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ES2353437T3 - Derivados de pirrolidina como inhibidores de erk. - Google Patents

Derivados de pirrolidina como inhibidores de erk. Download PDF

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ES2353437T3
ES2353437T3 ES07750497T ES07750497T ES2353437T3 ES 2353437 T3 ES2353437 T3 ES 2353437T3 ES 07750497 T ES07750497 T ES 07750497T ES 07750497 T ES07750497 T ES 07750497T ES 2353437 T3 ES2353437 T3 ES 2353437T3
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substituted
alkyl
group
independently selected
heteroaryl
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Gerald W. Shipps, Jr.
Hugh Zhu
Alan Cooper
Robert Sun
Tong Wang
Li Xiao
James Wang
Joseph Kelly
Neng-Yang Shih
Youhao Dong
Yongqi Deng
M. Arshad Siddiqui
Ronald Doll
Jagdish Desai
Alan Hruza
Vincent S. Madison
Yang Nan
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Merck Sharp and Dohme LLC
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Schering Corp
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/16—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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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D417/02—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 two hetero rings
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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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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

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Abstract

Un compuesto de formula 1.0: **Fórmula** o sus sales farmaceuticamente aceptables, donde: Y1, Y2, y Y3 se seleccionan cada uno independientemente del grupo que consiste en: -CH= y -CR9=; z es 1; Q es un sustituyente seleccionado del grupo que consiste en: **Fórmula** Cada Q1 representa un anillo seleccionado independientemente del grupo que consiste en: cicloalquilo, cicloalquilo sustituido, heterocicloalquilo, heterocicloalquilo sustituido, arilo, arilo sustituido, heteroarilo, y heteroarilo sustituido, donde dichos anillos sustituidos estan sustituidos con 1 a 3 sustituyentes seleccionados independientemente del grupo que consiste en: los radicales R10; siempre que cuando Q1 es arilo, heteroarilo, arilo sustituido o heteroarilo sustituido los atomos de carbono en la union del anillo no estan sustituidos; Q2 representa un anillo seleccionado del grupo que consiste en: cicloalquilo, cicloalquilo sustituido, heterocicloalquilo, y heterocicloalquilo sustituido, donde dichos anillos sustituidos estan sustituidos con 1 a 3 sustituyentes seleccionados independientemente del grupo que consiste en: los radicales R10; Z1 representa -(C(R24)2)w- donde cada R24 se selecciona independientemente del grupo que consiste en: H, alquilo y F, y donde w es 1, 2 o 3, y generalmente w es 1 o 2, y usualmente w es 1, y donde en un ejemplo cada R24 es H, y en otro ejemplo w es 1, y en otro ejemplo cada R24 es H y w es 1, preferiblemente w es 1 y cada R24 es H; Z2 se selecciona del grupo que consiste en: -N(R44)-, -O- y -C(R46)2-; m es de 1 a 6; n es de 1 a 6; p es de 0 a 6; t es 0, 1, o 2; R1 se selecciona del grupo que consiste en: (1) -CN, (2) -NO2, (3) -OR10, (4) -SR10, (5) -N(R10)2, (6) R10, (7) halo, (8) -CF3; (9) alquenilo; (10) -C(O)N(R10)2 donde cada R10 se selecciona independientemente, y preferiblemente cada R10 se selecciona independientemente del grupo que consiste en: (a) H, (b) alquilo, (c) heteroarilo, (d) arilo, y (e) cicloalquilo, donde por ejemplo, cada R10 se selecciona del grupo que consiste en: H, metilo, butilo, i-propilo, piridilo, fenilo y ciclopropilo, donde, por ejemplo, dicho -C(O)N(R10)2 radical se selecciona del grupo que consiste en: -C(O)NH2, -C(O)NH(CH3), -C(O)NH(CH)(CH3)2, -C(O)NH(C4H9), -C(O)NH(C6H5), -C(O)NH(C3H5), y -C(O)NH(C5H4N); (11) arilalquenilo-; R2 se selecciona del grupo que consiste en: (1) H, (2) -CN, (3) halo, (4) alquilo, (5) alquilo sustituido donde dicho alquilo sustituido esta sustituido con 1 a 3 sustituyentes seleccionados del grupo que consiste en: (a) -OH, (b) -O-alquilo (p. ej., -O-(alquilo C1-C3), (c) -Oalquilo (p. ej., -O-(alquilo C1-C3)) sustituido con 1 a 3 atomos de F, y (d) -N(R40)2 donde cada R40 se selecciona independientemente del grupo que consiste en: (i) H, (ii) alquilo C1-C3 y (iii) -CF3, (6) alquinilo, (7) alquenilo, (8) -(CH2)mR11, (9) -N(R26)2, (10) -OR23, (11) -N(R26)C(O)R42, (12) cicloalquilo, (13) cicloalquilalquilo, y (14) **Fórmula** cada R3, R4, R5, R6 y R7 se selecciona independientemente del grupo que consiste en: (1) H, (2) alquenilo, (3) alquenilo sustituido, (4) alquilo, (5) alquilo sustituido, (6) cicloalquilo, (7) cicloalquilo sustituido, (8) cicloalquilalquilo-, (9) cicloalquilalquilo- sustituido, (10) heterocicloalquilo, (11) heterocicloalquilo sustituido, (12) heterocicloalquilalquilo-, (13) heterocicloalquilalquilo- sustituido, (14) -C(O)R10 donde en un ejemplo R10 se selecciona del grupo que consiste en: alquilo, (15) arilheteroarilo-, (16) arilheteroarilo- sustituido, (17) heteroarilarilo-, tal como, por ejemplo, pirimidinilfenilo-, pirazinilfenilo-, piridinilfenilo-, furanilfenilo-, tienilfenilo-, y tiazolilfenilo-, (18) heteroarilarilo- sustituido, tal como, por ejemplo, pirimidinilfenilo- sustituido, sustituido pirazinilfenilo-, sustituido piridinilfenilo-, sustituido furanilfenilo-, sustituido tienilfenilo-, sustituido tiazolilfenilo-, y sustituido pirimidinilfenilo, (19) arilo, (20) arilo sustituido, (21) heteroarilo, (22) heteroarilo sustituido, (23) heteroarilheteroarilo-, (24) sustituido heteroarilheteroarilo-, (25) arilaminoheteroarilo-, (26) sustituido arilaminoheteroarilo-, (27) arilalquinilo-, (28) sustituido arilalquinilo-, (29) heteroarilalquinilo-, (30) sustituido heteroarilalquinilo-, (31) -C(O)NHR28, (32) cicloalquilheteroarilarilo-, (33) sustituido arilarilo-, (34) arilalquenilarilo-, (35) arilarilo-, (36) arilalquilo- sustituido, (37) arilalquilo-, (38) -SO2arilo, (39) benzoheteroaril-C(O)-(heterocicloalquilo sustituido)-, (40) heterocicloalquilo sustituido, (41) heterocicloalquil-C(O)-alquilo-, y (42) benzo[1,3]dioxolilo, donde dichos grupos R3, R4, R5, R6 y R7 sustituidos (7), (9), (11), (13), (16), (18), (20), (22), (24), (26), (28), (30), (33), (36), (39) y (40) estan sustituidos con 1 a 3 sustituyentes seleccionados independientemente del grupo que consiste en: -CH2OH, CN, -OH, -NH2, alquilo, alquenilo, halo, -C(O)-NH-R28, -C(O)NH2, -C(O)OR28, -C(O)R28, -C(alquil)=NOH, -C(alquil)=NO(alquilo), alcoxi, hidroxilo alquilo sustituido, dialquilamina donde cada grupo alquilo se selecciona independientemente, -CF3, -SO2alquilo, y -NHC(O)H, donde dichos grupos R3, R4, R5, R6 y R7 sustituidos (3) y (5) estan sustituidos con 1 a 3 sustituyentes seleccionados independientemente del grupo que consiste en: -NH2, halo, -C(O)-NH-R28, -C(O)OR28, y -C(O)R28; R8 se selecciona del grupo que consiste en: H, -OH, alquilo, arilo, -N(R10)2 y -NR10C(O)R12; cada R9 se selecciona independientemente del grupo que consiste en: halogeno, -CN, -NO2, -OR10, -SR10, -N(R10)2, y R10; cada R10 se selecciona independientemente del grupo que consiste en: H, alquilo, arilo, arilalquilo, heteroarilo, heteroarilalquilo, cicloalquilo, cicloalquilalquilo, heterocicloalquilo, heterocicloalquilalquilo, alquilheteroarilo-, alquilarilo-, alquilo sustituido, arilo sustituido, arilalquilo sustituido, heteroarilo sustituido, heteroarilalquilo sustituido, cicloalquilo sustituido, cicloalquilalquilo sustituido, heterocicloalquilo sustituido, heterocicloalquilalquilo sustituido, alquilheteroarilo- sustituido y alquilarilo- sustituido, y donde: dicho alquilo sustituido R10 esta sustituido con 1 a 3 sustituyentes seleccionados independientemente del grupo que consiste en: -NH2, -NHR20, -NO2, -CN, -OR26, halo, -C(O)-NH-R26, -C(O)OR26, y -C(O)R26, y dichos arilo sustituido, arilalquilo sustituido, heteroarilo sustituido, heteroarilalquilo sustituido, cicloalquilo sustituido, cicloalquilalquilo sustituido, heterocicloalquilo sustituido, heterocicloalquilalquilo sustituido, alquilheteroarilo- sustituido y alquilarilo- sustituido R10 estan sustituidos con 1 a 3 sustituyentes seleccionados independientemente del grupo que consiste en: (1) -NH2, (2) -NO2, (3) -CN, (4) -OH, (5) -OR20, (6) -OCF3, (7) -CF3, (8) -C(O)R38, (9) alquilo, (10) alquenilo, (11) halo, (12)-C(O)- NH-R26, (13) -C(O)OR38, (14) -C(O)-NR32-(C(R30)2)n- N(R38)2, (15) -S(O)tR38, (16) -C(O)-NR32-R38, (17) - NR32-C(O)-R38, **Fórmula** y (19) -NHR20; R11 se selecciona del grupo que consiste en: F, -OH, -CN, -OR10, -NHNR1R10, -SR10 y heteroarilo; R12 se selecciona del grupo que consiste en: alquilo, arilo, heteroarilo, cicloalquilo, cicloalquilalquilo, heterocicloalquilo y heterocicloalquilalquilo; R20 representa alquilo; R23 se selecciona del grupo que consiste en: H, alquilo, arilo, cicloalquilo, y cicloalquilalquil-; cada R26 se selecciona independientemente del grupo que consiste en: H y alquilo; R28 es alquilo; cada R30 se selecciona independientemente del grupo que consiste en: H, alquilo, y F; cada R32 se selecciona independientemente del grupo que consiste en: H y alquilo; cada R35 es H ; R36 se selecciona del grupo que consiste en: H y alquilo; cada R38 se selecciona independientemente del grupo que consiste en: H, alquilo, arilo, arilalquilo, heteroarilo, heteroarilalquilo, cicloalquilo, cicloalquilalquilo, heterocicloalquilo, heterocicloalquilalquilo, alquilheteroarilo-, alquilarilo-, alquilo sustituido, arilo sustituido, arilalquilo sustituido, heteroarilo sustituido, heteroarilalquilo sustituido, cicloalquilo sustituido, cicloalquilalquilo sustituido, heterocicloalquilo sustituido, heterocicloalquilalquilo sustituido, alquilheteroarilo- sustituido y alquilarilo- sustituido, y donde: dicho alquilo sustituido R38 esta sustituido con 1 a 3 sustituyentes seleccionados independientemente del grupo que consiste en: -NH2, -NO2, -CN, -OR26, halo, -C(O)-NH-R28, -C(O)OR28, y -C(O)R28, y dichos arilo sustituido, arilalquilo sustituido, heteroarilo sustituido, heteroarilalquilo sustituido, cicloalquilo sustituido, cicloalquilalquilo sustituido, heterocicloalquilo sustituido, heterocicloalquilalquilo sustituido, alquilheteroarilo- sustituido y alquilarilo- sustituido R38 estan sustituidos con 1 a 3 sustituyentes seleccionados independientemente del grupo que consiste en: (1) -NH2, (2) -NO2, (3) -CN, (4) -OH, (5) -OR20, (6) -OCF3, (7) -CF3, (8) -C(O)R26, (9) alquilo, (10) alquenilo, (11) halo, (12) -C(O)- NH-R26, (13) -C(O)OR26, (14) -C(O)-NR32-(C(R30)2)n- 30 N(R26)2, (15) -S(O)tR26, (16)-C(O)N(R32)(R26), (17) -NR32C(O)R26, (18) **Fórmula** y (19) -NHR20; R42 se selecciona del grupo que consiste en: alquilo, arilo, heteroarilo, y cicloalquilo; R44 se selecciona del grupo que consiste en: H, alquilo, cicloalquilo, y cicloalquilalquilo; y Cada R46 se selecciona independientemente del grupo que consiste en: H, alquilo, cicloalquilo, y cicloalquilalquilo; donde: cada alquilo incluyendo las porciones alquilicas de alquiloxi, arilalquilo, heteroarilalquilo, cicloalquilalquilo, heterocicloalquilalquilo, heterocicloalquil-C(O)-alquilo, alquilheteroarilo-, alquilarilo-, -C(alquil)=NOH, -C(alquil)=NO(alquilo), dialquilamina y -SO2alquilo significa un grupo hidrocarbonado alifatico que puede ser lineal o ramificado donde dicho grupo comprende de aproximadamente 1 a aproximadamente 20 atomos de carbono en la cadena; cada alcoxi o alquiloxi significa un grupo alquil-O-, es decir el enlace hacia el radical parental es a traves del ox
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