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AR047366A1 - Derivados de tiofeno como inhibidores de chk 1 - Google Patents

Derivados de tiofeno como inhibidores de chk 1

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Publication number
AR047366A1
AR047366A1 ARP050100025A ARP050100025A AR047366A1 AR 047366 A1 AR047366 A1 AR 047366A1 AR P050100025 A ARP050100025 A AR P050100025A AR P050100025 A ARP050100025 A AR P050100025A AR 047366 A1 AR047366 A1 AR 047366A1
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Argentina
Prior art keywords
alkyl
aryl
group
heterocyclyl
cho
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ARP050100025A
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English (en)
Inventor
Susan Ashwell
Thomas Gero
James Janetka
Paul Dermot Lyne
Mei Su
Dorin Toader
Dingwei Yu
Yan Yu
Stephanos Ioannidis
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Astrazeneca Ab
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Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of AR047366A1 publication Critical patent/AR047366A1/es

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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

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  • Steroid Compounds (AREA)

Abstract

La presente se refiere a derivados de tiofeno como inhibidores de CHK1. Compuestos que proveen tratamiento o profilaxis para el cáncer. Reivindicacion 1: Un compuesto, caracterizado porque es de formula (1) donde: X se selecciona entre NH, S y O; Y se selecciona entre CH o N; R1 se selecciona entre ciano, isociano, C1-6 alquilo, -NR11R12, C1-6alcoxi, C2-6alquenilo, C2-6 alquinilo, cicloalquilo, cicloalquenilo, arilo y heterociclilo, con la condicion que R1 no sea tienilo; y donde R1 puede estar sustituido opcionalmente en uno o más átomos de C por uno o más R9; y donde si dicho R1 contiene un grupo -NH-, el N de dicho grupo puede estar sustituido opcionalmente por un grupo seleccionado entre R10; R2 y R3 se seleccionan independientemente entre sí entre -C(=O)NR6R7, -SO2NR16R17, -NHC(=O)NHR4 y -NHC(=NR8)NH2; R4 se selecciona entre H, OH, -NR11R12, bencilo, C1-6 alcoxi, cicloalquilo, cicloalquenilo, arilo, heterociclilo, mercapto, CHO, -COarilo, -CO(C1-6alquilo), - CONR30R31, -CO2(C1-6 alquilo), -CO2arilo, -CO2NR30R31, -S-alquilo, -SO(C1-6 alquilo), -SO2(C1-6 alquilo), -S-arilo, -SOarilo, -SO2arilo, -SO2NR30R31 y -(C1-6 alquilo)SO2NR30R31 donde R4 puede estar sustituido opcionalmente en uno o más átomos de C por uno o más R15; y donde si dicho heterociclilo contiene un grupo NH-, el N puede estar sustituido opcionalmente por un grupo seleccionado entre R14; R6 y R7 se seleccionan independientemente entre sí entre H, OH, OCH3, C1-6 alcoxi, -NH2, -NHCH3, - N(CH3)2, (C1-3 alquilo)NR11R12, -CH2CH2OH, cicloalquilo y un anillo heterociclilo de 5, 6 o 7 miembros que contiene al menos un átomo de N, con la condicion que R6 y R7 no sean ambos H; como alternativa R6 y R7 tomados en conjunto con el N a cual están unidos forman un anillo heterocíclico; donde R6 y R7, independientemente entre sí, pueden estar sustituidos opcionalmente en uno o más átomos de C por uno o más R18; y donde si dicho heterociclilo contiene un grupo -NH-, el N de dicho grupo puede estar sustituido opcionalmente por un grupo seleccionado entre R19; R8 se selecciona entre ciano, isociano, -SO2(C1-6 alquilo), -SO2arilo, -SO2cicloalquilo, -SO2cicloalquenilo, -SO2heterociclilo y CF3; donde R8 puede estar sustituido opcionalmente en uno o más átomos de C por uno o más R23; R9; R15, R18, R23, R24 y R33 se seleccionan independientemente entre sí entre halogeno, nitro, -NR30R31, ciano, isociano, C1-6 alquilo, C2-6alquenilo, C2-6 alquinilo, arilo, cicloalquilo, heterociclilo, hidroxi, ceto(=O), -O(C1-6 alquilo), Oarilo, -OCOalquilo, -NHCHO, -N(C1-6 alquilo)CHO, -NHCONR30R31, -N(C1-6 alquil)CONR30R31, -NHCOalquilo, -NHCO2(C1-6 alquilo); -NHCO2H, -;N(C1-6 alquil)CO(C1-6 alquilo); -NHSO2(C1-6 alquilo); carboxi, -amidino, -CHO, -CONR30R31, -CO(C1-6 alquilo); -COheterociclilo, COcicloalquilo, -CO2H, CO2(C1-6 alquilo); -CO2(arilo), -CO2(NR30R31), mercapto, -S(C1-6 alquilo); -SO(C1-6 alquilo); -SO2(C1-6 alquilo);??-SO2NR31R31; donde R9, R15, R18, R23, R24 y R33, independientemente entre sí, pueden estar sustituidos opcionalmente en un C por uno o más R20 y en un N de cualquier grupo que contenga un NH o NH2 por R21; R10, R14, R19, R25 y R34 se seleccionan independientemente entre sí entre halogeno, nitro, -NR30R31, ciano, isociano, C1-6 alquilo, C2-6alquenilo, C2-6 alquinilo, arilo, cicloalquilo, heterociclilo, hidroxi, ceto(=O), -O(C1-6 alquilo), Oarilo, -OCOalquilo, -NHCHO, -N(C1-6 alquil)CHO, -NHCONR30R31, -N(C1-6 alquil)CONR30R31, -NHCOalquilo, -NHCO2(C1-6 alquilo); -NHCO2H; -N(C1-6 alquil)CO(C1-6 alquilo); -NHSO2(C1-6 alquilo); carboxi, -amidino, -CHO, -CONR30R31, -CO(C1-6 alquilo); -COheterociclilo, COcicloalquilo, -CO2H, CO2(C1-6 alquilo); -CO2(arilo), - CO2(NR30R31), mercapto, -S(C1-6 alquilo); -SO(C1-6 alquilo); -SO2(C1-6 alquilo);??-SO2NR30R31; donde R10, R14, R19, R25, y R34, independientemente entre sí, pueden estar sustituidos opcionalmente en un C por uno o más R22 y en un N de cualquier grupo que contenga un NH o NH2 por R23; R11 y R12 se seleccionan independientemente entre sí entre H, alquilo C1-6, cicloalquilo, arilo, heterociclilo; como alternativa R11 y R12 tomados en conjunto con el N al cual están unidos forman un anillo heterocíclico; donde R11 y R12, independientemente entre sí pueden estar sustituidos opcionalmente en un C por uno o más R33; y donde si dicho heterociclilo contiene un grupo NH-, el N de dicho grupo puede estar sustituido opcionalmente por un grupo seleccionado entre R34; R16 y R17 se seleccionan independientemente entre sí entre H, OH, OCH3, C1-6 alcoxi, NH2, -NHCH3, -N(CH3)2 (C1-3 alquilo)NR11R12, -CH2CH2OH; cicloalquilo, arilo, o un anillo heterociclilo de 5, 6 o 7 miembros que contiene al menos un átomo de N, con la condicion que R16 y R17 no sean ambos H; como alternativa R16 y R17 tomados en conjunto con el N al cual están unidos forman un anillo heterocíclico sustituido opcionalmente; donde R16 y R17, independientemente entre sí, pueden estar sustituidos opcionalmente en uno o más átomos e C por uno o más R24; y donde si dicho heterociclilo contiene un grupo -NH-, el N de dicho grupo puede estar sustituido opcionalmente por un grupo seleccionado entre R25; R20, R22 y R32 se seleccionan independientemente entre sí entre halogeno, nitro, -NR30R31, ciano, isociano, C1-6 alquilo, C2-6alquenilo, C2-6 alquinilo, arilo, cicloalquilo, heterociclilo, hidroxi, ceto(=O), -O(C1-6 alquilo), -Oarilo, -OCOalquilo, -NHCHO, -N(C1-6 alquil)CHO, -NHCONR30R31, -N(C1-6 alquil)CONR30R31, -NHCOalquilo, -NHCO2(C1-6 alquilo); -NHCO2H; -N(C1-6 alquil)CO(C1-6 alquilo); -NHSO2(C1-6 alquilo); carboxi, -amidino, -CHO, -CONR30R31, -CO(C1-6 alquilo); -COheterociclilo, COcicloalquilo, -CO2H, CO2(C1-6 alquilo); -CO2(arilo), -CO2(NR30R31), mercapto, -S(C1-6 alquilo); -SO(C1-6 alquilo); -SO2(C1-6 alquilo);??-SO2NR30R31; donde R20, R21 y R32, independientemente entre sí, pueden estar sustituidos opcionalmente en un C por uno o más R26 y en un N de cualquier grupo que contenga un NH o NH2 por R27; R21, R23 y R35 se seleccionan independientemente entre sí entre halogeno, nitro, -NR30R31, ciano, isociano, C1-6 alquilo, C2-6 alquenilo, C2-6 alquinilo, arilo, cicloalquilo, heterociclilo, hidroxi, ceto(=O), -O(C1-6 alquilo), -Oarilo, -OCOalquilo, -NHCHO, -N(C1-6 alquil)CHO, -NHCONR30R31, -N(C1-6 alquil)CONR30R31, -NHCOalquilo, -NHCO2(C1-6 alquilo); -NHCO2H, -;N(C1-6 alquil)CO(C1-6 alquilo); -NHSO2(C1-6 alquilo); carboxi, -amidino, - CHO, -CONR30R31, -CO(C1-6 alquilo); -COheterociclilo, COcicloalquilo, -CO2H, CO2(C1-6 alquilo); -CO2(arilo), -CO2(NR30R31), mercapto, -S(C1-6 alquilo); -SO(C1-6 alquilo); -SO2(C1-6 alquilo);??-SO2NR30R31; donde R21, R23 y R35, independientemente entre sí, pueden estar sustituidos opcionalmente en un C por uno o más R28 y en un N de cualquier grupo que contenga un NH por R29; R26 y R28 se seleccionan independientemente entre sí entre halogeno, nitro, -NR30R31, ciano, isociano, C1-6 alquilo, C2-6 alquenilo, C2-6 alquinilo, arilo, cicloalquilo, heterociclilo, hidroxi, ceto(=O), -O(C1-6 alquilo), -Oarilo, -OCOalquilo, -NHCHO, -N(C1-6 alquil)CHO, -NHCONR30R31, -N(C1-6 alquil)CONR30R31, -NHCOalquilo, -NHCO2(C1-6 alquilo); -NHCO2H, -;N(C1-6 alquil)CO(C1-6 alquilo); -NHSO2(C1-6 alquilo); carboxi, -amidino, -CHO, -CONR30R31, -CO(C1-6 alquilo); -COheterociclilo, -COcicloalquilo, -CO2H, CO2(C1-6 alquilo); -CO2(arilo), -CO2(NR30R31), mercapto, -S(C1-6 alquilo); -SO(C1-6 alquilo); -SO2(C1-6 alquilo);??-SO2NR31; R27 y R29 se seleccionan independientemente entre sí entre halogeno, nitro, -NR30R31, ciano, isociano, C1-6 alquilo, C2-6 alquenilo, C2-6 alquinilo, arilo, cicloalquilo, heterociclilo, hidroxi, ceto(=O), -O(C1-6 alquilo), - Oarilo, -OCOalquilo, -NHCHO, -N(C1-6 alquil)CHO, -NHCONR30R31, -N(C1-6 alquil)CONR30R31, -NHCOalquilo, -NHCO2(C1-6 alquilo); -NHCO2H, -;N(C1-6 alquil)CO(C1-6 alquilo); -NHSO2(C1-6 alquilo); carboxi, -amidino, -CHO, -CONR30R31, -CO(C1-6 alquilo); - COheterociclilo, -COcicloalquilo, -CO2H, CO2(C1-6 alquilo); -CO2(arilo), -CO2(NR30R31), mercapto, -S(C1-6 alquilo); -SO(C1-6 alquilo); -SO2(C1-6 alquilo);??-SO2NR30R31; R30 y R31 se seleccionan independientemente entre sí entre halogeno, nitro, -NH2, ciano, isociano, C1-6 alquilo, C2-6 alquenilo, C2-6 alquinilo, arilo, cicloalquilo, heterociclilo, hidroxi, ceto(=O), -O(C1-6 alquilo), -Oarilo, -OCOalquilo, -NHCHO, -N(C1-6 alquil)CHO, -NHCONR11R12, -N(C1-6 alquil)CONR11R12, -NHCOalquilo, -NHCO2(C1- 6 alquilo); -NHCO2H, -;N(C1-6 alquil)CO(C1-6 alquilo); -NHSO2(C1-6 alquilo); carbonilo, -amidino, -CHO, -CONR30R31, -CO(C1-6 alquilo); -COheterociclilo, -COcicloalquilo, -CO2H, CO2(C1-6 alquilo); -CO2(arilo), -CO2(NR30R31), mercapto, -S(C1-6 alquilo); -SO(C1-6 alquilo); -SO2(C1-6 alquilo);??-SO2NR11R12;donde R30 y R31, independientemente entre sí, pueden estar sustituidos opcionalmente en un C por uno o más R32, y donde si el heterociclilo mencionado contiene un grupo -NH- o -NH2, el N de dicho grupo puede estar sustituido opcionalmente por un grupo seleccionado entre R35; o una sal aceptable para uso farmacéutico del mismo; con la condicion que cuando X es S; Y es CH; R2 es C(=O)NR6R7; y R3 es NHC(=O)NHR4; entonces R1 no puede ser como se muestra en la formula (2) donde R5 se selecciona entre H, un carbociclilo sustituido opcionalmente, o un C1-6 alquilo sustituido opcionalmente; con la condicion adicional que dicho compuesto no sea: (1-etil-piperidin-3-il)-amida del ácido 5-metil-2-ureido-tiofeno-3-carboxílico; [3-((S)-3-amino-azepan-1-carbonil)-5-etil-tiofen-2-il]-urea; (S)-piperidin-3-ilamida del ácido 2-morfolin-4-il-4-ureido-tiazol-5-carboxílico; (S)-piperidin-3-ilamida del ácido 2-metil-5-ureido-oxazol-4- carboxílico; (S)-piperidin-3-ilamida del ácido 5-(4-cloro-fenil)-3-{3-[(R)-1-(2,2,2-trifluoro-acetil)-piperidin-3-il]-ureido}-tiofeno-2-carboxílico ácido; o N-(3-{[(3S)-3-aminoazepan-1-il]carbonil)-5-piridin-2-il-2-tienil)urea.
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