5-oxazolidin-2-one substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful as orl-1 receptor modulators

A process for the preparation of a compound of formula (I)

• wherein
• R1 is selected from the group consisting of hydrogen, C1-4alkyl, —C1-4alkyl-OH and —C1-4alkyl-O—C1-4alkyl;
• R2 is phenyl;
• wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C1-4alkyl and C1-4alkoxy;
• m is an integer from 0 to 1;
• R3 is selected from the group consisting of cycloalkyl, partially unsaturated carbocyclyl, aryl and heteroaryl;
• wherein the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C1-4alkyl and C1-4alkoxy;
• or a pharmaceutically acceptable salt thereof;
• comprising
• reacting a compound of formula (II) with a compound of formula (III), wherein LG1 is a leaving group, in the presence of a base, in an organic solvent, to yield the corresponding compound of formula (IV);
• reacting the compound of formula (IV) with a compound of formula (V), wherein LG2 is a leaving group, in the presence of an inorganic base, in an organic solvent, to yield the corresponding compound of formula (VI);
• reacting the compound of formula (VI) with a compound of formula (VII), in an organic solvent, to yield the corresponding compound of formula (VIII);
• reacting the compound of formula (VIII) with a compound of formula (IX), wherein LG3 and LG4 are independently selected leaving groups, in an organic solvent, to yield the corresponding compound of formula (I).

A process for the preparation of a compound of formula (Ib)

• wherein
• R1 is selected from the group consisting of C1-4alkyl, —C1-4alkyl-OH and —C1-4alkyl-O—C1-4alkyl;
• R2 is phenyl;
• wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C1-4alkyl and C1-4alkoxy;
• m is an integer from 0 to 1;
• R3 is selected from the group consisting of cycloalkyl, partially unsaturated carbocyclyl, aryl and heteroaryl;
• wherein the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C1-4alkyl and C1-4alkoxy;
• or a pharmaceutically acceptable salt thereof;
• comprising
• reacting a compound of formula (X) with a compound of formula (XI) wherein LG5 is a leaving group, in the presence of an inorganic base, in an organic solvent, to yield the corresponding compound of formula (Ib).

A process for the preparation of a compound of formula (I)

• wherein
• R1 is selected from the group consisting of hydrogen, C1-4alkyl, —C1-4alkyl-OH and —C1-4alkyl-O—C1-4alkyl;
• R2 is phenyl;
• wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C1-4alkyl and C1-4alkoxy;
• m is an integer from 0 to 1;
• R3 is selected from the group consisting of cycloalkyl, partially unsaturated carbocyclyl, aryl and heteroaryl;
• wherein the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C1-4alkyl and C1-4alkoxy;
• or a pharmaceutically acceptable salt thereof;
• comprising
• reacting a compound of formula (XIII) with a compound of formula (V), wherein LG2 is a leaving group, in the presence of a base, in an organic solvent, to yield the corresponding compound of formula (XIV);
• reacting the compound of formula (XIV) with a compound of formula (VII), in an organic solvent, to yield the corresponding compound of formula (XV);
• reacting the compound of formula (XV) with a compound of formula (IX), wherein LG3 and LG4 are independently selected leaving groups, in an organic solvent, to yield the corresponding compound of formula (XVI);
• de-protecting the compound of formula (XVI), to yield the corresponding compound of formula (XVII);
• reacting the compound of formula (XVII) with a compound of formula (III), wherein LG1 is a leaving group, in the presence of a base, in an organic solvent, to yield the corresponding compound of formula (I).

A process for the preparation of a compound of formula (I)

• wherein
• R1 is selected from the group consisting of hydrogen, C1-4alkyl, —C1-4alkyl-OH and —C1-4alkyl-O—C1-4alkyl;
• R2 is phenyl;
• wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C1-4alkyl and C1-4alkoxy;
• m is an integer from 0 to 1;
• R3 is selected from the group consisting of cycloalkyl, partially unsaturated carbocyclyl, aryl and heteroaryl;
• wherein the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C1-4alkyl and C1-4alkoxy;
• or a pharmaceutically acceptable salt thereof;
• comprising
• reacting a compound of formula (XVII) with a compound of formula (XII), in the presence of a reducing agent, in the presence of an acid, in an organic solvent, to yield the corresponding compound of formula (I).

A process for the preparation of a compound of formula (I)

• wherein
• R1 is selected from the group consisting of hydrogen, C1-4alkyl, —C1-4alkyl-OH and —C1-4alkyl-O—C1-4alkyl;
• R2 is phenyl;
• wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C1-4alkyl and C1-4alkoxy;
• m is an integer from 0 to 1;
• R3 is selected from the group consisting of cycloalkyl, partially unsaturated carbocyclyl, aryl and heteroaryl;
• wherein the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C1-4alkyl and C1-4alkoxy;
• or a pharmaceutically acceptable salt thereof;
• comprising
• reacting a compound of formula (IV) with a compound of formula (XIX), wherein LG6 is a leaving group, in the presence of a base, in an organic solvent, to yield the corresponding compound of formula (I).