Substituted acetophenones useful as PDE4 inhibitors

A compound according to formula I

• wherein X1, X2, X3, X4 and X5 independently of each other represent —CH— or N;
• or X3, X4 and X5 independently of each other represent —CH— or N, and X1 and X2 independently of each other represent C and form part of an additional 6-membered aromatic ring;
• wherein R1 represents alky, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, or alkylcarbonyl, all of which are optionally substituted by one or more, same or different substituents selected from R4, or R1 represents hydrogen;
• R2 represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, arylalkyl, alkylalkoxycarbonyl, alkylcarbonyloxy, or alkoxyalkyl, all of which are optionally substituted by one or more, same or different substituents selected from R5;
• or R2 represents hydrogen or —CH2—C(O)NR9-R12;
• R3 represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, arylalkyl, alkylalkoxycarbonyl, alkylcarbonyloxy, or alkoxyalkyl, all of which are optionally substituted by one or more, same or different substituents selected from R6;
• or R3 represents hydrogen, —CR2—C(O)-heterocycloalkyl or —CH2—C(O)NR9-R12;
• R4 represents hydrogen, alkyl, alkenyl, alkynyl, halogen, oxo, alkoxy, hydroxy, or haloalkyl;
• R5 represents alkylaryl, carboxy, alkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, carbamoyl, hydroxyalkyl, aryloxy, alkoxycarbonyloxy, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, a heterocyclic ring, aminocarbonyl, alkylthio, alkylcarbonylamino, hydroxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, or amino, all of which are optionally substituted by one or more, same or different substituents selected from R7;
• or R5 represents hydrogen, oxo, halogen, cyano, or nitro;
• R6 represents alkylaryl, carboxy, alkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, carbamoyl, hydroxyalkyl, aryloxy, alkoxycarbonyloxy, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, a heterocyclic ring, aminocarbonyl, alkylthio, alkylcarbonylamino, arylcarbonyl, hydroxy, alkylcarbonyl, alkylcarbonyloxy, or amino, all of which are optionally substituted by one or more, same or different substituents selected from R8;
• or R6 represents hydrogen, oxo, halogen, cyano, or nitro;
• R7 represents alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkynyl, alkoxy, haloalkyl, alkylthio, heterocycloalkenyl, heterocycloalkyl, aryl, alkylcarbonyl, heteroaryl, aryloxy, alkoxycarbonyl, hydroxyalkyl, amino, hydroxy, or carboxy;
• all of which are optionally substituted by one or more, same or different substituents selected from R10;
• or R7 represents hydrogen, halogen, or oxo;
• R8 represents alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkynyl, alkoxy, haloalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, heterocycloalkenyl, heterocycloalkyl, aryl, alkylcarbonyl, heteroaryl, aryloxy, alkoxycarbonyl, hydroxyalkyl, amino, hydroxy, or carboxy;
• all of which are optionally substituted by one or more, same or different substituents selected from R10;
• or R8 represents hydrogen, halogen, or oxo;
• R9 represents hydrogen, alkyl, haloalkyl, or hydroxyalkyl;
• R10 represents hydrogen, alkyl, oxo, hydroxy, halogen, carboxy, amino, alkoxy, haloalkyl, or hydroxyalkyl;
• R11 represents one or more, same or different substituents selected from hydrogen, halogen, cyano, amino, alkyl, methylsulfinyl, methylsulfonyl, amino, cyano, or alkoxy;
• R12 represents alkylaryl, arylalkyl, carboxy, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, carbamoyl, hydroxyalkyl, aryloxy, alkoxycarbonyloxy, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, a heterocyclic ring, aminocarbonyl, alkylthio, alkylcarbonylamino, hydroxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, or amino, all of which are optionally substituted by one or more, same or different substituents selected from R8, or R12 represents hydrogen;
• with the proviso R1, R2 and R3 cannot all be methyl;
• with the proviso that when R2 and R3 are both hydrogen, R1 cannot be methyl or hydrogen;
• with the proviso that when R1 is methyl or hydrogen, R2 is methyl and R3 is hydrogen, then ring B cannot be phenyl;
• and
• pharmaceutically acceptable esters, pharmaceutically acceptable salts, or N-oxides thereof.