Inhibitors of the interaction between MDM2 and P53

Patent metadata

Field	Value
Publication number	US-9573933-B2
Application number	US-67896108-A
Country	US
Kind code	B2
Filing date	Sep 18, 2008
Priority date	Sep 21, 2007
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

The present invention provides compounds of formula (I), their use as an inhibitor of a p53-MDM2 interaction as well as pharmaceutical compositions comprising said compounds:

wherein n, m, p, s, t, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 20 , X, Y, Q and Z have defined meanings.

First claim

The invention claimed is:

1. A compound of formula (I):

including any stereochemically isomeric form thereof, wherein
m is 0, 1 or 2 and when m is 0 then a direct bond is intended;
n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended;
p is 0 or 1 and when p is 0 then a direct bond is intended;
s is 0 or 1 and when s is 0 then a direct bond is intended;
t is 0 or 1 and when t is 0 then a direct bond is intended;
X is C(═O) or CHR 8 , wherein
R 8 is selected from hydrogen; C 1-6 alkyl; C 3-7 cycloalkyl; —C(═O)—NR 17 R 18 ; carboxyl; arylC 1-6 alkyloxycarbonyl; heteroaryl; heteroarylcarbonyl; heteroarylC 1-6 alkyloxycarbonyl; piperazinylcarbonyl; pyrrolidinyl; piperidinylcarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl; C 3-7 cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl; piperazinylcarbonyl substituted with a substituent selected from hydroxy, hydroxyC 1-6 alkyl and hydroxyC 1-6 alkyloxyC 1-6 alkyl; pyrrolidinyl substituted with hydroxyC 1-6 alkyl; and piperidinylcarbonyl substituted with one or two substituents selected from hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyl(dihydroxy)C 1-6 alkyl and C 1-6 alkyloxy(hydroxy)C 1-6 alkyl;
R 17 and R 18 are each independently selected from hydrogen, C 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, arylC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkyl(C 1-6 alkyl), or hydroxyC 1-6 alkyl(arylC 1-6 alkyl);

is —CR 9 ═C< and then the dotted line is a bond, —C(═O)—CH<, —C(═O)—N<, —CHR 9 —CH<, or —CHR 9 —N<, wherein each R 9 is independently hydrogen or C 1-6 alkyl, or wherein R 9 together with one of R 2 or R 20 form a direct bond;
R 1 is hydrogen; aryl; heteroaryl; C 1-6 alkyloxycarbonyl; C 1-12 alkyl; or C 1-12 alkyl substituted with one or two substituents independently selected from hydroxy, aryl, heteroaryl, amino,
C 1-6 alkyloxy, mono- or di(C 1-6 alkyl)amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,
C 1-6 alkylpiperazinyl, arylC 1-6 alkylpiperazinyl, heteroarylC 1-6 alkylpiperazinyl, C 3-7 cycloalkyl-piperazinyl and C 3-7 cycloalkylC 1-6 alkylpiperazinyl;
R 2 and R 20 are each independently selected from
halo, hydroxy, cyano, nitro, carboxyl;
polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy;
C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, aryl, heteroaryl, arylC 1-6 alkyl, heteroaryl-C 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C 1-6 alkyloxy, aryloxy, heteroaryloxy, C 1-6 alkylthio, arylthio, heteroarylthio,
C 1-6 alkylcarbonyl,
C 3-7 cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C 1-6 alkyloxycarbonyl, C 3-7 cycloalkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, C 1-6 alkylcarbonyloxy, C 3-7 cycloalkylcarbonyloxy, arylcarbonyloxy or heteroarylcarbonyloxy, any of said groups being optionally and independently substituted with one or more, preferably one or two, substituents selected from halo, hydroxy, cyano, nitro, carboxyl, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, polyhaloC 1-6 alkyl, aryl, heteroaryl, C 1-6 alkyloxy, C 1-6 alkylcarbonyl,
C 1-6 alkyloxycarbonyl and
C 1-6 alkylcarbonyloxy; and
—(CH 2 ) w —(C(═O)) y NR 21 R 22 wherein
w is 0, 1, 2, 3, 4, 5 or 6 and when w is 0 then a direct bond is intended;
y is 0 or 1 and when y is 0 then a direct bond is intended; and
wherein in the case R 2 or R 20 is selected from the group consisting of C 1-6 alkyl and C 1-6 alkyloxy, R 2 or R 20 cannot be fluorine;
R 21 and R 22 are each independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylcarbonyl and arylC 1-6 alkylcarbonyl, any of said groups being optionally and independently substituted with one or more, preferably one or two, substituents selected from halo, hydroxy, amino, mono- or
di(C 1-6 alkyl)amino, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy, aryl and heteroaryl;
or R 21 and R 22 together with the nitrogen to which they are attached form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl, any of said groups being optionally and independently substituted with one or more, preferably one or two, substituents selected from C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy,
C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl, arylC 1-6 alkyl and heteroarylC 1-6 alkyl;

or R 2 and R 20 together with the phenyl ring to which they are attached form a naphthalenyl group, optionally substituted with one or more, preferably one or two, substituents each independently selected from halo, hydroxy, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy, aryl and heteroaryl;
or R 2 and R 20 together form a bivalent radical of the formula —(CH 2 ) b — wherein b is 3, 4 or 5, optionally substituted with one or more, preferably one or two, substituents selected from halo, hydroxy, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, polyhaloC 1-6 alkyl,
C 1-6 alkyloxy, aryl and heteroaryl;
or one of R 2 or R 20 is as defined above and the other one of R 2 or R 20 together with R 9 form a direct bond;
R 3 is hydrogen; C 1-6 alkyl; heteroaryl; C 3-7 cycloalkyl; C 1-6 alkyl substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl; or C 3-7 cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and heteroaryl;
R 4 and R 5 are each independently hydrogen, halo, C 1-6 alkyl, hydroxyC 1-6 alkyl, polyhalo-
C 1-6 alkyl, cyano, cyanoC 1-6 alkyl, hydroxy, amino, C 2-6 alkenyl or C 1-6 alkyloxy; or
R 4 and R 5 together form a bivalent radical selected from methylenedioxy or ethylenedioxy;
R 6 is hydrogen, C 1-6 alkyloxycarbonyl, or C 1-6 alkyl;
when p is 1 then R 7 is hydrogen, arylC 1-6 alkyl, hydroxy, or heteroarylC 1-6 alkyl;
Z is a radical selected from

wherein
R 10 or R 11 are each independently selected from hydrogen, halo, hydroxy, amino,
C 1-6 alkyl, nitro, polyhaloC 1-6 alkyl, cyano, cyanoC 1-6 alkyl, tetrazoloC 1-6 alkyl, aryl, heteroaryl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, aryl(hydroxy)C 1-6 alkyl, heteroaryl(hydroxy)C 1-6 alkyl, arylcarbonyl, heteroarylcarbonyl, C 1-6 alkylcarbonyl, arylC 1-6 alkylcarbonyl, heteroarylC 1-6 alkylcarbonyl, C 1-6 alkyloxy, C 3-7 cycloalkylcarbonyl, C 3-7 cycloalkyl(hydroxy)C 1-6 alkyl, arylC 1-6 alkyloxyC 1-6 alkyl,
C 1-6 alkyloxyC 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkylcarbonyloxyC 1-6 alkyl,
C 1-6 alkyloxycarbonylC 1-6 alkyloxyC 1-6 alkyl, hydroxyC 1-6 alkyloxyC 1-6 alkyl,
C 1-6 alkyloxycarbonylC 2-6 alkenyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxycarbonyl,
C 1-6 alkylcarbonyloxy, aminocarbonyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, hydroxycarbonyl, hydroxycarbonylC 1-6 alkyl and —(CH 2 ) v —(C(═O)) r —(CHR 19 ) u —NR 13 R 14 , wherein
v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0 then a direct bond is intended;
r is 0 or 1 and when r is 0 then a direct bond is intended;
u is 0, 1, 2, 3, 4, 5, or 6 and when u is 0 then a direct bond is intended;
R 19 is hydrogen or C 1-6 alkyl;
R 13 and R 14 are each independently selected from hydrogen; C 1-12 alkyl;
C 1-6 alkylcarbonyl; C 1-6 alkylsulfonyl; arylC 1-6 alkylcarbonyl; C 3-7 cycloalkyl;
C 3-7 cycloalkylcarbonyl; —(CH 2 ) k —NR 15 R 16 ; C 1-12 alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano,
C 1-6 alkyloxycarbonyl, C 1-6 alkyloxy, aryl or heteroaryl; or C 3-7 cycloalkyl substituted with a substituent

Assignees

• Poncelet Virginie Sophie
• Coupa Sophie
• Storck Pierre-Henri
• Schoentjes Bruno
• Janssen Pharmaceutica Nv

Inventors

• Poncelet Virginie Sophie
• Coupa Sophie
• Storck Pierre-Henri
• Schoentjes Bruno

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

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

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title