Cyclic-alkylamine derivatives as inhibitors of the interaction between mdm2 and p53

A method of treating in a subject a disorder mediated by a p53-MDM2 interaction comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I),

• a N-oxide form, an addition salt or a stereochemically isomeric form thereof, wherein
• m is 0, and a direct bond is intended;
• n is 2, and a direct bond is intended;
• p is 1 and a direct bond is intended;
• t is 0 and a direct bond is intended;
• is —CR8═C< and then the dotted line is a bond, —C(═O)—CH<, —C(═O)—N<, —CHR8—CH< or —CHR8—N<;
• wherein each R8 is independently hydrogen or C1-6alkyl;
• R1 and R2 are each independently hydrogen
• R3 and R4 are each independently hydrogen
• R5 is hydrogen;
• R6 and R7 are each independently selected from hydrogen or C1-6alkyl;
• Z is a radical selected from
• wherein
• R10 and R11 are each independently selected from hydrogen, halo, hydroxy, amino, C1-6alkyl, nitro, polyhaloC1-6alkyl, cyano, cyanoC1-6alkyl, tetrazoloC1-6alkyl, aryl, heteroaryl, arylC1-6alkyl, heteroarylC1-6alkyl, aryl(hydroxy)C1-6alkyl, heteroaryl(hydroxy)C1-6alkyl, arylcarbonyl, heteroarylcarbonyl, C1-6alkylcarbonyl, arylC1-6alkylcarbonyl, heteroarylC1-6alkylcarbonyl, C1-6alkyloxy, C3-7cycloalkylcarbonyl, C3-7cycloalkyl(hydroxy)C1-6alkyl, arylC1-6alkyloxyC1-6alkyl, C1-6alkyloxyC1-6alkyloxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyloxyC1-6alkyl, hydroxyC1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonylC2-6alkenyl C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, aminocarbonyl, hydroxyC1-6alkyl, aminoC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl and —(CH2)v—(C(═O)r)—(CHR17)u—NR13R14;
• 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;
• R17 is hydrogen or C1-6alkyl;
• R12 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6alkyl substituted with a substituent selected from hydroxy, amino, C1-6alkyloxy and aryl;
• or C3-7cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and C1-6alkyloxy;
• R13 and R14 are each independently selected from hydrogen, C1-12alkyl, C1-6alkylcarbonyl, C1-6alkylsulfonyl, arylC1-6alkylcarbonyl, C3-7cycloalkyl, C3-7cycloalkylcarbonyl, —(CH2)k—NR15R16, C1-12alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C1-6alkyloxycarbonyl, C1-6alkyloxy, aryl or heteroaryl;
• or C3-7cycloalkyl substituted with a substituent selected from hydroxy, C1-6alkyloxy, aryl, amino, arylC1-6alkyl, heteroaryl or heteroarylC1-6alkyl;
• or
• R13 and R14 together with the nitrogen to which they are attached can optionally form a morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or piperazinyl substituted with a substituent selected from C1-6alkyl, arylC1-6alkyl, arylC1-6alkyloxycarbonyl, heteroarylC1-6alkyl, C3-7cycloalkyl and C3-7cycloalkylC1-6alkyl;
• wherein
• k is 0, 1, 2, 3, 4, 5, or 6 and when k is 0 then a direct bond is intended;
• R15 and R16 are each independently selected from hydrogen, C1-6alkyl, arylC1-6alkyloxycarbonyl, C3-7cycloalkyl, C1-12alkyl substituted with a substituent selected from hydroxy, C1-6alkyloxy, aryl, and heteroaryl;
• and C3-7cycloalkyl substituted with a substituent selected from hydroxy, C1-6alkyloxy, aryl, arylC1-6alkyl, heteroaryl, and heteroarylC1-6alkyl;
• or
• R15 and R16 together with the nitrogen to which they are attached can optionally form a morpholinyl, a piperazinyl or a piperazinyl substituted with C1-6alkyloxycarbonyl;
• 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, C1-6alkyl, amino, polyhaloC1-6alkyl and C1-6alkyloxy;
• 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, C1-6alkyl, amino, polyhaloC1-6alkyl, aryl, arylC1-6alkyl or C1-6alkyloxy;
• and
• each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with a bivalent radical selected from methylenedioxy or ethylenedioxy and a pharmaceutically acceptable carrier.

A process for preparing a compound formula (I),

• a N-oxide form, an addition salt or a stereochemically isomeric form thereof, wherein
• m is 0, and a direct bond is intended;
• n is 2, and a direct bond is intended;
• p is 1 and a direct bond is intended;
• t is 0 and a direct bond is intended;
• is —CR8═C< and then the dotted line is a bond, —C(═O)—CH<, —C(═O)—N<, —CHR8—CH< or —CHR8—N<;
• wherein each R8 is independently hydrogen or C1-6alkyl;
• R1 and R2 are each independently hydrogen
• R3 and R4 are each independently hydrogen
• R5 is hydrogen;
• R6 and R7 are each independently selected from hydrogen or C1-6alkyl;
• Z is a radical selected from
• wherein
• R10 and R11 are each independently selected from hydrogen, halo, hydroxy, amino, C1-6alkyl, nitro, polyhaloC1-6alkyl, cyano, cyanoC1-6alkyl, tetrazoloC1-6alkyl, aryl, heteroaryl, arylC1-6alkyl, heteroarylC1-6alkyl, aryl(hydroxy)C1-6alkyl, heteroaryl(hydroxy)C1-6alkyl, arylcarbonyl, heteroarylcarbonyl, C1-6alkylcarbonyl, arylC1-6alkylcarbonyl, heteroarylC1-6alkylcarbonyl, C1-6alkyloxy, C3-7cycloalkylcarbonyl, C3-7cycloalkyl(hydroxy)C1-6alkyl, arylC1-6alkyloxyC1-6alkyl, C1-6alkyloxyC1-6alkyloxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyloxyC1-6alkyl, hydroxyC1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonylC2-6alkenyl C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, aminocarbonyl, hydroxyC1-6alkyl, aminoC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl and —(CH2)v—(C(═O)r)—(CHR17)u—NR13R14;
• 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;
• R17 is hydrogen or C1-6alkyl;
• R12 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6alkyl substituted with a substituent selected from hydroxy, amino, C1-6alkyloxy and aryl;
• or C3-7cycloalkyl substituted with a substituent selected from hydroxy, amino, aryl and C1-6alkyloxy;
• R13 and R14 are each independently selected from hydrogen, C1-12alkyl, C1-6alkylcarbonyl, C1-6alkylsulfonyl, arylC1-6alkylcarbonyl, C3-7cycloalkyl, C3-7cycloalkylcarbonyl, —(CH2)k—NR15R16, C1-12alkyl substituted with a substituent selected from hydroxy, hydroxycarbonyl, cyano, C1-6alkyloxycarbonyl, C1-6alkyloxy, aryl or heteroaryl;
• or C3-7cycloalkyl substituted with a substituent selected from hydroxy, C1-6alkyloxy, aryl, amino, arylC1-6alkyl, heteroaryl or heteroarylC1-6alkyl;
• or
• R13 and R14 together with the nitrogen to which they are attached can optionally form a morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or piperazinyl substituted with a substituent selected from C1-6alkyl, arylC1-6alkyl, arylC1-6alkyloxycarbonyl, heteroarylC1-6alkyl, C3-7cycloalkyl and C3-7cycloalkylC1-6alkyl;
• wherein
• k is 0, 1, 2, 3, 4, 5, or 6 and when k is 0 then a direct bond is intended;
• R15 and R16 are each independently selected from hydrogen, C1-6alkyl, arylC1-6alkyloxycarbonyl, C3-7cycloalkyl, C1-12alkyl substituted with a substituent selected from hydroxy, C1-6alkyloxy, aryl, and heteroaryl;
• and C3-7cycloalkyl substituted with a substituent selected from hydroxy, C1-6alkyloxy, aryl, arylC1-6alkyl, heteroaryl, and heteroarylC1-6alkyl;
• or
• R15 and R16 together with the nitrogen to which they are attached can optionally form a morpholinyl, a piperazinyl or a piperazinyl substituted with C1-6alkyloxycarbonyl;
• 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, C1-6alkyl, amino, polyhaloC1-6alkyl and C1-6alkyloxy;
• 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, C1-6alkyl, amino, polyhaloC1-6alkyl, aryl, arylC1-6alkyl or C1-6alkyloxy;
• and
• each pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl can optionally be substituted with a bivalent radical selected from methylenedioxy or ethylenedioxy, said process comprising the steps of:
• a) reacting an intermediate of formula (II) with an intermediate of formula (III) wherein W is an appropriate leaving group
• b) converting an intermediate of formula (IV) into compounds of formula (I), wherein p is 1, herein referred to as compounds of formula (I-a), in the presence of lithium aluminium hydride in a suitable solvent,
• c) reacting an appropriate carboxaldehyde of formula (VI), with an intermediate of formula (V), in the presence of an appropriate reagent, in a suitable solvent, or
• d) reacting an intermediate of formula (II) with an appropriate carboxaldehyde of formula (VII) with the formation of a compound of formula (I), wherein t is 1, herein referred to as compounds of formula (I-b).