Heterocyclylalkylpiperidine derivatives, their preparation and compositions containing them

A compound of general formula (I):

• wherein:
• X1 is >C—R′1;
• X2 is >C—R′2;
• X3 is >C—R′3;
• X4 is >C—R′4;
• X5 is >C—R′5;
• and, optionally, one of X1, X2, X3, X4, and X5 is a nitrogen atom;
• R1, R′1, R′2, R′3, R′4, and R′5 are identical or different, and each independently is:
• a hydrogen or halogen atom or an alkyl, cycloalkyl, phenyl, phenylthio, mono- or bicyclic aromatic heterocyclyl or heterocyclylthio, hydroxyl, alkyloxy, trifluoromethoxy, alkylthio, trifluoromethylthio, cycloalkyloxy, cycloalkylthio cyano, carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, —NRaRb or —CONRaRb radical
• for which Ra and Rb are independently hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl, or
• Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain an additional heteroatom chosen from O, S and N and, when the additional heteroatom is N, the additional heteroatom optionally is substituted with an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent and, when the additional heteroatom is S, the additional heteroatom optionally is sulfinyl or sulfonyl,
• or a methylene radical substituted with fluoro, hydroxyl, alkyloxy, alkylthio, cycloalkyloxy, cycloalkylthio, phenyl, mono- or bicyclic aromatic heterocyclyl, carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, —NRaRb or —CONRaRb
• for which Ra and Rb are defined as above, and are additionally chosen from phenoxy, heterocyclyloxy, benzyloxy, and heterocyclylmethyloxy, and, optionally,
• R1 is difluoromethoxy, or a radical of structure —CmF2m+1, —SCmF2m+1, or —OCmF2m+1 wherein m is an integer from 1 to 6;
• and, optionally,
• R′5 is trifluoroacetyl;
• R2 is:
• carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, cyano, —CONRaRb, wherein
• Ra and Rb are, independently, hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl, and
• optionally, one of Ra and Rb is hydroxyl, alkyloxy, or cycloalkyloxy, or
• Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain an additional heteroatom chosen from O, S and N and, when the additional heteroatom is N, the additional heteroatom optionally is substituted with an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent and, when the additional heteroatom is S, the additional heteroatom optionally is sulfinyl or sulfonyl;
• or
• R2 is hydroxymethyl, alkyl containing 1 or 2 carbon atoms substituted with carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, cyano, or —CONRaRb, wherein
• Ra and Rb are, independently, hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl, and
• optionally one of Ra and Rb is hydroxyl, alkyloxy, or cycloalkyloxy, or
• Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain an additional heteroatom chosen from O, S and N and, when the additional heteroatom is N, the additional heteroatom optionally is substituted with an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent, and, when the additional heteroatom is S, the additional heteroatom optionally is sulfinyl or sulfonyl;
• or
• R2 is —CF2—Rc, —C(CH3)2—Rc, —CO—Rc, —CHOH—Rc, —C(cycloalkyl)-Rc, or —CH═CH—Rc, wherein
• Rc is carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, or —CONRaRb wherein Ra and Rb are, independently, hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl, and optionally
• one of Ra and Rb is hydroxyl, alkyloxy, or cycloalkyloxy, or
• Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain an additional heteroatom chosen from O, S and N and, when the additional heteroatom is N, the additional heteroatom optionally is substituted with an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent, and, when the additional heteroatom is S, the additional heteroatom optionally is sulfinyl or sulfonyl;
• R3 is a phenyl, mono- or bicyclic aromatic heterocyclyl or alk-R°3 radical, wherein
• alk is an alkyl radical, and
• R°3 is hydrogen, halogen, hydroxyl, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylamino, N-cycloalkyl-N-alkylamino, —N-(cycloalkyl)2, acyl, cycloalkylcarbonyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylamino, N-alkyl-N-phenylamino, N-cycloalkyl-N-phenylamino, —N-(phenyl)2, phenylalkyloxy, phenylalkylthio, phenylalkylsulfinyl, phenylalkylsulfonyl, phenylalkylamino, N-alkyl-N-phenylaminoalkyl, N-cycloalkyl-N-phenylalkylamino, benzoyl, mono- or bicyclic aromatic heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, heterocyclylamino, N-alkyl-N-heterocyclylamino, N-cycloalkyl-N-heterocyclylamino, heterocyclylcarbonyl, heterocyclylalkyloxy, heterocyclylalkylthio, heterocyclylalkylsulfinyl, heterocyclylalkylsulfonyl, heterocyclylalkylamino, N-alkyl-N-heterocyclylaminoalkyl, N-cycloalkyl-N-heterocyclylaminoalkyl, carboxyl, alkyloxycarbonyl, —NRaRb, or —CO—NRaRb, wherein Ra and Rb are, independently, hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl, and optionally
• one of Ra and Rb is hydroxyl, alkyloxy, or cycloalkyloxy, or
• Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain an additional heteroatom chosen from O, S and N and, when the additional heteroatom is N, the additional heteroatom optionally is substituted with an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent, and, when the additional heteroatom is S, the additional heteroatom optionally is sulfinyl or sulfonyl, and
• wherein any heterocyclyl mentioned above is mono- or bicyclic aromatic;
• or alternatively
• R°3 is —CR′b=CR′c-R′a, wherein
• R′a is phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl, phenoxyalkyl, phenylthioalkyl, phenylsulfinylalkyl, phenylsulfonylalkyl, phenylaminoalkyl, N-alkyl-N-phenylaminoalkyl, heterocyclyloxyalkyl, heterocyclylthioalkyl, heterocyclylsulfinylalkyl, heterocyclyl-sulfonylalkyl, heterocyclylaminoalkyl, N-alkyl-N-heterocyclylaminoalkyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, phenylthio, phenylsulfinyl, or phenylsulfonyl,
• wherein any heterocyclyl mentioned above is mono- or bicyclic aromatic, and
• R′b and R′c are hydrogen, alkyl or cycloalkyl;
• or alternatively
• R°3 is a radical —C≡C—Rd wherein
• Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, heterocyclylthioalkyl, heterocyclylaminoalkyl, N-alkyl-N-heterocyclylaminoalkyl, wherein
• any heterocyclyl mentioned above is mono- or bicyclic aromatic;
• or alternatively
• R°3 is a —CF2-phenyl, or mono- or bicyclic aromatic —CF2-heterocyclyl radical;
• Y is a radical >CH—Re, wherein
• Re is hydrogen, fluoro, hydroxyl, alkyloxy, cycloalkyloxy, carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, —NRaRb or —CO—NRaRb, wherein Ra and Rb are, independently, hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl, and optionally
• one of Ra and Rb is hydroxyl, alkyloxy, or cycloalkyloxy, or
• Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain an additional heteroatom chosen from O, S and N and, when the additional heteroatom is N, the additional heteroatom optionally is substituted with an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent, and, when the additional heteroatom is S, the additional heteroatom optionally is sulfinyl or sulfonyl,
• or one of Ra and Rb is a hydrogen atom and the other is an alkyloxycarbonyl, acyl, cycloalkylcarbonyl, benzoyl or heterocyclylcarbonyl radical, wherein
• any heterocyclyl portion is mono- or bicyclic aromatic;
• or alternatively
• Y is a difluoromethylene, carbonyl, hydroxyimino-methylene, alkyloxyiminomethylene, or cycloalkyloxyimino-methylene radical, or a 1,1-cycloalkylene radical containing 3 to 6 carbon atoms;
• and
• n is an integer from 0 to 4;
• wherein any phenyl, benzyl, benzoyl or heterocyclyl radical or portion mentioned above are unsubstituted, or substituted on the ring with 1 to 4 substituents independently chosen from halogen, hydroxyl, alkyl, alkyloxy, alkyloxyalkyl, haloalkyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, carboxyl, alkyloxycarbonyl, cyano, alkylamino, phenyl, hydroxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, and —NRaRb
• wherein Ra and Rb are, independently, hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl, and optionally
• one of Ra and Rb is hydroxyl, alkyloxy, or cycloalkyloxy, or
• Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain an additional heteroatom chosen from O, S and N and, when the additional heteroatom is N, the additional heteroatom optionally is substituted with an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent, and, when the additional heteroatom is S, the additional heteroatom optionally is sulfinyl or sulfonyl,
• or one of Ra and Rb is a hydrogen atom and the other is an alkyloxycarbonyl, acyl, cycloalkylcarbonyl, benzoyl or heterocyclylcarbonyl radical, wherein
• any heterocyclyl portion is mono- or bicyclic aromatic,
• wherein any alkyl or acyl radical or portion, unless otherwise indicated, comprises from 1 to 10 carbon atoms in a straight or branched chain, and any cycloalkyl radical comprises from 3 to 6 carbon atoms;
• in any enantiomeric or diastereoisomeric form, in any syn or anti form, or any salt thereof.