde R1a se selecciona a partir de H y halogeno; R3a se selecciona a partir de heterocicloalquiloxilo C2-6 y heteroarilo C1-6-alcoxilo C1-4; en donde este heterocicloalquiloxilo C2-6 y heteroarilo C1-6-alcoxilo C1-4 est n cada uno opcionalmente sustituidos por un grupo Rw; R4a se selecciona a partir de H, un anillo de tiazol, un anillo de pirazol, un anillo de triazol, un anillo de tetrazol, un anillo de piridina, cicloalquilo C3-6, ciano, halogeno, alquinilo C2-6, heteroarilo C1-6-alquilo C1-4, heteroarilo C1-6-alquinilo C1-4, -C(=O)Ra, y -C(=O)NRbRc; en donde el anillo de tiazol, el anillo de pirazol. el anillo de triazol, el anillo de tetrazol, el anillo de piridina, heteroarilo C1-6-alquilo C1-4 y heteroarilo C1-6-alquinilo C1-4 est n cada uno opcionalmente sustituidos por 1 o 2 grupos Rx'' independientemente seleccionados; Ar1a se selecciona a partir de fenilo opcionalmente sustituido en la posicion meta por un Ry' o, de una manera alternativa, en la posicion para por un grupo Ry''; cada Rw se selecciona independientemente a partir de halogeno, alquilo C1-6, amino, alquilo C1-6-amino, di-alquilo C1-4-amino, alcoxilo C1-6-carbonilo, y alquilo C1-6-carbamilo; en donde este alquilo C1-6, y alquilo C1-6-amino est n cada uno opcionalmente sustituidos por un grupo seleccionado a partir de hidroxilo, alcoxilo C1-6, amino, alquilo C1-6-amino, y di-alquilo C1-4-amino; cada Rx'' se selecciona independientemente a partir de halogeno, hidroxilo, alquilo C1-6, alcoxilo C1-6-carbonilo, y carbamilo; en donde este alquilo C1-6, y alcoxilo C1-6-carbonilo est n cada uno opcionalmente sustituidos por un grupo seleccionado a partir de hidroxilo, amino, alquilo C1-4-amino, y amino-sulfonilo; Ry' se selecciona a partir de halogeno. alcoxilo C1-6, alquilo C1-6, carbamilo, amino-sulfonilo, y alquilo C1-6-sulfonil-amino, en donde este alquilo C1-6, y alcoxilo C1-6 est n cada uno sustituidos por 1 o 2 grupos independientemente seleccionados a partir de hidroxilo, amino, alquilo C1-4-amino, y amino-sulfonilo; Ry'' se selecciona a partir de halo-alquilo C1-6; Ra se selecciona a partir de H, alcoxilo C1-6, y heterocicloalquilo C2-6; Rb se selecciona a partir de H y alquilo C1-6; y Rc se selecciona a partir de alquilo C1-6, cicloalquilo C3-6, heteroarilo C1-6, heterocicloalquilo C2-6, heterocicloalquilo C2-6-alquilo C1-4, y heteroarilo C1-6-alquilo C1-4; en donde este alquilo C1-6 est  opcionalmente sustituido por un grupo seleccionado a partir de hidroxilo y alcoxilo C1-4; en el entendido de que: (a) cuando R3a es piperidin-4-il-oxilo o N-metilpiperidin-4-iloxilo, entonces R4 no se selecciona a partir de tiazol-2-ilo, tiazol-4-ilo, tiazol-5-ilo, 5-metil-tiazol-2-ilo, 5-(hidroxi-metil)-tiazol-2-ilo, 5-(hidroxi-metil)-tiazol-4-ilo, piridin-2-ilo, piridin-4-ilo, piridin-3-ilo, 4-metil-piridin-3-ilo, 5-cloro-piridin-4-ilo, 3-metil-piridin-2-ilo, y 1-metil-pirazol-5-ilo; (b) cuando R4a es etinilo y Ar1a es 3-fluoro-fenilo, entonces R3 no se selecciona a partir de piridin-3-il-metoxilo, 6-cloro-piridin-3-il-metoxilo, piridin-2-il-metoxilo, piridin-4-il-metoxilo, 1-(piridin-4-il)-etoxilo, 6-metoxi-piridin-2-il-metoxilo, tiazol-5-il-metoxilo, pirazin-2-il-metoxilo, 5-metil-iso-oxazol-3-ilo, azetidin-3-iloxilo, N-metil-azetidin-3-iloxilo, N-isopropil-azetidin-3-iloxilo. pirrolidin-3-iloxilo, N-metilo, y pirrolidin-3-il-oxilo; (c) cuando R4a es etinilo, entonces Ar1a no se selecciona a partir de 3-(2-hidroxi-propan-2-il)-fenilo, 3-(1-hidroxietil)-fenilo, 3-amino-sulfonil-fenilo, fenilo, 3-(metil-sulfonil-amino)-fenilo, 3-(N,N-dimetil-amino-metil)-fenilo, 3-amino-sulfonil-fenilo, y 3-carbamil-fenilo; (d) cuando R4a es tiazol-2-ilo, entonces Ar1a no se selecciona a partir de 3-(metil-amino-sulfonil)-fenilo, 3-cloro-fenilo, 3-carbamil-fenilo, 3-fluoro-fenilo, 2-(hidroxi-propan-2-il)-fenilo, 1-hidroxi-etilo, 3-amino-sulfonil-fenilo, y fenilo; (e) cuando R4a es tiazol-2-ilo y Ar1a es 3-fluoro-fenilo, entonces R3 no se selecciona a partir de piridin-3-il-metoxilo, 6-cloro-piridin-3-il-metoxilo, 2-cloro-piridin-4-il-metoxilo, 5-metil-iso-oxazol-3-ilo, azetidin-3-iloxilo, N-metil-azetidin-3-iloxilo, N-isopropil-azetidin-3-iloxilo, pirrolidin-3-iloxilo, N-metilo, pirrolidin-3-iloxilo, piperidin-4-iloxilo, y N-metil-piperidin-4-il-oxilo; (f) cuando R4a es bromo, entonces Ar1a no se selecciona a partir de fenilo, 3-fluoro-fenilo, 2-(hidroxi-propan-2-il)-fenilo, 1-hidroxi-etilo, y 3-amino-sulfonil-fenilo; (g) cuando R4a es ciano, entonces R3a no se selecciona a partir de piridin-4-il-metoxilo, piridin-2-il-metoxilo, y 6-metoxi-piridin-2-il-metoxilo; (h) cuando R4a es ciclopropilo, entonces R3a no se selecciona a partir de azetidin-3-il-oxilo; y (i) cuando R4a es hidrogeno, entonces Ar1a es 3-(amino-sulfonil)-fenilo. Reivindicacion 10: Un compuesto de la formula (2) o una sal farmaceuticamente aceptable del mismo, en donde R1 se selecciona a partir de H y halogeno; R2 se selecciona a partir de H, halogeno, y alcoxilo C1-6; R3 se selecciona a partir de H, -OCH2-fenilo, -O-CH2-Het, -OCH2-CH2-Het, y -O-Hy; en donde Het es heteroarilo de 6 miembros que est  opcionalmente sustituido por 1 o 2 grupos independientemente seleccionados a partir de hidroxilo, alquilo C1-6, alcoxilo C1-4, amino, alquilo C1-4-amino, di-alquilo C1-4-amino, y alquilo C1-6-carbamilo; Hy es heterocicloalquilo de 6 miembros, el cual est  opcionalmente sustituido por 1 o 2 grupos independientemente seleccionados a partir de hidroxilo, alquilo C1-6, alcoxilo C1-4, amino, alquilo C1-4-amino, di-alquilo C1-4-amino, y alquilo C1-6-carbamilo; y fenilo est  opcionalmente sustituido por 1 o 2 grupos independientemente seleccionados a partir de hidroxilo, alquilo C1-6, alcoxilo C1-4, amino, alquilo C1-4-amino, di-alquilo C1-4-amino, y alquilo C1-6-carbamilo; R4 se selecciona a partir de ciano, halogeno, alquilo C1-6, alquinilo C2-6, cicloalquilo C3-6, un anillo de tiazol, un anillo de pirazol, y un anillo de piridina; cada uno de los cuales est  opcionalmente sustituido por 1 o 2 grupos independientemente seleccionados a partir de hidroxilo, alquilo C1-6, alcoxilo C1-4, amino, alquilo C1-4-amino, y di-alquilo C1-4-amino; en donde este alquilo C1-6 est  adem s opcionalmente sustituido por 1 o 2 grupos hidroxilo; Ar1 es una fraccion del grupo de formulas (3), (4), o (5); A es un anillo de pirazol; que est  opcionalmente sustituido por 1 o 2 grupos independientemente seleccionados a partir de hidroxilo, alquilo C1-6, alcoxilo C1-4, amino, alquilo C1-4-amino, y di-alquilo C1-4-amino; A' se selecciona a partir de -L2-Ar2 y -L1-Cy1; A'' se selecciona a partir de -L2a-Ar2a y -Cy1a; L1 se selecciona partir de un enlace, -O-, -C(=O)-, -CH2C(=O)-, y -CH2-; en donde el extremo izquierdo del enlazador est  unido al anillo de fenilo, y el extremo derecho del enlazador est  unido a Cy1; Cy1 se selecciona a partir de un anillo de morfolina, un anillo de tetrahidro-2H-pirano, un anillo de pirrolidina, un anillo de 2-oxo-pirrolidina, y un anillo de piperidina, cada uno de los cuales est  opcionalmente sustituido por 1 o 2 grupos independientemente seleccionados a partir de halogeno, hidroxilo, alquilo C1-6, alcoxilo C1-4, amino, alquilo C1-4-amino, di-alquilo C1-4-amino, alquilo C1-6-carbonilo, y alcoxilo C1-6-carbonilo; Cy1a se selecciona a partir de un anillo de morfolina, un anillo de 2-oxo-pirrolidina y un anillo de piperidina; cada uno de los cuales est  opcionalmente sustituido por 1 o 2 grupos independientemente seleccionados a partir de halogeno, hidroxilo, alquilo C1-6, alcoxilo C1-4, amino, alquilo C1-4-amino, di-alquilo C1-4-amino, alquilo C1-6-carbonilo, y alcoxilo C1-6-carbonilo; L2 y L2a se seleccionan cada uno independientemente a partir de un enlace, -O-, y -OCH2-; y Ar2 se selecciona a partir de un anillo de pirazol, un anillo de oxazol, un anillo de imidazol, un anillo de triazol, un anillo de tiadiazol, un anillo de piridina, y un anillo de pirimidina; cada uno de los cuales est  opcionalmente sustituido con 1, 2 o 3 grupos independientemente seleccionados a partir de hidroxilo, alquilo C1-6, alcoxilo C1-4, amino, alquilo C1-4-amino, y di-alquilo C1-4-amino; Ar2a se selecciona a partir de un anillo de pirazol, un anillo de triazol, un anillo de piridina, y un anillo de pirimidina; cada uno de los cuales est  opcionalmente sustituido con 1 o 2 grupos independientemente seleccionados a partir de hidroxilo, alquilo C1-6, alcoxilo C1-4, amino, alquilo C1-4-amino, y di-alquilo C1-4-amino; en el entendido de que: (i) cuando R1 y R2 son cada uno H, R4 es tiazol-2-ilo, R3 es piperidin-4-iloxilo opcionalmente sustituido, y Ar1 es una fraccion del grupo de formula (3), entonces A' no se selecciona a partir de 1,2,4-triazol-1-H-metilo, 1-metil-pirazol-3-ilo, 2-oxo-pirrolidinilo, oxazol-5-ilo, pirazol-1-ilo, 1-metil-1,2,4-triazol-2-ilo, morfolin-4-il-carbonil-metilo, imidazol-2-ilo, 2-metil-tiazol-4-ilo, 1,3,5-trimetil-pirazol-4-ilo, pirimidin-5-ilo, 1,2,4-triazol-1-ilo, 4,5-dimetil-oxazol-2-ilo, pirimidin-5-ilo, 2-metoxi-pirimidin-5-ilo, 6-metoxi-piridin-3-ilo y piridin-3-ilo; (ii) cuando R1 y R2 son cada uno H, Ar1 es una fraccion del grupo de formula (3), A' se selecciona a partir de 1-metil-pirazol-3-ilo, y R3 se selecciona a partir de piridin-3-il-metoxilo y pirazin-2-il-metoxilo, entonces R4 no es tiazol-2-ilo; (iii) cuando R1 y R2 son cada uno H, R4 es tiazol-2-ilo, R3 es piperidin-4-iloxilo opcionalmente sustituido, y Ar1 es una fraccion del grupo de formula (4), entonces A'' no se selecciona a partir de morfolin-4-ilo, morfolin-4-il-carbonil-metilo, pirimidin-5-ilo, y pirazol-1-il-metilo; (iv) cuando R1 y R2 son cada uno H, R4 es bromo, R3 es piridin-3-il-met
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