Substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives and their use as neurokinin antagonists

A compound according to the general Formula (I)

• the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein
• n is an integer, equal to 0, 1 or 2;
• m is an integer, equal to 1 or 2, provided that if m is 2, then n is 1;
• p is an integer equal to 1 or 2;
• q is an integer equal to 0 or 1;
• Q is O or NR3;
• X is a covalent bond or a bivalent radical of formula —O—, —S— or —NR3—;
• each R3 independently from each other, is hydrogen or alkyl;
• each R1 independently from each other, is selected from the group of Ar1, Ar1-alkyl and di(Ar1)-alkyl;
• R2 is Ar2, Ar2-alkyl, di(Ar2)alkyl, Het1 or Het1-alkyl;
• Y is a covalent bond or a bivalent radical of formula —C(═O)—, —SO2— >C═CH—R or >C═N—R, wherein R is H, CN or nitro;
• each Alk represents, independently from each other, a covalent bond;
• a bivalent straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms;
• or a cyclic saturated or unsaturated hydrocarbon radical having from 3 to 6 carbon atoms each radical optionally substituted on one or more carbon atoms with one or more , phenyl, halo, cyano, hydroxy, formyl and amino radicals;
• L is selected from the group of hydrogen, alkyl, alkyloxy, alkyloxyalkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, mono- and di(alkyl)amino, mono- and di(alkyloxycarbonyl)amino, mono- and di(alkylcarbonyl)amino, mono- and di(Ar3)amino, mono- and di(Ar3alkyl)amino, mono- and di(Het2)amino, mono- and di(Het2alkyl)amino, alkylsulfanyl, adamantyl, Ar3, Ar3-oxy, Ar3carbonyl, Het2, Het-oxy and Het2carbonyl
• Ar1 is phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, alkyl, cyano, aminocarbonyl and alkyloxy;
• Ar2 is naphthalenyl or phenyl, each optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, nitro, amino, mono- and di(alkyl)amino, cyano, alkyl, hydroxy, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl and mono- and di(alkyl)aminocarbonyl;
• Ar3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of alkyloxy, Ar1carbonyloxyalkyl, Ar1alkyloxycarbonyl, Ar1alkyloxyalkyl, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[1,2-a]pyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano;
• Het1 is a monocyclic heterocyclic radical selected from the the group of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl;
• or a bicyclic heterocyclic radical selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, indanyl and chromenyl;
• each heterocyclic radical may optionally be substituted on any atom by one or more radicals elected from the group of halo, oxo and alkyl;
• Het2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, dioxolyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 2H-pyrrolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, furanyl, thienyl, oxazolyl, dioxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl;
• or a bicyclic heterocyclic radical selected from the group of 2,3-dihydro-benzo[1,4]dioxine, octahydro-benzo[1,4]dioxine, benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl, isoindolyl, chromanyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl or benzothienyl
• or the tricyclic heterocyclic radical 8,9-dihydro-4H-1-oxa-3,5,7a-triaza-cyclopenta[f]azulenyl;
• each radical may optionally be substituted with one or more radicals selected from the group of Ar1, Ar1alkyl, Ar1alkyloxyalkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo, alkyloxy, alkylcarbonyl, Ar1carbonyl, mono- and di(alkyl)aminoalkyl, alkyloxyalkyl and alkyloxycarbonyl;
• and
• alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms;
• optionally substituted on one or more carbon atoms with one or more radicals selected from the group of phenyl, halo, cyano, oxo, hydroxy, formyl and amino.