US2013005769A1PendingUtilityA1
Inhibitors of the interaction between mdm2 and p53
Est. expirySep 21, 2027(~1.2 yrs left)· nominal 20-yr term from priority
Inventors:Pierre-Henri StorckBruno SchoentjesArnaud PiettrePhilipp ErmertVirginie Sophie PonceletImre Christian Francis Csoka
A61P 37/08A61P 7/06A61P 37/02A61P 7/00A61P 3/06A61P 37/06A61P 35/02A61P 43/00A61P 27/12A61P 27/02A61P 35/00A61P 29/00A61P 25/00A61P 25/28A61P 3/10A61P 21/02C07D 413/14A61P 17/00A61P 13/12A61P 19/02A61P 1/04A61P 21/04
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Claims
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, s, t, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Q, Z, G, E and D have defined meanings.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
including any stereochemically isomeric form thereof, wherein
n is 0, 1, 2, 3 or 4 and when n is 0 then a direct bond is intended, and wherein
R 1 on each carbon of the —(CHR 1 ) n — group is each independently selected from hydrogen, halo, hydroxy, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, aryl, heteroaryl, C 3-7 cycloalkyl, heteroarylC 1-6 alkyl, and C 3-7 cycloalkyl-C 1-6 alkyl,
any of said mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, aryl, heteroaryl, C 3-7 cycloalkyl, heteroarylC 1-6 alkyl or C 3-7 cycloalkylC 1-6 alkyl being optionally and independently substituted with one or more, substituents selected from hydroxy, amino, aryl and heteroaryl;
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;
R 2 is selected from
hydrogen, halo, cyano, amino;
polyhaloC 1-6 alkyl;
C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, aryl, heteroaryl, 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, heteroarylcarbonyloxy, mono- or di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylaminoC 1-6 alkyl, mono- or di(C 1-6 alkyl)aminocarbonyl and mono- or di(C 1-6 alkyl)aminocarbonylC 1-6 alkyl, any of said groups being optionally and independently substituted with one or more, substituents selected from halo, hydroxy, cyano, 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;
R 3 is hydrogen; C 1-6 alkyl; aryl; 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;
X is NR 6 , S or O;
is —CR 7 ═R 8 — and then the dotted line is a bond, —CR 7 R 9 —CR 8 R 10 —, —C(═O)—CR 8 R 10 — or —CR 7 R 9 —C(═O)—, wherein
R 7 , R 8 , R 9 or R 10 are each independently selected from:
hydrogen, halo, hydroxy, cyano;
polyhaloC 1-6 alkyl;
C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, aryl, heteroaryl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C 1-6 alkyloxy, C 3-7 cycloalkyloxy, 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, heteroarylcarbonyloxy, mono- or di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylaminoC 1-6 alkyl, mono- or di(C 1-6 alkyl)aminocarbonyl and mono- or
di(C 1-6 alkyl)aminocarbonylC 1-6 alkyl, any of said groups being optionally and independently substituted with one or more, substituents selected from halo, hydroxy, cyano, 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;
or wherein any of R 7 and R 9 together, or R 8 and R 10 together form a bivalent radical selected from —(CH 2 ) 2 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —S—(CH 2 ) 2- and —(CH 2 ) 2 —NR 21 —(CH 2 ) 2- wherein R 21 is hydrogen, C 1-6 alkyl or C 1-6 alkyloxyalkyl;
or wherein any of R 7 and R 9 together, or R 8 and R 10 together form a bivalent radical —(CH 2 ) m —, wherein m is 2, 3, 4, 5 or 6;
-D- is CHR 20 —, wherein R 20 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl and C 1-6 alkyloxycarbonyl;
is —CR 19 ═C< and then the dotted line is a bond, —C(═O)—CH<, —C(═O)—N<, —CHR 19 —CH<, or —CHR 19 —N<, wherein each R 19 is independently hydrogen or C 1-6 alkyl;
R 4 and R 5 are each independently hydrogen, halo, C 1-6 alkyl, hydroxyC 1-6 alkyl, polyhaloC 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 alkyl, C 1-6 alkylcarbonyl or C 1-6 alkyloxycarbonyl;
Z is a radical selected from
wherein
R 11 or R 12 are each independently selected from hydrogen, halo, hydroxy, amino, C 1-6 alkyl, nitro, polyhaloC 1-6 alkyl, cyano, cyanoC 1-6 alkyl, tetrazolo-C 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 18 ) u —NR 14 R 15 , 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 18 is hydrogen or C 1-6 alkyl;
R 14 and R 15 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 16 R 17 ; 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 selected from hydroxy, C 1-6 alkyloxy, aryl, amino, arylC 1-6 alkyl, heteroaryl or heteroarylC 1-6 alkyl, or
R 14 and R 15 together with the nitrogen to which they are attached form morpholinyl; piperidinyl; pyrrolidinyl; piperazinyl; or piperazinyl substituted with a substituent selected from C 1-6 alkyl, arylC 1-6 alkyl, arylC 1-6 alkyloxycarbonyl, heteroarylC 1-6 alkyl, C 3-7 cycloalkyl and C 3-7 cycloalkylC 1-6 alkyl; wherein
k is 0, 1, 2, 3, 4, 5, or 6 and when k is 0 then a direct bond is intended;
R 16 and R 17 are each independently selected from hydrogen;
C 1-12 alkyl; arylC 1-6 alkyloxycarbonyl; C 3-7 cycloalkyl; C 1-12 alkyl substituted with a substituent selected from hydroxy, C 1-6 alkyloxy, aryl, and heteroaryl; and C 3-7 cycloalkyl substituted with a substituent selected from hydroxy, C 1-6 alkyloxy, aryl, arylC 1-6 alkyl, heteroaryl, and heteroarylC 1-6 alkyl; or
R 16 and R 17 together with the nitrogen to which they are attached form morpholinyl, piperazinyl, or piperazinyl substituted with C 1-6 alkyloxycarbonyl;
R 13 is hydrogen; C 1-6 alkyl; C 3-7 cycloalkyl; C 1-6 alkyl substituted with a substituent selected from hydroxy, amino, C 1-6 alkyloxy and aryl; or C 3-7 cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and C 1-6 alkyloxy;
aryl is phenyl or naphthalenyl;
each phenyl or naphthalenyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C 1-6 alkyl, amino, polyhaloC 1-6 alkyl and C 1-6 alkyloxy; and
each phenyl or naphthalenyl can optionally be substituted with a bivalent radical selected from methylenedioxy and ethylenedioxy;
heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl;
each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C 1-6 alkyl, amino, polyhaloC 1-6 alkyl, aryl, arylC 1-6 alkyl or C 1-6 alkyloxy; and
each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with a bivalent radical selected from methylenedioxy or ethylenedioxy;
an N-oxide form thereof, an addition salt thereof or a solvate thereof.
2 . The compound according to claim 1 wherein
R 1 on each carbon of the —(CHR 1 ) n — group is each independently selected from hydrogen, halo, hydroxy, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, aryl, heteroaryl, C 3-7 cycloalkyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, and C 3-7 cycloalkyl-C 1-6 alkyl,
any of said mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, heteroaryl, C 3-7 cycloalkyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl or C 3-7 cycloalkylC 1-6 alkyl being optionally and independently substituted with one or more, substituents selected from hydroxy, amino, aryl and heteroaryl;
R 2 is selected from
hydrogen, halo, cyano, amino;
polyhaloC 1-6 alkyl;
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, heteroarylcarbonyloxy, mono- or di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylaminoC 1-6 alkyl, mono- or di(C 1-6 alkyl)aminocarbonyl and mono- or di(C 1-6 alkyl)aminocarbonylC 1-6 alkyl, any of said groups being optionally and independently substituted with one or more, substituents selected from halo, hydroxy, cyano, 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;
X is NR 6 ;
is —CR 7 ═R 8 — and then the dotted line is a bond, —CR 7 R 9 —CR 8 R 10 —, —C(═O)—CR 8 R 10 — or —CR 7 R 9 —C(═O)—, wherein
R 7 , R 8 , R 9 or R 10 are each independently selected from:
hydrogen, halo, hydroxy, cyano;
polyhaloC 1-6 alkyl;
C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, aryl, heteroaryl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, C 1-6 alkyloxy, C 3-7 cycloalkyloxy, 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, heteroarylcarbonyloxy, mono- or di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylaminoC 1-6 alkyl, mono- or di(C 1-6 alkyl)aminocarbonyl and mono- or
di(C 1-6 alkyl)aminocarbonylC 1-6 alkyl, any of said groups being optionally and independently substituted with one or more, substituents selected from halo, hydroxy, cyano, 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;
or wherein any of R 7 and R 9 together, or R 8 and R 10 together form a bivalent radical selected from —(CH 2 ) 2 —O—(CH 2 ) 2 — and —(CH 2 ) 2 —NR 21 —(CH 2 ) 2- wherein R 21 is hydrogen, C 1-6 alkyl or C 1-6 alkyloxyalkyl;
or wherein any of R 7 and R 9 together, or R 8 and R 10 together form a bivalent radical selected from —(CH 2 ) m —, wherein m is 2, 3, 4, 5 or 6;
R 4 and R 5 are each independently hydrogen, halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, cyano, cyanoC 1-6 alkyl, hydroxy, amino, 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 alkyl, C 1-6 alkylcarbonyl or C 1-6 alkyloxycarbonyl;
Z is a radical selected from
wherein
R 11 or R 12 are each independently selected from hydrogen, halo, hydroxy, amino, C 1-6 alkyl, nitro, polyhaloC 1-6 alkyl, cyano, cyanoC 1-6 alkyl, tetrazolo-C 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 18 ) u —NR 14 R 15 , 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 18 is hydrogen or C 1-6 alkyl;
R 14 and R 15 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 16 R 17 ; 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 selected from hydroxy, C 1-6 alkyloxy, aryl, amino, arylC 1-6 alkyl, heteroaryl or heteroarylC 1-6 alkyl, or
R 14 and R 15 together with the nitrogen to which they are attached form morpholinyl; piperidinyl; pyrrolidinyl; piperazinyl; or piperazinyl substituted with a substituent selected from C 1-6 alkyl, arylC 1-6 alkyl, arylC 1-6 alkyloxycarbonyl, heteroarylC 1-6 alkyl, C 3-7 cycloalkyl and C 3-7 cycloalkylC 1-6 alkyl; wherein
k is 0, 1, 2, 3, 4, 5, or 6 and when k is 0 then a direct bond is intended;
R 16 and R 17 are each independently selected from hydrogen; C 1-6 alkyl; arylC 1-6 alkyloxycarbonyl; C 3-7 cycloalkyl; C 1-12 alkyl substituted with a substituent selected from hydroxy, C 1-6 alkyloxy, aryl, and heteroaryl; and C 3-7 cycloalkyl substituted with a substituent selected from hydroxy, C 1-6 alkyloxy, aryl, arylC 1-6 alkyl, heteroaryl, and heteroarylC 1-6 alkyl; or
R 16 and R 17 together with the nitrogen to which they are attached form morpholinyl, piperazinyl, or piperazinyl substituted with C 1-6 alkyloxycarbonyl.
3 . The compound according to claim 1 , wherein
R 1 on each carbon of the —(CHR 1 ) n — group is each independently selected from hydrogen, hydroxy, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, arylC 1-6 alkyl and heteroarylC 1-6 alkyl; when any one R 1 substituent in the —(CHR 1 ) n — group is different from hydrogen, the other R 1 substituents in the —(CHR 1 ) n — group are each hydrogen; s is 0; t is 0 or 1; R 2 is selected from hydrogen, halo, cyano, amino, mono- or di(C 1-6 alkyl)amino, C 1-6 alkyl, aryl, heteroaryl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, hydroxyC 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy, arylC 1-6 alkyloxy, heteroarylC 1-6 alkyloxy, C 1-6 alkylthio, arylthio, C 1-6 alkylcarbonyl, hydroxyC 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylcarbonylamino, morpholinyl, piperidinyl, pyrrolidinyl and piperazinyl; R 3 is hydrogen or C 1-6 alkyl; R 20 is selected from hydrogen and C 1-6 alkyl;
is —CR 19 ═C< wherein R 19 is hydrogen or C 1-6 alkyl;
R 4 and R 5 are each independently hydrogen, halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, cyano, cyanoC 1-6 alkyl, hydroxy, amino, or C 1-6 alkyloxy;
Z is a radical selected from (a-1), (a-2), (a-3), (a-4) and (a-5);
R 11 or R 12 are each independently selected from hydrogen, hydroxy, amino, C 1-6 alkyl, nitro, polyhaloC 1-6 alkyl, cyano, aryl, arylC 1-6 alkyl, aryl(hydroxy)C 1-6 alkyl, arylcarbonyl, C 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxycarbonyl, aminocarbonyl, hydroxyl-C 1-6 alkyl, aminoC 1-6 alkyl, hydroxycarbonyl and —(CH 2 ) v —(C(═O)) r —(CH 2 ) u —NR 14 R 15 ;
v is 0 or 1;
r is 0 or 1;
u is 0;
R 14 and R 15 are each independently selected from hydrogen, C 1-6 alkyl, —(CH 2 ) k —NR 16 R 17 and C 1-12 alkyl substituted with hydroxy;
R 14 and R 15 together with the nitrogen to which they are attached form pyrrolidinyl;
k is 2;
R 16 and R 17 are each independently C 1-6 alkyl;
R 13 is hydrogen or C 1-6 alkyl;
aryl is phenyl or phenyl substituted with halo; and
heteroaryl is pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and each pyridinyl, indolyl, oxadiazolyl or tetrazolyl can optionally be substituted with one substituent selected from C 1-6 alkyl, aryl and arylC 1-6 alkyl.
4 . The compound according to claim 1 , wherein
n is 2; each R 1 is hydrogen; s is 0; t is 0; R 2 is selected from hydrogen halo, cyano, C 1-6 alkyl, hydroxyC 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylcarbonylamino and morpholinyl; R 3 is hydrogen;
is —CH═C<;
R 4 and R 5 are each independently hydrogen, C 1-6 alkyl or C 1-6 alkyloxy;
R 6 is hydrogen;
Z is a radical selected from (a-1), (a-2) and (a-4), and
R 11 or R 12 are each independently selected from hydrogen, hydroxy and hydroxyl-C 1-6 alkyl.
5 . The compound according to claim 1 wherein X is NR 6 .
6 . The compound according to claim 1 wherein t is 0; s is 0; n is 2; X is NR 6 , S or O; R 1 is hydrogen; R 2 is hydrogen or halo; R 3 is hydrogen; R 4 and R 5 are each independently hydrogen, C 1-6 alkyl or C 1-6 alkyloxy; R 6 is hydrogen;
is —CR 19 ═C< and then the dotted line is a bond, wherein R 19 is hydrogen; —CH 2 — wherein R 20 is hydrogen or C 1-6 alkyl; Z is a radical of formula (a-2) or (a-4); R 11 and R 12 are each independently selected from hydrogen, hydroxyl and hydroxyC 1-6 alkyl.
7 . (canceled)
8 . The compound according to claim 1 wherein
is —CR 19 ═C< and then the dotted line is a bond, wherein R 19 is hydrogen.
9 . The compound according to claim 1 , wherein
is —CR 7 ═CR 8 —, —CR 7 R 9 —CR 8 R 10 —, —C(═O)—CR 8 R 10 — or —CR 7 R 9 —C(═O)—, and R 7 , R 8 , R 9 or R 10 are each independently selected from
hydrogen, halo, hydroxy;
perhaloC 1-6 alkyl;
C 1-6 alkyl, C 3-7 cycloalkyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, C 1-6 alkyloxy, aryl-C 1-6 alkyloxy, heteroarylC 1-6 alkyloxy, C 1-6 alkylcarbonyl, mono- or di(C 1-6 alkyl)amino,
C 1-6 alkylcarbonylamino and morpholinyl, any of said groups optionally substituted with one or more, substituents selected from halo, hydroxy, amino, C 1-6 alkyl, polyhaloC 1-6 alkyl, aryl, heteroaryl and C 1-6 alkyloxy;
or wherein any of R 7 and R 9 together, or R 8 and R 10 together form a bivalent radical —(CH 2 ) m —, wherein m is 2, 3, 4, 5 or 6.
10 . The compound according to claim 1 , wherein
is —CR 7 ═CR 8 —, —CR 7 R 9 —CR 8 R 10 —, —C(═O)—CR 8 R 10 — or —CR 7 R 9 —C(═O)—, and R 7 , R 8 , R 9 or R 10 are each independently selected from hydrogen, halo, C 1-6 alkyl, perhaloC 1-6 alkyl, or wherein any of R 7 and R 9 together, or R 8 and R 10 together form a bivalent radical —(CH 2 ) m — wherein m is 2, 3, 4, 5 or 6.
11 . The compound according to claim 1 wherein
is —CH 2 —CH 2 —; —CH 2 —CH(CH 3 )—; —CH 2 —C(CH 3 ) 2 —; —CH 2 —CH(CH 2 OH)—; —CH 2 —C(CH 3 )(CH 2 CH 3 )—;
—C(═O)—CH 2 —; —C(═O)—CH(CH 3 )—; —C(═O)—C(CH 3 ) 2 —; —C(═O)—CF 2 —;
12 . The compound according to claim 1 , wherein the compound is
including any stereochemically isomeric form thereof;
an N-oxide form thereof, an addition salt thereof or a solvate thereof.
13 . A compound according to claim 1 for use as a medicine.
14 . A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1 .
15 . A method for the manufacture of a medicament for the treatment of a disorder mediated by a p53-MDM2 interaction with a compound according to claim 1 .
16 . A method for the manufacture of a medicament for the treatment of cancer by administering an effective amount compound according to claim 1 .
17 . The method according to claim 16 wherein the cancer is breast cancer, colorectal cancer, non-small cell lung cancer or acute myelogenous leukaemia.
18 . A combination of an anti-cancer agent and a compound according to claim 1 .
19 . A process for preparing a compound as claimed in claim 1 , characterized by
a) reacting an intermediate of formula (II) with an intermediate of formula (III) or an appropriate acid addition salt thereof, wherein W is an appropriate leaving group
with the variables as defined in claim 1 ;
b) reacting an intermediate of formula (XIX) wherein P represents a suitable protective group, with an intermediate of formula (III) or an appropriate acid addition salt thereof, wherein W is an appropriate leaving group
with the variables as defined in claim 1 ;
c) reacting an intermediate of formula (XX) with an intermediate of formula (III) or an appropriate acid addition salt thereof, wherein W is an appropriate leaving group
with the variables as defined in claim 1 ;
d) reacting an intermediate of formula (XXI) with a suitable deprotection agent for the alcohol function in the presence of a suitable solvent
with the variables as defined in claim 1 ;
e) reacting an intermediate of formula (IV), wherein A is an appropriate leaving group, with an intermediate of formula (V
with the variables as defined in claim 1 ;
f) reducing an intermediate of formula (VI) with lithium aluminium hydride in a suitable solvent
with the variables as defined in claim 1 ;
g) reacting an appropriate carboxaldehyde of formula (VII), with an intermediate of formula (V), in the presence of an appropriate reducing reagent and a suitable solvent,
with the variables as defined in claim 1 ;
h) reacting an intermediate of formula (II) with an appropriate carboxaldehyde of formula HC(═O)Z to obtain compounds of formula (I) wherein t is 1, herein referred to as compounds of formula (I-b);
g) reducing an intermediate of formula (VIII) with lithium aluminium hydride in a suitable solvent
with the variables as defined in claim 1 ;
h) converting a compound of formula (I) wherein
is —C(═O)—CR 8 R 10 —, with R 8 and R 10 representing hydrogen, herein referred to as compounds of formula (I-f), into a compound of formula (I) wherein
is —CH 2 —CH 2 —, herein referred to as compounds of formula (I-g), by reaction with a suitable reducing agent,
with the variables as defined in claim 1 .Cited by (0)
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