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AR085908A1 - DERIVADOS DE 3-BUTIN-2-OL Y DE CARBONITRILO CON ACTIVIDAD INHIBIDORA DE LA QUINASA INDUCTORA DE NF-kB (NIK) - Google Patents

DERIVADOS DE 3-BUTIN-2-OL Y DE CARBONITRILO CON ACTIVIDAD INHIBIDORA DE LA QUINASA INDUCTORA DE NF-kB (NIK)

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Publication number
AR085908A1
AR085908A1 ARP120100848A ARP120100848A AR085908A1 AR 085908 A1 AR085908 A1 AR 085908A1 AR P120100848 A ARP120100848 A AR P120100848A AR P120100848 A ARP120100848 A AR P120100848A AR 085908 A1 AR085908 A1 AR 085908A1
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Argentina
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alkyl
group
alkylene
heterocycloalkyl
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ARP120100848A
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Inventor
Jianwen Feng
Pui Leng Loke
Christian A G N Montalbetti
Steven Staben
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Hoffmann La Roche
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Publication of AR085908A1 publication Critical patent/AR085908A1/es

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Abstract

Estos compuestos y las composiciones farmacéuticas que los contienen son útiles para el tratamiento de enfermedades y trastornos, en los que se observa una señalización no deseada o sobreactivada de la NF-kB.Reivindicación 1: Compuestos de la fórmula (1) en los que en la fórmula (1): Y es nitrógeno y el subíndice b es el número entero 0, o Y es carbono y el subíndice b es el número entero 1; R1 es alquilo C1-2, haloalquilo C1-2 o -CH2-OH; R2 es alquilo C1-6, haloalquilo C1-6, cicloalquilo de 3 - 7 eslabones, alquileno C1-6-cicloalquilo de 3 - 7 eslabones, fenilo, heteroarilo de 5 - 6 eslabones, C(=O)Rx2a, -C(=O)ORx2a o -C(=O)NRx2aRx2b, en el que Rx2a se elige entre el grupo formado por hidrógeno, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, heteroalquilo C1-6, cicloalquilo de 3 - 8 eslabones, heteroalquilo de 3 - 8 eslabones, -(alquileno C1-6)-(cicloalquilo de 3 - 8 eslabones), -(alquileno C1-6)-(heterocicloalquilo de 3 - 8 eslabones), -(alquileno C1-6)-(arilo de 6 eslabones) y -(alquileno C1-6)-(heteroarilo de 5 - 6 eslabones), y Rx2b se elige entre el grupo formado por hidrógeno, alquilo C1-6, alquenilo C2-6, alquinilo C2-6 y heteroalquilo C1-6; en la que, si Rx2a y Rx2b están unidos al mismo átomo de nitrógeno, entonces podrán combinarse opcionalmente entre sí para formar un heterocicloalquilo de 3 - 7 eslabones que contiene además 0 - 2 heteroátomos adicionales elegidos entre N, O y S; o como alternativa, R1 y R2 se combinan para formar un cicloalquilo de 3 - 8 eslabones o un heterocicloalquilo de 3 - 8 eslabones y opcionalmente está fusionado a ellos un anillo heteroarilo de 5 - 6 eslabones que contiene 1 - 3 heteroátomos elegidos entre N, O y S; y en la que porciones alifática y/o aromática de R1 y R2 ya sea con independencia, ya sea en combinación, están opcionalmente sustituidas por 1 - 5 sustituyentes RR1/2 elegidos entre el grupo formado por F, Cl, Br, I, -OH, -NH2, -SH, -CF3, -OCF3, -SF5, -OCH3, -(Xa)0-1-CN, -(Xa)0-1-NO2, -(Xa)0-1-N3, -(Xa)0-1-OH, -(Xa)0-1-H, -(Xa)0-1-ORa, -(Xa)0-1-N(H)Ra, -(Xa)0-1-N(H)2, -(Xa)0-1-N(Ra)2, -(Xa)0-1-SRa, -(Xa)0-1-SH, -(Xa)0-1C(O)Ra, -(Xa)0-1-S(O)2Ra, -(Xa)0-1-S(O)Ra, -(Xa)0-1-N(H)-S(O)2Ra, -(Xa)0-1-N(Ra)S(O)2Ra, -(Xa)0-1-OC(O)Ra, -(Xa)0-1-N(H)-C(O)ORa, -(Xa)0-1-N(Ra)C(O)ORa, -(Xa)0-1-C(=O)ORa, -(Xa)0-1-C(=O)OH, -(Xa)0-1-C(=O)N(H)Ra, -(Xa)0-1-C(=O)N(Ra)Ra, -(Xa)0-1-N(H)C(=O)Ra, -(Xa)0-1-N(Ra)C(=O)Ra, -(Xa)0-1-N(H)C(=O)ORa y -(Xa)0-1-N(Ra)C(=O)ORa, en los que Xa se elige entre el grupo formado por alquileno C1-6, alquenileno C2-6, alquinileno C2-6, heteroalquileno C1-6,cicloalquileno de 3 - 6 eslabones y heterocicloalquileno de 3 - 6 eslabones, y Ra con independencia de cada aparición se elige entre el grupo formado por alquilo C1-6, haloalquilo C1-6, heteroalquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo de 3 - 7 eslabones y heterocicloalquilo de 3 - 7 eslabones; A se elige entre el grupo de fórmulas (2), en los que X1, X2 y X3 son con independencia N o CR5, en los que por lo menos uno de X1, X2 y X3 es CR5, en el que R5 se elige entre el grupo formado por hidrógeno, alquilo C1-4, haloalquilo C1-4, halógeno, -O(alquilo C1-6), (heterocicloalquilo de 3 - 6 eslabones)-(alquileno C1-3)-oxi-, -CN, -NO2, -NH-(alquilo C1-6), -NH2 y -N(alquilo C1-6)2; R3 es heteroarilo de 5 - 10 eslabones opcionalmente sustituido por NRx3aRx3b, en el que Rx3a y Rx3b con independencia entre sí se eligen entre el grupo formado por hidrógeno, alquilo C1-6, haloalquilo C1-6, alquenilo C2-6, alquinilo C2-6, alcoxi C1-6, heteroalquilo C1-6, arilo de 6 - 10 eslabones y heteroarilo de 5 - 10 eslabones; en la fórmula (1), R3 y los grupos Rx3a y Rx3b de R3, si están presentes, están además opcionalmente sustituidos con independencia entre sí por 1 - 5 sustituyentes RR3 elegidos entre el grupo formado por F, Cl, Br, I, -OH, -NH2, -SH, -CF3, -OCF3, -SF5, -OCH3, -(Xb)0-1-CN, -(Xb)0-1-NO2, -(Xb)0-1-N3, -(Xb)-OH, -(Xb)-H, -(Xb)0-1-ORb, -(Xb)0-1-N(H)Rb, -(Xb)-N(H)2, -(Xb)0-1-N(Rb)2, -(Xb)0-1-SRb, -(Xb)0-1-SH, -(Xb)0-1-C(O)Rb, -(Xb)0-1-S(O)2Rb, -(Xb)0-1-S(O)Rb, -(Xb)0-1-N(H)S(O)2Rb, -(Xb)0-1-N(Rb)S(O)2Rb, -(Xb)0-1-OC(O)Rb, -(Xb)0-1-N(H)C(O)ORb, -(Xb)0-1-N(Rb)C(O)ORb, -(Xb)0-1-C(=O)ORb, -(Xb)0-1-C(=O)OH, -(Xb)0-1-C(=O)N(H)Rb, -(Xb)0-1-C(=O)N(Rb)Rb, -(Xb)0-1-N(H)C(=O)Rb, -(Xb)0-1-N(Rb)C(=O)Rb, -(Xb)0-1-N(H)C(=O)ORb y -(Xb)0-1-N(Rb)C(=O)ORb, en los que Xb se elige entre el grupo formado por alquileno C1-6, alquenileno C2-6, alquinileno C2-6, heteroalquileno C1-6, cicloalquileno C3-6 y heterocicloalquileno C3-6, y Rb con independencia de cada aparición se elige entre el grupo formado por alquilo C1-6, haloalquilo C1-6, heteroalquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo de 3 - 7 eslabones y heterocicloalquilo de 3 - 7 eslabones; R4 es -(L)0-1-Rx4a, en el que L se elige entre el grupo formado por -O-, -N(H)-, -C(=O)-, alquileno C1-4, haloalquileno C1-4, alquenileno C2-4, alquinileno C2-4 y heteroalquileno C1-4 y Rx4a se elige entre el grupo formado por hidrógeno, alquilo C1-6, haloalquilo C1-6, alquenilo C2-6, alquinilo C2-6 y heteroalquilo C1-6, cicloalquilo de 3 - 6 eslabones, heterocicloalquilo de 3 - 9 eslabones, arilo de 6 - 10 eslabones y heteroarilo de 5 - 10 eslabones; en la que las porciones alifática o aromática de R4 están sustituidas con independencia por 0 - 5 sustituyentes RR4 elegidos entre el grupo formado por alquilo C2-6, haloalquilo C1-6, heteroalquilo C1-6, alcoxi C1-6, (alquil C1-6)amino, di(alquil C1-6)amino, heterocicloalquilo C3-6, F, Cl, Br, I, -OH, -NH2, -SH, -CF3, -OCF3, -SF5, -(Xc)0-1-CN, -(Xc)0-1-NO2, -(Xc)0-1-N3, -(Xc)-OH, -(Xc)0-1-ORc, -(Xc)-H, -(Xc)0-1-Rc, -(Xc)0-1-N(H)Rc, -(Xc)0-1-N(Rc)2, -(Xc)0-1-SRc, -(Xc)0-1-C(O)Rc, -(Xc)0-1-S(O)2Rc, -(Xc)0-1-S(O)Rc, -(Xc)0-1-N(H)S(O)2Rc, -(Xc)0-1-N(Rc)-S(O)2Rc, -(Xc)0-1-C(=O)ORc, -(Xc)0-1-C(=O)OH, -(Xc)0-1-C(=O)N(H)Rc, -(Xc)0-1-C(=O)N(Rc)Rc, -(Xc)0-1-N(H)C(=O)Rc y -(Xc)0-1-N(Rc)C(=O)Rc, en los que Xc se elige entre el grupo formado por alquileno C1-6, alquenileno C2-6, alquinileno C2-6, heteroalquileno C1-6, cicloalquileno C3-6 y heterocicloalquileno C3-6, y Rc con independencia de cada aparición se elige entre el grupo formado por alquilo C1-6, haloalquilo C1-6, heteroalquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo de 3 - 7 eslabones, heterocicloalquilo de 3 - 7 eslabones, fenilo y heteroarilo de 5 - 6 eslabones; en la que cualesquiera dos grupos Rc unidos al mismo átomo de nitrógeno se combinan opcionalmente para formar un heterocicloalquilo de 3 - 7 eslabones o un heteroarilo de 5 - 10 eslabones que contienen 1 - 3 heteroátomos elegidos entre N, O y S.
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