Inhibitors of the interaction between mdm2 and p53

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.

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; 
 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 selected from hydroxy, C 1-6 alkyloxy, aryl, amino, arylC 1-6 alkyl, heteroaryl or heteroarylC 1-6 alkyl; or 
         R 13  and R 14  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 15  and R 16  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 15  and R 16  together with the nitrogen to which they are attached form morpholinyl, piperazinyl, or piperazinyl substituted with 
         C 1-6 alkyloxycarbonyl; 
         R 12  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; or 
         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 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 15  and R 16  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 15  and R 16  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 
       
         
           
           
               
               
           
         
       
       is —CR 9 ═C< and then the dotted line is a bond, —C(═O)—CH<, —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. 
     
     
         4 . The compound according to  claim 3  wherein 
       
         
           
           
               
               
           
         
       
       is —CR 9 ═C< and then the dotted line is a bond, —CHR 9 —CH<, or —CHR 9 —N<. 
     
     
         5 . The compound according to  claim 4  wherein 
       
         
           
           
               
               
           
         
       
       is —CR 9 ═C< and then the dotted line is a bond. 
     
     
         6 . The compound according to  claim 1 , wherein
 X is C(═O) or CHR 8  and R 8  is hydrogen; —C(═O)—NR 17 R 18 ; arylC 1-6 alkyloxycarbonyl; C 1-6 alkyl substituted with hydroxyl; piperazinylcarbonyl substituted with hydroxyl; hydroxyC 1-6 alkyl; hydroxyC 1-6 alkyloxyC 1-6 alkyl; pyrrolidinyl substituted with hydroxyl-C 1-6 alkyl; or 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 or   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 or hydroxyC 1-6 alkyl;   
       
         
           
           
               
               
           
         
       
       is —CR 9 ═C<, —CHR 9 —CH< or —CHR 9 —N<;
 R 1  is hydrogen, heteroaryl, C 1-6 alkyloxycarbonyl, C 1-12 alkyl or C 1-12 alkyl substituted with heteroaryl; 
 R 3  is hydrogen, C 1-6 alkyl or heteroaryl; 
 R 4  and R 5  are each independently hydrogen, halo, C 1-6 alkyl, cyano, cyanoC 1-6 alkyl, hydroxy or C 1-6 alkyloxy; 
 when p is 1 then R 7  is arylC 1-6 alkyl or hydroxy; 
 Z is a radical selected from (a-5), (a-6), (a-7), (a-8) and (a-9); 
 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, heteroarylC 1-6 alkyl, aryl(hydroxy)C 1-6 alkyl, arylcarbonyl, C 1-6 alkylcarbonyl, 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, 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 13 R 14 ; 
 v is 0 or 1; 
 u is 0 or 1; 
 R 12  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 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 or aryl; or 
 R 13  and R 14  together with the nitrogen to which they are attached form morpholinyl, pyrrolidinyl, piperazinyl or piperazinyl substituted with a substituent selected from C 1-6 alkyl or arylC 1-6 alkyloxycarbonyl; 
 k is 2; 
 R 15  and R 16  are each independently selected from hydrogen, C 1-6 alkyl or arylC 1-6 alkyloxycarbonyl; or 
 R 15  and R 16  together with the nitrogen to which they are attached form morpholinyl or piperazinyl, or piperazinyl substituted with C 1-6 alkyloxycarbonyl; 
 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 or arylC 1-6 alkyl. 
 
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein R 2  and R 20  are each independently selected from halo, cyano, polyhaloC 1-6 alkyl, C 1-6 alkyl, morpholinyl, C 1-6 alkyloxy, hydroxyC 1-6 alkyl, —NR 21 R 22  wherein R 21  is hydrogen and R 22  is C 1-6 alkylcarbonyl; or R 2  and R 20  together with the phenyl ring to which they are attached form a naphthalenyl group, 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. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound of  claim 1 . 
     
     
         12 . A method of treating a disorder mediated by a p53-MDM2 interaction comprising administering to a patient in need thereof a compound of  claim 1 . 
     
     
         13 . A method for the treatment of cancer comprising administering to a patient in need thereof a compound of  claim 1 . 
     
     
         14 . The method of  claim 13  wherein the cancer is breast cancer, colorectal cancer, non-small cell lung cancer or acute myelogenous leukaemia. 
     
     
         15 . A combination of an anti-cancer agent and a compound of  claim 1 . 
     
     
         16 . A process for preparing a compound as claimed in  claim 1 , characterized by
 a) reacting an intermediate of formula (IV) with an intermediate of formula (V) wherein W is an appropriate leaving group   
       
         
           
           
               
               
           
         
         with the variables as defined in  claim 1 ; 
         b) converting compounds of formula (I) wherein X is C(═O), herein referred to as compounds of formula (I-b), to compounds of formula (I) wherein X is CH 2 , herein referred to as compounds of formula (I-a), in the presence of lithium aluminium hydride in a suitable solvent 
       
       
         
           
           
               
               
           
         
         with the variables as defined in  claim 1 ; 
         c) reacting a carboxaldehyde of formula (VI), with an intermediate of formula (VII) 
       
       
         
           
           
               
               
           
         
         with the variables as defined in  claim 1 ; 
         d) reacting an intermediate of formula (IV) with a carboxaldehyde of formula HC(═O)Z to obtain compounds of formula (I) wherein t is 1, herein referred to as compounds of formula 
         (I-c), 
       
       
         
           
           
               
               
           
         
         with the variables as defined in  claim 1 ; 
         e) reacting an intermediate of formula (VIII) with lithium aluminium hydride in a suitable solvent, to obtain compounds of formula (I) wherein s is 1, herein referred to as compounds of formula (I-d) 
       
       
         
           
           
               
               
           
         
         with the variables as defined in  claim 1 ; 
         f) reacting an intermediate of formula (XXIV) with lithium aluminium hydride in a suitable solvent, to obtain compounds of formula (I) wherein R 4  is —CH 2 —OH, herein referred to as compounds of formula (I-e), 
       
       
         
           
           
               
               
           
         
         with the variables as defined in  claim 1 ; 
         g) converting an intermediate of formula (XIX) in the presence of a strong acid in a suitable solvent to obtain compounds of formula (III) 
       
       
         
           
           
               
               
           
         
         with the variables as defined in  claim 1 ; 
         h) reacting an intermediate of formula (IV) wherein s is 0, R 3  is hydrogen, 
       
       
         
           
           
               
               
           
         
       
       is —CR 9 ═C< and R 9  together with R 20  forms a direct bond, herein referred to as intermediates of formula (IV-c), with an intermediate of formula (V) wherein W is a suitable leaving group in a reaction-inert solvent to obtain compounds of formula (III) wherein s is 0 and R 3  is hydrogen, herein referred to as compounds of formula (III-a), 
       
         
           
           
               
               
           
         
         with the variables as defined in  claim 1 ; 
         h) Fisher indole synthesis starting form intermediates of formula (XXII) and (XXIII) to obtain compounds of formula (III) wherein R 6  is hydrogen, herein referred to as compounds of formula (III-b), 
       
       
         
           
           
               
               
           
         
         with the variables as defined in  claim 1 .