AR082763A1 - Derivados de piperidinona como inhibidores mdm2 para el tratamiento de cancer - Google Patents

Derivados de piperidinona como inhibidores mdm2 para el tratamiento de cancer

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Publication number
AR082763A1
AR082763A1 ARP110101928A ARP110101928A AR082763A1 AR 082763 A1 AR082763 A1 AR 082763A1 AR P110101928 A ARP110101928 A AR P110101928A AR P110101928 A ARP110101928 A AR P110101928A AR 082763 A1 AR082763 A1 AR 082763A1
Authority
AR
Argentina
Prior art keywords
alkylene
alkyl
heterocycle
cycloalkyl
optionally
Prior art date
Application number
ARP110101928A
Other languages
English (en)
Inventor
Jeffrey T Mihalic
Steven H Olson
Xiaodong Wang
Yingcai Wang
Xuelei Yan
Lawrence R Mgee
Michael W Gribble Jr
Darin J Gustin
Ming Yu
David J Kopecky
Sujen Lai
Zice Fu
Julie A Heath
Dustin Mminn
Daqing Sun
Xin Huang
Michael Johnson
Jason Duquette
Zhihong Li
Zhihua Ma
Xianyun Jiao
Benjamin Fisher
Yihong Li
Lopez De Turiso Felix Gonzalez
John Eksterowicz
Philip M Roveto
Jiwen Liu
Yosup Rew
Jiang Zhu
Michael D Bartberger
Jiasheng Fu
Joel Mintosh
Jeffrey Deignan
Brian S Lucas
Brian M Fox
Julio C Medina
Richard V Connors
Frank Kayser
Jonathan D Low
Xiaoqi Chen
Gonzalez Ana Buenrostro
Hilary P Beck
Original Assignee
Amgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44504412&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=AR082763(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Amgen Inc filed Critical Amgen Inc
Publication of AR082763A1 publication Critical patent/AR082763A1/es

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
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    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pyridine Compounds (AREA)
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Abstract

Cuyos compuestos son útiles como agentes terapéuticos, particularmente para el tratamiento de cánceres. La presente también se refiere a composiciones farmacéuticas que contienen un inhibidor MDM2.Reivindicación 1: Un compuesto de la fórmula (1), o una sal farmacéuticamente aceptable del mismo, caracterizado porque: Q es un enlace u opcionalmente se puede seleccionar de O, NR7 o S(O)v, cuando n* es un entero desde 1 hasta 6; Z es C=O o S(=O)2; Ra cada que se presentan se selecciona independientemente de H, alquilo C1-3, (halo)alquilo C1-3, (hidroxi)alquilo C1-3, (alcoxi)alquilo C1-3, o ciano; Rb es H, halo, alquilo C1-3, (halo)alquilo C1-3, (hidroxi)alquilo C1-3, (alcoxi)alquilo C1-3, o ciano; Rc y Rd se seleccionan independientemente de H, halo, alquilo C1-3, alcoxi C1-3, (halo)alquilo C1-3, (halo)alcoxi C1-3, (alcoxi)alquilo C1-3, o (hidroxi)alquilo C1-3, o Rc y Rd puede opcionalmente combinar para formar un sistema de anillo espiro-cicloalquilo o heterociclo; Re es (a) H o halo; o (b) alquilo C1-8, cicloalquilo C3-8, heterociclo C3-8, ciano, halógeno, hidroxilo, -OR5, NR7R8, o heterocicloalquilo, cualquiera de los cuales se puede opcionalmente sustituir con 1 o más grupos Rx como se permite por la valencia, o Re y cualquiera de los grupos R’ o R’’ puede opcionalmente combinar para formar un sistema de anillo espiro-cicloalquilo o heterociclo, o Rd y cualquiera de los grupos R’ o R’’ puede opcionalmente combinar para formar un sistema de anillo cicloalquilo o heterociclo fusionado, o Rd y Re puede opcionalmente combinar para formar un sistema de anillo cicloalquilo o heterociclo fusionado; R’ y R’’ cada que se presentan, respectivamente, son independientemente H, halo, alquilo C1-3, alcoxi C1-3, (halo)alquilo C1-3, (halo)alcoxi C1-3, (alcoxi)alquilo C1-3, (hidroxi)alquilo C1-3, -S-alquilo C1-3, C(O)alquilo C1-3, -NR7R8, o hidroxilo, o R’ y R’’ enlazado al mismo átomo de carbono puede opcionalmente combinar para formar =O, o R’ y R’’ enlazado al mismo átomo de carbono puede opcionalmente combinar para formar un sistema de anillo cicloalquilo fusionado espiro o heterociclo; R1 es (a) -COOH, -C(O)OR10, -C(O)NHOH, -C(O)NH-NH2, -C(O)NHS(O)2R10, -S(O)2NHC(O)R10, -S(O)2NR7R8, -NR7C(O)R10, -NR7C(O)OR5, -C(O)NR7R8, -NR7S(O)2R10, -NR7C(O)NR7R8, -S(O)vR10, hidroxilalquilo, -ciclopropil-COOH, o CN; o (b) heteroarilo o heterociclo, cualquiera de los cuales se puede opcionalmente sustituir independientemente con uno o más grupos Rx corno se permitió por la valencia; R2 es (a) -NR7R8, NR7C(O)OR10, NR7C(O)NR7R10, o -C(Ra)R5R6; o (b) arilo, heteroarilo, cicloalquilo, o heterociclo, cualquiera de los cuales se puede opcionalmente sustituir independientemente con uno o más grupos Rx como se permitió por la valencia; R3 y R4 son independientemente arilo o heteroarilo, cualquiera de los cuales se puede opcionalmente sustituir independientemente con uno o más grupos Rx como se permitió por la valencia, o cualquiera R3 y Ra junto con el átomo de carbono de anillo a los cuales ambos se enlazan, o R4 y Rb junto con el átomo de carbono de anillo a los cuales ambos se enlazan pueden opcionalmente combinar para formar un sistema de anillo bicíclico fusionado de espiro seleccionado del grupo de fórmulas (2), en donde K es -O-, -NR7-, o -C(=O)NR7-; R5 y R6 cada que se presentan, respectivamente, se seleccionan independientemente de (a) H o CN; (b) -(alquileno)t-OH, -(alquileno)t-OR9, -(alquileno)t-SR9, -(alquileno)t-NR10R11, -(alquileno)t-C(O)R9, -(alquileno)t-C(O)OR9, -(alquileno)t-OC(O)R9, -(alquileno)t-S(O)vR9, -(alquileno)t-NHS(O)2R10, -(alquileno)t-N(R11)S(O)2R10, -(alquileno)t-S(O)2NR10R11, -(alquileno)t-N(R11)S(O)2NR10R11, -NR10C(O)R9, -C(O)NR10R11, -NR10S(O)2R9, S(O)2NR10, o NR10C(O)NR10R11; o (c) haloalquilo, haloalcoxi, -alquilo C1-6, alquenilo C2-6, -alquinilo C2-6, -cicloalquilo C3-8, (-cicloalquilo C3-8)(alquilo C1-3), -cicloalquenilo C4-8, arilo, aril(-alquilo C1-3), heteroarilo, heteroaril(-alquilo C1-3), heterociclo o heterociclo(-alquilo C1-3), cualquiera de los cuales se puede opcionalmente sustituir independientemente con uno o más grupos Rx como se permitió por la valencia; R7 y R8 cada que se presentan, respectivamente, se seleccionan independientemente de H, ciano, -O-alquilo C1-6, -alquilo C1-6, halo-alquilo C1-6, cicloalquilo, -alquenilo C2-6, -alquinilo C2-6, arilo, heteroarilo, heterociclo, arilalquilo, heteroarilalquilo, heterociclo(alquilo C1-10), o (-cicloalquilo C3-8)(alquilo C1-3), cualquiera de los cuales se puede opcionalmente sustituir como se permitió por la valencia con uno o más Rx, o R7 y R8 puede combinar para formar un anillo -heterociclo C4-8 opcionalmente sustituido con uno o más Rx; R9 es haloalquilo, haloalcoxi, -alquilo C1-6, alquenilo C2-6, -alquinilo C2-6, -cicloalquilo C3-8, (-cicloalquilo C3-8)(alquilo C1-3), -cicloalquenilo C4-8, arilo, heteroarilo, heterociclo, o heterocicloalquilo, cualquiera de los cuales se puede opcionalmente sustituir independientemente con uno o más grupos Rx como se permitió por la valencia; R10 y R11 cada que se presentan, respectivamente, se seleccionan independientemente de H, alquilo, haloalquilo, cicloalquilo, alquenilo, alquinilo, arilo, heteroarilo, heterociclo, arilalquilo, heteroarilalquilo, heterocicloalquilo, o cicloalquilalquilo, cualquiera de los cuales se puede opcionalmente sustituir como se permitió por la valencia con uno o más Rx, o R10 y R11 puede combinar para formar un anillo heterociclo opcionalmente sustituido con uno o más Rx; Rx cada que se presentan es independientemente, deuterio, halo, ciano, nitro, oxo, alquilo, haloalquilo, alquenilo, alquinilo, cicloalquilo, cicloalquenilo, heterociclo, arilo, heteroarilo, arilalquilo, heteroarilalquilo, cicloalquilalquilo, heterocicloalquilo, -(alquileno)t-OR*, -(alquileno)t-S(O)vR*, -(alquileno)t-NR+R++, -(alquileno)t-C(=O)R*, -(alquileno)t-C(=S)R*, -(alquileno)t-C(=O)OR*, -(alquileno)t-OC(=O)R*, -(alquileno)t-C(=S)OR*, -(alquileno)t-C(=O)NR+R++, -(alquileno)t-C(=S)NR+R++, -(alquileno)t-N(R+)C(=O)NR+R++, -(alquileno)t-N(R+)C(=S)NR+R++, -(alquileno)t-N(R+)C(=O)R*, -(alquileno)t-N(R+)C(=S)R*, -(alquileno)t-OC(=O)NR+R++, -(alquileno)t-OC(=S)NR+R++, -(alquileno)t-SO2NR+R++, -(alquileno)t-N(R+)SO2R*, -(alquileno)t-N(R+)SO2R+R++, -(alquileno)t-N(R+)C(=O)OR*, -(alquileno)t-N(R+)C(=S)OR*, o -(alquileno)t-N(R+)SO2R*, en donde los grupos alquilo, haloalquilo, alquenilo, alquinilo, cicloalquilo, cicloalquenilo, heterociclo, arilo, heteroarilo, arilalquilo, heteroarilalquilo, cicloalquilalquilo, y heterocicloalquilo se pueden además sustituir independientemente con uno o más halo, ciano, oxo, -(alquileno)t-OR*, -(alquileno)t-S(O)vR*, -(alquileno)t-NR+R++, -(alquileno)t-C(=O)R*, -(alquileno)t-C(=S)R*, -(alquileno)t-C(=O)OR*, -(alquileno)t-OC(=O)R*, -(alquileno)t-C(=S)OR*, -(alquileno)t-C(=O)NR+R++, -(alquileno)t-C(=S)NR+R++, -(alquileno)t-N(R+)C(=O)NR+R++, -(alquileno)t-N(R+)C(=S)NR+R++, -(alquileno)t-N(R+)C(=O)R*, -(alquileno)t-N(R+)C(=S)R*, -(alquileno)t-OC(=O)NR+R++, -(alquileno)t-OC(=S)NR+R++, -(alquileno)t-SO2NR+R++, -(alquileno)t-N(R+)SO2R*, -(alquileno)t-N(R+)SO2R+R++, -(alquileno)t-N(R+)C(=O)OR*, -(alquileno)t-N(R+)C(=S)OR*, o -(alquileno)t-N(R+)SO2R*; R* es H, haloalquilo, haloalcoxi, -alquilo C1-6, alquenilo C2-6, -alquinilo C2-6, -cicloalquilo C3-8, -cicloalquenilo C4-8, arilo, heteroarilo, o heterociclo; R+ y R++ son independientemente H, alquilo, haloalquilo, cicloalquilo, alquenilo, alquinilo, arilo, heteroarilo, heterociclo, arilalquilo, heteroarilalquilo, heterocicloalquilo, o cicloalquilalquilo, o R+ y R++ enlazado al mismo átomo de nitrógeno puede opcionalmente combinar para formar un sistema de anillo heterociclo; m es 1, 2 ó 3; n y n* son cada uno independientemente seleccionados de 0 o un entero desde 1 hasta 6; p es 0, 1, 2 ó 3; t cada que se presenta es independientemente 0 o un entero desde 1 hasta 6; y v cada que se presenta es independientemente 0, 1 ó 2.
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