Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9593129-B2
Application number	US-201615008342-A
Country	US
Kind code	B2
Filing date	Jan 27, 2016
Priority date	Jun 4, 2010
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

The present invention provides MDM2 inhibitor compounds of Formula I,

wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Q is a bond or optionally can be selected from O, NR 7 or S(O) v , when n* is an integer from 1 to 6;
Z is C═O;
R a at each occurrence is independently selected from H, (C 1 -C 3 )alkyl, (halo)(C 1 -C 3 )alkyl, (hydroxy)(C 1 -C 3 )alkyl, (alkoxy)(C 1 -C 3 )alkyl, or cyano;
R b is H, halo, (C 1 -C 3 )alkyl, (halo)(C 1 -C 3 )alkyl, (hydroxy)(C 1 -C 3 )alkyl, (alkoxy)(C 1 -C 3 )alkyl, or cyano;
R c and R d are independently selected from H, halo, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, (halo)(C 1 -C 3 )alkyl, (halo)(C 1 -C 3 )alkoxy, (alkoxy)(C 1 -C 3 )alkyl, or (hydroxy)(C 1 -C 3 )alkyl, or R c and R d may optionally combine to form a spiro-cycloalkyl or heterocyclo ring system;
R e is
(a) H or halo; or
(b) (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocyclo, cyano, halogen, hydroxyl, —OR 5 , NR 7 R 8 , or heterocycloalkyl, any of which may be optionally substituted with 1 or more R x groups as allowed by valence, or R e and any one of the R′ or R″ groups may optionally combine to form a spiro-cycloalkyl or heterocyclo ring system;

R′ and R″ at each occurrence, respectively, are independently H, halo, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, (halo)(C 1 -C 3 )alkyl, (halo)(C 1 -C 3 )alkoxy, (alkoxy)(C 1 -C 3 )alkyl, (hydroxy)(C 1 -C 3 )alkyl, —S—(C 1 -C 3 )alkyl, C(O)(C 1 -C 3 )alkyl, —NR 7 R 8 , or hydroxyl, or R′ and R″ bound to the same carbon atom may optionally combine to form ═O, or R′ and R″ bound to the same carbon atom may optionally combine to form a cycloalkyl or heterocyclo ring system;
R 1 is
(a) —COOH, —C(O)OR 10 , —C(O)NHOH, —C(O)NH—NH 2 , —C(O)NHS(O) 2 R 10 , —S(O) 2 NHC(O)R 10 , —S(O) 2 NR 7 R 8 , —NR 7 C(O)R 10 , —NR 7 C(O)OR 5 , —C(O)NR 7 R 8 , —NR 7 S(O) 2 R 10 , —NR 7 C(O) NR 7 R 8 , —S(O) v R 10 , hydroxylalkyl, -cyclopropyl-COOH, or CN; or
(b) heteroaryl or heterocyclo, either of which may be optionally independently substituted with one or more R x groups as allowed by valence;

R 2 is
(a) —NR 7 R 8 , NR 7 C(O)OR 10 , NR 7 C(O)NR 7 R 10 , or —C(R a )R 5 R 6 ; or
(b) aryl, heteroaryl, cycloalkyl, or heterocyclo, any of which may be optionally independently substituted with one or more R x groups as allowed by valence;

R 3 and R 4 are independently aryl or heteroaryl, either of which may be optionally independently substituted with one or more R x groups as allowed by valence, or either R 3 and R a together with the ring carbon atom to which they are both bonded, or R 4 and R b together with the ring carbon atom to which they are both bonded may optionally combine to form a spiro-fused bicyclic ring system selected from

wherein K is —O—, —NR 7 —, or C(═O)NR 7 —;
R 5 and R 6 at each occurrence, respectively, are independently selected from
(a) H or CN;
(b) -(alkylene) t -OH, -(alkylene) t -OR 9 , -(alkylene) t -SR 9 ,

-(alkylene) t -NR 10 R 11 , -(alkylene) t -C(O)R 9 , -(alkylene) t -C(O)OR 9 , -(alkylene) t -OC(O)R 9 , -(alkylene) t -
S(O) v R 9 , -(alkylene) t -NHS(O) 2 R 10 , -(alkylene) t -N(R 11 )S(O) 2 R 10 , -(alkylene) t -S(O) 2 NR 10 R 11 , -(alkylene) t -N(R 11 )S(O) 2 NR 10 R 11 , —NR 10 C(O)R 9 , —C(O)NR 10 R 11 , —NR 10 S(O) 2 R 9 , S(O) 2 NR 10 , or NR 10 C(O)NR 10 R 11 ; or
(c) haloalkyl, haloalkoxy, C 1-6 -alkyl, C 2-6 alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, (C 3-8 -cycloalkyl)(C 1-3 alkyl), C 4-8 -cycloalkenyl, aryl, aryl(C 1-3 -alkyl), heteroaryl, heteroaryl(C 1-3 -alkyl), heterocyclo or heterocyclo(C 1-3 -alkyl), any of which may be optionally independently substituted with one or more R x groups as allowed by valence;
R 7 and R 8 at each occurrence, respectively, are independently selected from H, cyano, —O C 1-6 -alkyl, C 1-6 -alkyl, halo(C 1-6 )-alkyl, cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocyclo(C 1-10 alkyl), or (C 3-8 -cycloalkyl)(C 1-3 alkyl), any of which may be optionally substituted as allowed by valence with one or more R x , or R 7 and R 8 may combine to form a C 4 -C 8 -heterocyclo ring optionally substituted with one or more R x ;
R 9 is haloalkyl, haloalkoxy, C 1-6 -alkyl, C 2-6 alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, (C 3-8 -cycloalkyl)(C 1-3 alkyl), C 4-8 -cycloalkenyl, aryl, heteroaryl, heterocyclo, or heterocycloalkyl, any of which may be optionally independently substituted with one or more R x groups as allowed by valence;
R 10 and R 11 at each occurrence, respectively, are independently selected from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl, any of which may be optionally substituted as allowed by valence with one or more R x , or R 10 and R 11 may combine to form a heterocyclo ring optionally substituted with one or more R x ;
R x at each occurrence is independently, deuterium, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,

heterocycloalkyl, -(alkylene) t -OR*, -(alkylene) t -S(O) v R*, -(alkylene) t -NR + R ++ , -(alkylene) t -C(═O)R*, -(alkylene) t -C(═S)R*, -(alkylene) t -C(═O)OR*, -(alkylene) t -OC(═O)R*, -(alkylene) t -C(═S)OR*,
-(alkylene) t -C(═O)NR + R ++ , -(alkylene) t -C(═S)NR + R ++ , -(alkylene) t -N(R + )C(═O)NR + R ++ , -(alkylene) t -N(R + )C(═S)NR + R ++ , -(alkylene) t -N(R + )C(═O)R*, -(alkylene) t -N(R + )C(═S)R*, -(alkylene) t -OC(═O)NR + R ++ , -(alkylene) t -OC(═S)NR + R ++ , -(alkylene) t -SO 2 NR + R ++ , -(alkylene) t -N(R + )SO 2 R*, -(alkylene) t -N(R + )SO 2 NR + R ++ , -(alkylene) t -N(R + )C(═O)OR*, -(alkylene) t -N(R + )C(═S)OR*, or -(alkylene) t -N(R + )SO 2 R*, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more halo, cyano, oxo, -(alkylene) t -OR*, -(alkylene) t -S(O) v R*, -(alkylene) t -NR + R ++ , -(alkylene) t -C(═O)R*, -(alkylene) t -C(═S)R*, -(alkylene) t -C(═O)OR*, -(alkylene) t -OC(═O)R*, -(alkylene) t -C(═S)OR*, -(alkylene) t -C(═O)NR + R ++ , -(alkylene) t -C(═S)NR + R ++ , -(alkylene) t -N(R + )C(═O)NR + R ++ , -(alkylene) t -N(R + )C(═S)NR + R ++ , -(alkylene) t -N(R + )C(═O)R*, -(alkylene) t -N(R + )C(═S)R*, -(alkylene) t -OC(═O)NR + R ++ , -(alkylene) t -OC(═S)NR + R ++ , -(alkylene) t -SO 2 NR + R ++ , -(alkylene) t -N(R + )SO 2 R*, -(alkylene) t -N(R + )SO 2 NR + R ++ , -(alkylene) t -N(R + )C(═O)OR*, -(alkylene) t -N(R + )C(═S)OR*, or -(alkylene) t -N(R + )SO 2 R*;
R* is H, haloalkyl, haloalkoxy, C 1-6 -alkyl, C 2-6 alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, aryl, heteroaryl, or heterocyclo;
R + and R ++ are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl, or R + and R ++ bound to the same nitrogen atom may optionally combine to form a heterocyclo ring system;
m is 1, 2 or 3;
n and n* are each independently selected from 0 or an integer from 1 to 6;
p is 0, 1, 2 or 3;
t at each occurrence is independently 0 or an integer from 1 to 6; and
v at each occurrence is independently 0, 1 or 2;
wherein
(i) R c and R d combine to form a spiro-cycloalkyl or heterocyclo ring system; or
(ii) R e and any one of the R′ or R″ groups combine to form a spiro-cycloalkyl or heterocyclo ring system; or
(iii) R 3 and R a together with the ring carbon atom to whic

Assignees

• Amgen Inc
• Amgen Inc

Inventors

• Bartberger Michael D
• Gonzalez Buenrostro Ana
• Beck Hilary Plake
• Chen Xiaoqi
• Connors Richard Victor
• Deignan Jeffrey
• Duquette Jason A
• Eksterowicz John
• Fisher Benjamin
• Fox Brian M
• Fu Jiasheng
• Fu Zice
• Gonzalez Lopez De Turiso Felix
• Gribble Jr Michael W
• Gustin Darin J
• Heath Julie A
• Huang Xin
• Jiao Xianyun
• Johnson Michael G
• Kayser Frank
• Kopecky David John
• Lai Sujen
• Li Yihong
• Li Zhihong
• Liu Jiwen
• Low Jonathan D
• Lucas Brian S
• Ma Zhihua
• Mcgee Lawrence R
• Mcintosh Joel
• Mcminn Dustin L
• Medina Julio C
• Mihalic Jeffrey Thomas
• Olson Steven H
• Rew Yosup
• Roveto Philip M
• Sun Daqing
• Wang Xiaodong
• Wang Yingcai
• Yan Xuelei
• Yu Ming
• Zhu Jiang

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title