SUBSTITUTED AMINOQUINOLONES AS DGKALPHA INHIBITORS FOR IMMUNE ACTIVATION

Abstract

The present invention covers aminoquinolone compounds of general formula (I): in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, X and n are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment and/or prophylaxis of diseases, in particular of diacylglycerol kinase alpha regulated disorders, as a sole agent or in combination with other active ingredients.

##STR00001##

Claims

1. A compound of formula (I): ##STR00288## wherein: n is selected from the group consisting of 1, 2, and 3; X is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O).sub.2—, *-(C(R.sup.16)(R.sup.17)).sub.o-#, *—O—C(R.sup.16).sub.2—(C(R.sup.16)(R.sup.17)).sub.p-#, *-(C(R.sup.16)(R.sup.17)).sub.p—C(R.sup.16).sub.2—O—#, ##STR00289## wherein * indicates the point of attachment to R.sup.2 and #indicates the point of attachment to the pyrrolidine, piperidine, azepane moiety; R.sup.1 selected from the group consisting of cyano, —C(═O)NH.sub.2, —C(═O)N(H)CH.sub.3, —C(═O)N(H)C.sub.2H.sub.5, —C(═O)N(CH.sub.3).sub.2, and —C(═O)OR.sup.15; R.sup.2 is selected from the group consisting of phenyl, naphthyl, and 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl group is connected to the rest of the molecule via a carbon atom of said 5- to 10-membered heteroaryl group, wherein the phenyl, naphthyl, and 5- to 10-membered heteroaryl group are optionally substituted, one, two, three, or four times, wherein each substituent independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-hydroxyalkyl, C.sub.1-C.sub.6-haloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.6-alkyl)-, C.sub.1-C.sub.6-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.6-alkoxy)-, C.sub.1-C.sub.6-haloalkoxy, C.sub.3-C.sub.6-cycloalkyloxy, phenoxy, —SR.sup.14, —S(═O)R.sup.14, —S(═O).sub.2R.sup.14, —P(═O)(R.sup.14).sub.2, nitro, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —C(═O)N(R.sup.9)(R.sup.10), —C(═O)R.sup.11, —C(═O).sub.2R.sup.15, —N(R.sup.12)C(═O)R.sup.13, —N(R.sup.12)S(═O).sub.2R.sup.14, —N═S(═NH)(R.sup.14).sub.2, —N═S(═O)(R.sup.14).sub.2, —S(═O)(═NR.sup.14)R.sup.13, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl, or two substituents of said phenyl group, when they are attached to adjacent ring atoms, are linked to one another in such a way that they jointly form a group selected from the group consisting of —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —O—(CH.sub.2).sub.2—, —(CH.sub.2).sub.2—O—, —CH.sub.2—O—CH.sub.2—, —O—(CH.sub.2).sub.3—, —(CH.sub.2).sub.3—O—, —CH.sub.2—O—(CH.sub.2).sub.2—, —(CH.sub.2).sub.2O—CH.sub.2—, —O—CH.sub.2—O—, and —O—(CH.sub.2).sub.2—O—, wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and (4- to 7-membered heterocycloalkyl)oxy group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein said C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-alkoxy groups are optionally substituted with a group selected from the group consisting of C.sub.3-C.sub.4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, each substituent independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein the phenyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10), which C.sub.3-C.sub.4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, and hydroxy, wherein said C.sub.3-C.sub.6-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C.sub.1-C.sub.4-alkyl group, wherein said phenyl, phenoxy, and 5- or 6-membered heteroaryl group are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.3 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.4-C.sub.6-cycloalkenyl, C.sub.1-C.sub.6-hydroxyalkyl, C.sub.1-C.sub.6-haloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.6-alkyl)-, C.sub.1-C.sub.6-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.6-alkoxy)-, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.6-cycloalkyloxy, phenoxy, —SR.sup.14, —S(═O)R.sup.14, —S(═O).sub.2R.sup.14, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —C(═O)N(R.sup.9)(R.sup.10), —C(═O)R.sup.11, —N(R.sup.12)C(═O)R.sup.13, —N(R.sup.12)S(═O).sub.2R.sup.14, —N═S(═NH)(R.sup.14).sub.2, —N═S(═O)(R.sup.14).sub.2 and —P(═O)(R.sup.14).sub.2, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl, wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and (4- to 7-membered heterocycloalkyl)oxy group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein said C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, and C.sub.1-C.sub.6-alkoxy group is optionally substituted with a group selected from C.sub.3-C.sub.4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein the phenyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10), wherein the C.sub.3-C.sub.4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, and hydroxy, wherein said C.sub.3-C.sub.6-cycloalkyl and C.sub.4-C.sub.6-cycloalkenyl groups are optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C.sub.1-C.sub.4-alkyl group, wherein said phenyl, phenoxy, and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.4 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.4-C.sub.6-cycloalkenyl, C.sub.1-C.sub.6-hydroxyalkyl, C.sub.1-C.sub.6-haloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.6-alkyl)-, C.sub.1-C.sub.6-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.6-alkoxy)-, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.6-cycloalkyloxy, —S(═O)R.sup.14, —S(═O).sub.2R.sup.14, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —N(R.sup.18)(R.sup.19), —C(═O)N(R.sup.9)(R.sup.10), —C(═O)R.sup.11, —N(R.sup.12)C(═O)R.sup.13, —N(R.sup.12)S(═O).sub.2R.sup.14, —N═S(═NH)(R.sup.14).sub.2, —N═S(═O)(R.sup.14).sub.2, —P(═O)(R.sup.14).sub.2, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl, wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and (4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein said C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, and C.sub.1-C.sub.6-alkoxy groups are optionally substituted with a group selected from the group consisting of C.sub.3-C.sub.4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein the phenyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10), wherein the C.sub.3-C.sub.4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, and hydroxy, wherein said C.sub.3-C.sub.6-cycloalkyl and C.sub.4-C.sub.6-cycloalkenyl groups are optionally substituted, one or two times, wherein each substituent is independently selected from a halogen atom or a C.sub.1-C.sub.4-alkyl group, wherein said phenyl and 5- or 6-membered heteroaryl groups are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.5 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.4-C.sub.6-cycloalkenyl, C.sub.1-C.sub.6-hydroxyalkyl, C.sub.1-C.sub.6-haloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.6-alkyl)-, C.sub.1-C.sub.6-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.6-alkoxy), —C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.6-cycloalkyloxy, phenoxy, —SR.sup.14, —S(═O)R.sup.14, S(═O).sub.2R.sup.14, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —C(═O)N(R.sup.9)(R.sup.10), —C(═O)R.sup.11, —N(R.sup.12)C(═O)R.sup.13, —N(R.sup.12)S(═O).sub.2R.sup.14, —N═S(═NH)(R.sup.14).sub.2, —N═S(═O)(R.sup.14).sub.2, —P(═O)(R.sup.14).sub.2, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl, wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and (4- to 7-membered heterocycloalkyl)oxy group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein said C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, and C.sub.1-C.sub.6-alkoxy group is optionally substituted with a group selected from the group consisting of C.sub.3-C.sub.4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein the phenyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10), wherein the C.sub.3-C.sub.4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, and hydroxy, wherein said C.sub.3-C.sub.6-cycloalkyl and C.sub.4-C.sub.6-cycloalkenyl group is optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C.sub.1-C.sub.4-alkyl group, wherein said phenyl, phenoxy, and 5- or 6-membered heteroaryl group are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.6 is selected from the group consisting of a hydrogen atom, a fluorine atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-hydroxyalkyl, C.sub.1-C.sub.4-alkoxy, hydroxy, and oxo; R.sup.7 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, hydroxy, and cyano, R.sup.8 is methyl or ethyl; R.sup.9 and R.sup.10 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, (C.sub.1-C.sub.4-alkoxy)-(C.sub.2-C.sub.4-alkyl)-, C.sub.3-C.sub.4-cycloalkyl, and C.sub.2-C.sub.4-haloalkyl, or R.sup.9 and R.sup.10 together with the nitrogen to which they are attached form a nitrogen containing 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said nitrogen containing 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, hydroxy, and oxo, or two substituents, which are attached to the same carbon atom of said nitrogen containing 4- to 7-membered heterocycloalkyl group, together with the carbon atom to which they are attached, represent form a 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-haloalkyl, hydroxy, and oxo; R.sup.11 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-hydroxyalkyl, C.sub.1-C.sub.4-haloalkyl, phenyl, and 5- or 6-membered heteroaryl, wherein said phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.12 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; R.sup.13 is selected from the group consisting of a hydrogen atom C.sub.1-C.sub.6-alkyl, phenyl, and 5- or 6-membered heteroaryl, wherein said phenyl group and 5- or 6-membered heteroaryl group are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.14 is selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.6-cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, wherein said phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.15 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; each R.sup.16 is independently selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.2-alkyl, and C.sub.1-C.sub.2-haloalkyl; each R.sup.17 is independently selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, C.sub.1-C.sub.2-alkoxy, C.sub.1-C.sub.2-haloalkoxy, and hydroxy; R.sup.18 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, and C.sub.2-C.sub.4-haloalkyl; R.sup.19 is a 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, hydroxy, and oxo, and wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group; o is 1 or 2; and p is 0 or 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

2. The compound according to claim 1, wherein: n is selected from the group consisting of 1, 2, and 3; X is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O).sub.2—, *-(C(R.sup.16)(R.sup.17)).sub.o-#, *—O—C(R.sup.16).sub.2—(C(R.sup.16)(R.sup.17)).sub.p-#, *-(C(R.sup.16)(R.sup.17)).sub.p—C(R.sup.16).sub.2—O—#, ##STR00290## wherein * indicates the point of attachment to R.sup.2 and #indicates the point of attachment to the pyrrolidine, piperidine, or azepane moiety; R.sup.1 is selected from the group consisting of cyano, —C(═O)NH.sub.2, —C(═O)N(H)CH.sub.3, —C(═O)N(H)C.sub.2H.sub.5, —C(═O)N(CH.sub.3).sub.2, and —C(═O)OR.sup.15; R.sup.2 is selected from the group consisting of phenyl, naphthyl, and 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl group is connected to the rest of the molecule via a carbon atom of said 5- to 10-membered heteroaryl group, wherein the phenyl, naphthyl, and 5- to 10-membered heteroaryl group is optionally substituted, one, two, three, or four times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, C.sub.1-C.sub.4-hydroxyalkyl, C.sub.1-C.sub.4-haloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkyl)-, C.sub.1-C.sub.4-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkoxy)-, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.5-cycloalkyloxy, phenoxy, —SR.sup.14, —S(═O)R.sup.14, —S(═O).sub.2R.sup.14, —P(═O)(R.sup.14).sub.2, nitro, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —C(═O)N(R.sup.9)(R.sup.10), —C(═O)R.sup.11, —C(═O).sub.2R.sup.15, —N(R.sup.12)C(═O)R.sup.13, —N(R.sup.12)S(═O).sub.2R.sup.14, —N═S(═NH)(R.sup.14).sub.2, —N═S(═O)(R.sup.14).sub.2, —S(═O)(═NR.sup.14)R.sup.13, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl and 5- or 6-membered heteroaryl, or two substituents of said phenyl group, when they are attached to adjacent ring atoms, are linked to one another in such a way that they jointly form a group selected from —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —O—(CH.sub.2).sub.2—, —(CH.sub.2).sub.2—O—, —CH.sub.2—O—CH.sub.2—, —O—(CH.sub.2).sub.3—, —(CH.sub.2).sub.3—O—, —CH.sub.2—O—(CH.sub.2).sub.2—, —(CH.sub.2).sub.2O—CH.sub.2—, —O—CH.sub.2—O—, and —O—(CH.sub.2).sub.2—O—, wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and (4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein said C.sub.1-C.sub.4-alkyl and C.sub.1-C.sub.4-alkoxy groups are optionally substituted with a group selected from the group consisting of C.sub.3-C.sub.4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein the phenyl group is optionally substituted, one or two times, wherein each substituent independently is selected from a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10), wherein the C.sub.3-C.sub.4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, and hydroxy, wherein said C.sub.3-C.sub.5-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C.sub.1-C.sub.4-alkyl group, wherein said phenyl, phenoxy, and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.3 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.3-C.sub.5-cycloalkyl, C.sub.4-C.sub.5-cycloalkenyl, C.sub.1-C.sub.4-hydroxyalkyl, C.sub.1-C.sub.4-haloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkyl)-, C.sub.1-C.sub.4-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkoxy)-, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.5-cycloalkyloxy, phenoxy, —SR.sup.14, —S(═O)R.sup.14, —S(═O).sub.2R.sup.14, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —C(═O)N(R.sup.9)(R.sup.10), —C(═O)R.sup.11, —N(R.sup.12)C(═O)R.sup.13, —N(R.sup.12)S(═O).sub.2R.sup.14, —N═S(═NH)(R.sup.14).sub.2, —N═S(═O)(R.sup.14).sub.2, —P(═O)(R.sup.14).sub.2, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl, wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and (4- to 7-membered heterocycloalkyl)oxy group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10)z and oxo, wherein said C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, and C.sub.1-C.sub.4-alkoxy groups are optionally substituted with a group selected from the group consisting of C.sub.3-C.sub.4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein the phenyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10), wherein the C.sub.3-C.sub.4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, and hydroxy, wherein said C.sub.3-C.sub.5-cycloalkyl and C.sub.4-C.sub.5-cycloalkenyl groups are optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C.sub.1-C.sub.4-alkyl group, wherein said phenyl, phenoxy, and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.4 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.3-C.sub.5-cycloalkyl, C.sub.4-C.sub.5-cycloalkenyl, C.sub.1-C.sub.4-hydroxyalkyl, C.sub.1-C.sub.4-haloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkyl)-, C.sub.1-C.sub.4-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkoxy)-, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.5-cycloalkyloxy, —S(═O)R.sup.14, —S(═O).sub.2R.sup.14, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —N(R.sup.18)(R.sup.19), —C(═O)N(R.sup.9)(R.sup.10), —C(═O)R.sup.11, —N(R.sup.12)C(═O)R.sup.13, —N(R.sup.12)S(═O).sub.2R.sup.14, —N═S(═NH)(R.sup.14).sub.2, —N═S(═O)(R.sup.14).sub.2, —P(═O)(R.sup.14).sub.2, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl, wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and (4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein said C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, and C.sub.1-C.sub.4-alkoxy groups are optionally substituted with a group selected from C.sub.3-C.sub.4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein the phenyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10), wherein the C.sub.3-C.sub.4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, and hydroxy, wherein said C.sub.3-C.sub.5-cycloalkyl and C.sub.4-C.sub.5-cycloalkenyl groups are optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C.sub.1-C.sub.4-alkyl group, wherein said phenyl and 5- or 6-membered heteroaryl groups are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.5 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.3-C.sub.5-cycloalkyl, C.sub.4-C.sub.5-cycloalkenyl, C.sub.1-C.sub.4-hydroxyalkyl, C.sub.1-C.sub.4-haloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkyl)-, C.sub.1-C.sub.4-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkoxy), —C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.5-cycloalkyloxy, phenoxy, —SR.sup.14, —S(═O)R.sup.14, S(═O).sub.2R.sup.14, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —C(═O)N(R.sup.9)(R.sup.10), —C(═O)R.sup.11, —N(R.sup.12)C(═O)R.sup.13, —N(R.sup.12)S(═O).sub.2R.sup.14, —N═S(═NH)(R.sup.14).sub.2, —N═S(═O)(R.sup.14).sub.2, —P(═O)(R.sup.14).sub.2, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl, wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and (4- to 7-membered heterocycloalkyl)oxy group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein said C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, and C.sub.1-C.sub.4-alkoxy group is optionally substituted with a group selected from the group consisting of C.sub.3-C.sub.4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo, wherein the phenyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10), wherein the C.sub.3-C.sub.4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, and hydroxy, wherein said C.sub.3-C.sub.5-cycloalkyl and C.sub.4-C.sub.5-cycloalkenyl groups are optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C.sub.1-C.sub.4-alkyl group, wherein said phenyl, phenoxy, and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.6 is selected from the group consisting of a hydrogen atom, a fluorine atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-hydroxyalkyl, C.sub.1-C.sub.4-alkoxy, hydroxy, and oxo; R.sup.7 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, hydroxy, and cyano; R.sup.8 is methyl or ethyl; R.sup.9 and R.sup.10 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, (C.sub.1-C.sub.4-alkoxy)-(C.sub.2-C.sub.4-alkyl)-, C.sub.3-C.sub.4-cycloalkyl, and C.sub.2-C.sub.4-haloalkyl, or R.sup.9 and R.sup.10 together with the nitrogen to which they are attached form a nitrogen containing 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said nitrogen containing 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, hydroxy, and oxo, or two substituents, which are attached to the same carbon atom of said nitrogen containing 4- to 7-membered heterocycloalkyl group, together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-haloalkyl, hydroxy, and oxo; R.sup.11 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-hydroxyalkyl, C.sub.1-C.sub.4-haloalkyl, phenyl, and 5- or 6-membered heteroaryl, wherein said phenyl group and 5- or 6-membered heteroaryl groups are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.12 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group, R.sup.13 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, phenyl, and 5- or 6-membered heteroaryl, wherein said phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl and —N(R.sup.9)(R.sup.10), R.sup.14 represents a group selected from C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.5-cycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein said phenyl group and 5- or 6-membered heteroaryl groups are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.15 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; each R.sup.16 is independently selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.2-alkyl, and C.sub.1-C.sub.2-haloalkyl; each R.sup.17 is independently selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, C.sub.1-C.sub.2-alkoxy, C.sub.1-C.sub.2-haloalkoxy, and hydroxy; R.sup.18 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, and C.sub.2-C.sub.4-haloalkyl; R.sup.19 is a 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, hydroxy, and oxo, and wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group; o is 1 or 2, and p is 0 or 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

3. The compound according to claim 1, wherein: n is selected from the group consisting of 1, 2, and 3; X is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O).sub.2—, *-(C(R.sup.16)(R.sup.17)).sub.o-#, *—O—C(R.sup.16).sub.2—(C(R.sup.16)(R.sup.17)).sub.p-#, *-(C(R.sup.16)(R.sup.17)).sub.p—C(R.sup.16).sub.2—O—#, ##STR00291## wherein * indicates the point of attachment to R.sup.2 and #indicates the point of attachment to the pyrrolidine, piperidine, azepane moiety, R.sup.1 is selected from the group consisting of cyano, —C(═O)NH.sub.2, —C(═O)N(H)CH.sub.3, —C(═O)N(H)C.sub.2H.sub.5, —C(═O)N(CH.sub.3).sub.2, and —C(═O)OR.sup.15; R.sup.2 is selected from the group consisting of phenyl, naphthyl, and 5- to 10-membered heteroaryl, which 5- to 10-membered heteroaryl group is connected to the rest of the molecule via a carbon atom of said 5- to 10-membered heteroaryl group, wherein the phenyl, naphthyl, and 5- to 10-membered heteroaryl group are optionally substituted, one, two, three, or four times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkoxy)-, C.sub.1-C.sub.4-haloalkoxy, —SR.sup.14, —S(═O)R.sup.14, —S(═O).sub.2R.sup.14, —P(═O)(R.sup.14).sub.2, nitro, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —C(═O)N(R.sup.9)(R.sup.10), —C(═O).sub.2R.sup.15, —N(R.sup.12)S(═O).sub.2R.sup.14, —N═S(═O)(R.sup.14).sub.2, —S(═O)(═NR.sup.14)R.sup.13, 4- to 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, wherein said 5- or 6-membered heteroaryl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.3 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkyl)-, C.sub.1-C.sub.4-alkoxy, —S(═O).sub.2R.sup.14, cyano, hydroxy, —N(R.sup.9)(R.sup.10), and —P(═O)(R.sup.14).sub.2, R.sup.4 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkyl)-, C.sub.1-C.sub.4-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkoxy)-, C.sub.3-C.sub.5-cycloalkyloxy, hydroxy, —N(R.sup.9)(R.sup.10), —N(R.sup.18)(R.sup.19), —P(═O)(R.sup.14).sub.2, 4- to 7-membered heterocycloalkyl, and (4- to 7-membered heterocycloalkyl)oxy, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group and (4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, —N(R.sup.9)(R.sup.10), and oxo; R.sup.5 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, C.sub.1-C.sub.4-alkoxy, S(═O).sub.2R.sup.14, cyano, —N(R.sup.9)(R.sup.10), —N═S(═O)(R.sup.14).sub.2, and —P(═O)(R.sup.14).sub.2; R.sup.6 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-hydroxyalkyl, C.sub.1-C.sub.4-alkoxy, hydroxy, and oxo; R.sup.7 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; R.sup.8 is methyl or ethyl; R.sup.9 and R.sup.10 is a hydrogen atom or C.sub.1-C.sub.4-alkyl group, or R.sup.9 and R.sup.10 together with the nitrogen to which they are attached form a nitrogen containing 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said nitrogen containing 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, hydroxy, and oxo, or two substituents, which are attached to the same carbon atom of said nitrogen containing 4- to 7-membered heterocycloalkyl group, together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom or a group selected from C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-haloalkyl, hydroxy, and oxo; R.sup.12 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; R.sup.13 represents is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, phenyl, and 5- or 6-membered heteroaryl, wherein said phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.14 is a C.sub.1-C.sub.4-alkyl group; R.sup.15 represents is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; each R.sup.16 is independently a hydrogen atom or a C.sub.1-C.sub.2-alkyl group; each R.sup.17 is a hydroxy group; R.sup.18 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; R.sup.19 is a 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, with a C.sub.1-C.sub.4-alkyl group, and wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group; o is 1 or 2; and p is 0 or 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

4. The compound according to claim 1, wherein: n selected from the group consisting of 1, 2, and 3; X is selected from the group consisting of —O—, —S—, *-(C(R.sup.16)(R.sup.17)).sub.o-#, *—O—C(R.sup.16).sub.2—(C(R.sup.16)(R.sup.17)).sub.p-#and *-(C(R.sup.16)(R.sup.17)).sub.p—C(R.sup.16).sub.2—O—#, wherein * indicates the point of attachment to R.sup.2 and #indicates the point of attachment to the pyrrolidine, piperidine, azepane moiety; R.sup.1 is selected from the group consisting of cyano, —C(═O)NH.sub.2, —C(═O)N(H)CH.sub.3, —C(═O)N(CH.sub.3).sub.2, and —C(═O)OR.sup.15; R.sup.2 is selected from the group consisting of phenyl, naphthyl, and 5- to 10-membered heteroaryl, wherein 5- to 10-membered heteroaryl group is connected to the rest of the molecule via a carbon atom of said 5- to 10-membered heteroaryl group, wherein phenyl, naphthyl, and 5- to 10-membered heteroaryl group is optionally substituted, one, two, three, or four times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkoxy)-, C.sub.1-C.sub.4-haloalkoxy, —SR.sup.14, —S(═O)R.sup.14, —S(═O).sub.2R.sup.14, nitro, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —C(═O)N(R.sup.9)(R.sup.10), —C(═O).sub.2R.sup.15, —N═S(═O)(R.sup.14).sub.2.sub.2 and 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, cyano, hydroxy, C.sub.1-C.sub.2-alkoxy, C.sub.3-C.sub.4-cycloalkyl, and —N(R.sup.9)(R.sup.10); R.sup.3 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, C.sub.1-C.sub.4-alkoxy, cyano, and hydroxy; R.sup.4 is a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkyl)-, C.sub.1-C.sub.4-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkoxy)-, C.sub.3-C.sub.5-cycloalkyloxy, hydroxy, —N(R.sup.9)(R.sup.10), —N(R.sup.18)(R.sup.19), —P(═O)(R.sup.14).sub.2, 4- to 7-membered heterocycloalkyl, and (4- to 7-membered heterocycloalkyl)oxy, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group; R.sup.5 represents is selected from the group consisting of a hydrogen atom, a halogen atom, S(═O).sub.2R.sup.14, cyano, —N(R.sup.9)(R.sup.10), —N═S(═O)(R.sup.14).sub.2, and —P(═O)(R.sup.14).sub.2; R.sup.6 is a hydrogen atom; R.sup.7 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; R.sup.8 is a methyl group; R.sup.9 and R.sup.10 is a hydrogen atom or C.sub.1-C.sub.4-alkyl group, or R.sup.9 and R.sup.10 together with the nitrogen to which they are attached form a nitrogen containing 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said nitrogen containing 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, and oxo; R.sup.14 is a C.sub.1-C.sub.4-alkyl group; R.sup.15 is C.sub.1-C.sub.4-alkyl group; R.sup.16 is a hydrogen atom or a methyl group; R.sup.17 is a hydroxy group; R.sup.18 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; R.sup.19 is a 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, with a C.sub.1-C.sub.4-alkyl group, and wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group; o is 1; and p is 0, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

5. The compound according to claim 1, wherein: n is selected from the group consisting of 1, 2, and 3; X is selected from the group consisting of —O—, —S—, *-(C(R.sup.16)(R.sup.17)).sub.o-#, *—O—C(R.sup.16).sub.2—(C(R.sup.16)(R.sup.17)).sub.p-#, and *-(C(R.sup.16)(R.sup.17)).sub.p—C(R.sup.16).sub.2—O—#, wherein * indicates the point of attachment to R.sup.2 and #indicates the point of attachment to the pyrrolidine, piperidine, azepane moiety; R.sup.1 is selected from the group consisting of cyano, —C(═O)NH.sub.2, —C(═O)N(H)CH.sub.3, —C(═O)N(CH.sub.3).sub.2, and —C(═O)OR.sup.15; R.sup.2 is selected from the group consisting of phenyl, naphthyl, and 5- to 10-membered heteroaryl, wherein 5- to 10-membered heteroaryl group is selected from the group consisting of pyridinyl, pyrimidinyl, 1,2-benzoxazolyl, 1,3-benzoxazolyl, and 1,3-benzothiazolyl, wherein phenyl, naphthyl, and 5- to 10-membered heteroaryl group is optionally substituted, one, two, three, or four times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkoxy)-, C.sub.1-C.sub.4-haloalkoxy, —SR.sup.14, —S(═O)R.sup.14, —S(═O).sub.2R.sup.14, nitro, cyano, hydroxy, —N(R.sup.9)(R.sup.10), —C(═O)N(R.sup.9)(R.sup.10), —C(═O).sub.2R.sup.15, —N═S(═O)(R.sup.14).sub.2.sub.2 and 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl group is optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C.sub.1-C.sub.2-alkyl group; R.sup.3 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, C.sub.1-C.sub.4-alkoxy, cyano, and hydroxy; R.sup.4 is selected from the group consisting of a hydrogen atom, a halogen atom, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkyl)-, C.sub.1-C.sub.4-alkoxy, (C.sub.1-C.sub.2-alkoxy)-(C.sub.1-C.sub.4-alkoxy)-, C.sub.3-C.sub.5-cycloalkyloxy, hydroxy, —N(R.sup.9)(R.sup.10), —N(R.sup.18)(R.sup.19), —P(═O)(R.sup.14).sub.2, 4- to 7-membered heterocycloalkyl, and (4- to 7-membered heterocycloalkyl)oxy, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group; R.sup.5 is selected from the group consisting of a hydrogen atom, a halogen atom, S(═O).sub.2R.sup.14, cyano, —N(R.sup.9)(R.sup.10), —N═S(═O)(R.sup.14).sub.2, and —P(═O)(R.sup.14).sub.2; R.sup.6 is a hydrogen atom; R.sup.7 is a hydrogen atom or C.sub.1-C.sub.4-alkyl group; R.sup.8 represents a methyl group, R.sup.9 and R.sup.10 are each independently a hydrogen atom or C.sub.1-C.sub.4-alkyl group, or R.sup.9 and R.sup.10 together with the nitrogen to which they are attached form a nitrogen containing 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group, wherein said nitrogen containing 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.4-alkyl, and oxo; R.sup.14 is a C.sub.1-C.sub.4-alkyl group; R.sup.15 C.sub.1-C.sub.4-alkyl group; each R.sup.16 is independently a hydrogen atom or a methyl group; R.sup.17 is a hydroxy group; R.sup.18 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; R.sup.19 is a 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group; o is 1; and p is 0, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

6. The compound according to claim 1, wherein: n is selected from the group consisting of 1, 2, and 3; X is selected from the group consisting of —O—, —S—, —CH.sub.2—, —CH(OH)—, *—OCH.sub.2-#, *-CH.sub.2O—#, and *-CH(CH.sub.3)O—#, wherein * indicates the point of attachment to R.sup.2 and #indicates the point of attachment to the pyrrolidine, piperidine, or azepane moiety; R.sup.1 is cyano or —C(═O)NH.sub.2; R.sup.2 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, 1,2-benzoxazol-6-yl, 1,3-benzoxazol-4-yl, and 1,3-benzothiazol-2-yl, wherein R.sup.2 is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, cyclopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, difluoromethoxy, trifluormethoxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, nitro, cyano, amino, dimethylamino, azetidin-1-yl, 2-oxopyrrolidin-1-yl, 3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-oxopiperidin-1-yl, 4-methyl-2-oxopiperazin-1-yl, morpholino-4-yl, 3-methyl-2-oxoimidazolidin-1-yl, 3-methyl-2-oxo-1,3-diazinan-1-yl, carbamoyl, dimethylcarbamoyl, ethoxycarbonyl, [dimethyl(oxido)-λ.sup.6-sulfanylidene]amino, 1H-imidazol-1-yl, 1-methyl-1H-pyrazol-4-yl, and 1H-1,2,4-triazol-1-yl; R.sup.3 is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, cyclopropyl, methoxy, cyano, and hydroxy; R.sup.4 is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, cyclopropyl, 2-methoxyethyl, methoxy, propoxy, 2-methoxyethoxy, cyclopropyloxy, hydroxy, 2-oxopyrrolidin-1-yl, 4-methylpiperazin-1-yl, methyl(tetrahydrofuran-3-yl)amino, dimethylphosphoryl, oxetan-3-yl, (oxetan-3-yl)oxy, tetrahydrofuranyl-3-oxy, (tetrahydro-2H-pyran-3-yl)oxy, and (tetrahydro-2H-pyran-4-yl)oxy; R.sup.5 is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methanesulfonyl, cyano, 2-oxopyrrolidin-1-yl, [dimethyl(oxido)-λ.sup.6-sulfanylidene]amino, and dimethylphosphoryl; R.sup.6 is a hydrogen atom; R.sup.7 is a hydrogen atom or a methyl group; and R.sup.8 is a methyl group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

7. The compound according to claim 1, wherein the compound is selected from the group consisting of: 1-methyl-4-[4-(4-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-[4-(3-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(3-methoxyphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(3-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-bromophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(2-methoxyphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; ethyl 4-{[1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]oxy}benzoate; 1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-[4-(2-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-{4-[3-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(2-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-{4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-{4-[4-(2-oxopyrrolidin-1-yl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[4-(1H-imidazol-1-yl)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-{4-[4-(morpholin-4-yl)phenoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-{4-[4-(3-methyl-2-oxo-1,3-diazinan-1-yl)phenoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-{4-[4-(3-methyl-2-oxoimidazolidin-1-yl)phenoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-{4-[4-(2-oxopiperidin-1-yl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-{4-[4-(4-methyl-2-oxopiperazin-1-yl)phenoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-{4-[4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{[1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]oxy}-N,N-dimethylbenzamide; 4-{4-[(1,3-benzoxazol-4-yl)oxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-(4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}piperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(1,2-benzoxazol-6-yl)oxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-{[dimethyl(oxo)-λ.sup.6-sulfanylidene]amino}phenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(2-methoxy-4-methylphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-cyanophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(2-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(2-cyanophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{[1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]oxy}benzamide; 1-methyl-2-oxo-4-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-cyclopropylphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[4-(difluoromethoxy)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-[4-methyl-4-(4-nitrophenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-aminophenoxy)-4-methylpiperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-bromophenoxy)-4-methylpiperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[4-(methanesulfonyl)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[4-(2-methoxyethoxy)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[4-(dimethylamino)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-methoxyphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-(4-{4-[(propan-2-yl)oxy]phenoxy}piperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carboxamide; 4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; ethyl 4-{[1-(3-carbamoyl-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]oxy}benzoate; 4-{4-[4-(difluoromethoxy)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile; 7-bromo-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile; 7-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile; 7-bromo-4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 7-bromo-4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 7-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 7-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 7-bromo-4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 7-bromo-1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 7-hydroxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 7-fluoro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 7-chloro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-chlorophenoxy)piperidin-1-yl]-7-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 7-methoxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1,7-dimethyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 7-cyclopropyl-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile; 7-butoxy-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile; 7-(cyclopropyloxy)-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile; 7-methoxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-7-(oxetan-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-7-(oxetan-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(3-chlorophenoxy)piperidin-1-yl]-7-(2-methoxyethyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-chlorophenoxy)piperidin-1-yl]-7-(2-methoxyethyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 7-(2-methoxyethyl)-1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-7-(oxetan-3-yl)-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 7-(dimethylphosphoryl)-1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 7-(dimethylphosphoryl)-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-7-(4-methylpiperazin-1-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 7-(2-methoxyethoxy)-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 7-cyclopropyl-1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1,7-dimethyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile[[,]]; 7-methoxy-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile; 7-methoxy-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile; 4-(4-benzylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(4-fluorophenyl)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(1,3-benzothiazol-2-yl)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(2-methoxyphenyl)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(4-cyanophenyl)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carboxamide; 4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-1,2-dihydroquinoline-3-carboxamide; 7-chloro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carboxamide; 7-fluoro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carboxamide; (rac)-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]azepan-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-{(4S)-4-[4-(trifluoromethoxy)phenoxy]azepan-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-{(4R)-4-[4-(trifluoromethoxy)phenoxy]azepan-1-yl}-1,2-dihydroquinoline-3-carbonitrile; (rac)-4-[4-(4-bromophenoxy)azepan-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; (rac)-4-{4-[4-(azetidin-1-yl)phenoxy]azepan-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; (rac)-1-methyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)phenoxy]azepan-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(benzyloxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-{4-[(4-methylphenyl)methoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-{4-[(3-methylphenyl)methoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(4-methoxyphenyl)methoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(4-fluorophenyl)methoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(2-fluorophenyl)methoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; (rac)-1-methyl-2-oxo-4-{4-[1-phenylethoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(3-fluorophenyl)methoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-4-{4-[(2-methylphenyl)methoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(3-methoxyphenyl)methoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(4-chlorophenoxy)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(2-methoxyphenyl)methoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-[4-(phenoxymethyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(3-chlorophenoxy)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-{4-[(2-chlorophenoxy)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(benzyloxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 1-methyl-4-{4-[(4-methylphenyl)methoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carboxamide; 1-methyl-4-{4-[(3-methylphenyl)methoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carboxamide; 1-methyl-4-{4-[(2-methylphenyl)methoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carboxamide; 4-{4-[(3-methoxyphenyl)methoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 4-{4-[(2-fluorophenyl)methoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 4-{4-[(4-fluorophenyl)methoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 4-{4-[(3-fluorophenyl)methoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 8-fluoro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 8-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 8-chloro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3,8-dicarbonitrile; 1-methyl-2-oxo-8-(2-oxopyrrolidin-1-yl)-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 8-{[dimethyl(oxo)-λ.sup.6-sulfanylidene]amino}-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 8-(dimethylphosphoryl)-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 8-(methanesulfonyl)-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 6-bromo-4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 6-bromo-4-[4-(3-methoxyphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 6-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 6-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(4-fluorophenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1,6-dimethyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile; 1,6-dimethyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3,6-dicarbonitrile; 1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3,6-dicarbonitrile; 4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3,6-dicarbonitrile 6-cyclopropyl-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile; 6-cyclopropyl-4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1,6-dimethyl-4-[4-(3-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 1,6-dimethyl-4-[4-(2-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(2-chlorophenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(3-methoxyphenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(2-methoxy-4-methylphenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(2-methoxyphenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 4-[4-(2-cyanophenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile; 6-methoxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 6-chloro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 1,6-dimethyl-4-[4-(3-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide; 4-[4-(3-methoxyphenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 1,6-dimethyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carboxamide; 4-[4-(2-methoxy-4-methylphenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 4-[4-(2-methoxyphenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 4-[4-(2-chlorophenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carboxamide; 8-chloro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carboxamide; 6-fluoro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carboxamide; 6-fluoro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 6-hydroxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; 8-bromo-1,6-dimethyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile; and 8-bromo-4-[4-(3-chlorophenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

8. A method for treatment or prophylaxis of a disease, comprising administering a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.

9. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

10. A pharmaceutical combination comprising: one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof, and one or more further active ingredients.

11-14. (canceled)

15. The method of claim 8, wherein the disease is cancer, a condition with dysregulated immune response, or a disorder associated with aberrant DGKα signalling.

16. The pharmaceutical combination of claim 10, wherein the one or more further active ingredients comprises an immune checkpoint inhibitor.

17. The pharmaceutical combination of claim 10, wherein the immune checkpoint inhibitor is an aPD-1/L-1 axis antagonist.

18. The pharmaceutical combination of claim 10, wherein the immune checkpoint inhibitor is an inhibitor of DKGζ.

Description

DESCRIPTION OF THE FIGURES

[1493] FIG. 1: human DGKα M1 to S735 plus C-terminal Flag-Tag, DGKα_hu_1, as described under SEQ ID No. 1.

[1494] FIG. 2: human DGKα M1 to S735 plus N-terminal Avi-Tag and C-terminal Flag-Tag, DGKα_hu_1Avi, as described under SEQ ID No. 2.

[1495] FIG. 3: SIINFEKL amino acid sequence, as described under SEQ ID No. 3.

[1496] FIG. 4: GCCACC DNA sequence

[1497] FIG. 5: Flag-Tag sequence, as described under SEQ ID No. 4.

[1498] FIG. 6: OVA-30 peptide sequence, as described under SEQ ID No. 5.

EXPERIMENTAL SECTION

[1499] NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. The multiplicities are stated according to the signal form which appears in the spectrum, NMR-spectroscopic effects of a higher order were not taken into consideration. Multiplicity of the NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, spt=septed, br=broad signal, m=multiplet. NMR signals: shift in [ppm]. Combinations of multiplicity could be e.g. dd=doublet from doublet.

[1500] Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.

[1501] Table 1 lists the abbreviations used in this paragraph and in the examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.

TABLE-US-00001 TABLE 1 Abbreviations ACN acetonitrile AcOH acetic acid BOC tert-butoxycarbonyl CDCl3 deuterochloroform CFSE carboxyfluorescein succinimidyl ester DAD diode array detector DMF N,N-dimethylformamide DMSO-d6 deuterated dimethyl sulphoxide DMSO dimethyl sulphoxide ELSD evaporative light scattering detector ESIpos electrospray ionization positive Expl. Example h hour/hours HATU (7-aza-1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate HBTU O-benzotriazole-N,N,N′,N′- tetramethyluronium hexafluorophosphate HPLC high-pressure liquid chromatography LCMS liquid chromatography coupled with mass spectrometry LPS lipopolysaccharide mL milliliter min. minute(s) MTBE methyl tert-butyl ether PBMC peripheral blood mononuclear cells PyBOP (benzotriazol-1-yl)oxytripyrrolidinophosphonium hexafluorophosphate RP-HPLC reverse-phase high-pressure liquid chromatography rt room temperature Rt retention time sat. saturated T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide THF tetrahydrofurane TFA trifluoroacetic acid TLC thin layer chromatography TNFα tumour necrosis factor alpha μM micromolar UPLC Ultra high performance chromatography

[1502] The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

[1503] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

EXPERIMENTAL SECTION—GENERAL PART

[1504] All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

[1505] The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4© or Isolera Four®) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier system equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[1506] In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

Chromatographic Conditions

[1507] LC-MS (Method 1): Instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC BEH C18 1.7 μm, 50×2.1 mm; eluent A: water+0.1 vol. % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min. 1-99% B, 1.6-2.0 min. 99% B; flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

[1508] LC-MS (Method 2): Instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC BEH C18 1.7 μm, 50×2.1 mm; eluent A: water+0.2 vol. % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min. 1-99% B, 1.6-2.0 min. 99% B; flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

[1509] LC-MS (Method 3): Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 18 1.7 μm, 50×2.1 mm; eluent A: water+0.05 vol. % formic acid (99%); eluent B: acetonitrile+0.05 vol. % formic acid (99%); gradient: 0-1.7 min. 2-90% B, 1.7-2.0 min. 90% B; flow 1.2 ml/min; temperature: 60° C.; DAD scan: 190-400 nm.

[1510] LC-MS (Method 4): Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 18 1.7 μm, 50×2.1 mm; eluent A: water+0.05 vol. % formic acid (99%); eluent B: acetonitrile+0.05 vol. % formic acid (99%); gradient: 0-1.7 min. 2-90% B, 1.7-2.0 min. 90% B; flow 1.2 ml/min; temperature: 60° C.; DAD scan: 190-400 nm.

EXPERIMENTAL SECTION—INTERMEDIATES

Intermediate 1

4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1511] ##STR00051##

[1512] A suspension of 800 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (3.66 mmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 444 mg piperidin-4-ol (4.39 mmol, CAS 5382-16-1) and 1.9 mL N,N-diisopropylethylamine (11 mmol) in 18 mL 2-propanol was stirred for 2 h at 90° C. The mixture was cooled down to rt, water was added, the precipitate was collected by filtration, washed with ethanol and dried in vacuum. 820 mg of the title compound were obtained (75% yield, 95% purity).

[1513] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.66 (m, 2H), 1.96 (m, 2H), 3.41 (m, 2H), 3.56 (s, 3H), 3.72 (m, 2H), 3.84 (m, 1H), 4.89 (d, 1H), 7.34 (m, 1H), 7.56 (m, 1H), 7.70 (m, 1H), 7.82 (m, 1H).

[1514] LC-MS (Method 1): R.sub.t=0.79 min; MS (ESIpos): m/z=284 [M+H].sup.+

Intermediate 2

tert-butyl 4-[(methanesulfonyl)oxy]piperidine-1-carboxylate

[1515] ##STR00052##

[1516] To 10.0 g tert-butyl 4-hydroxypiperidine-1-carboxylate (49.7 mmol, CAS 109384-19-2) and 15 mL triethylamine (110 mmol) in 150 mL THF at 0° C. was added carefully 4.2 mL methanesulfonyl chloride (55 mmol) and the mixture was stirred 5 h at 0° C. The mixture was poured into an aqueous solution of bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with water, dried and concentrated under reduced pressure to give 13.8 g of the title compound (95% purity, 94% yield).

[1517] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.40 (s, 9H), 1.61 (m, 2H), 1.90 (m, 2H), 3.17 (m, 5H), 3.61 (m, 2H), 4.82 (m, 1H).

Intermediate 3

tert-butyl 4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]piperidine-1-carboxylate

[1518] ##STR00053##

[1519] A mixture of 500 mg tert-butyl 4-[(methanesulfonyl)oxy]piperidine-1-carboxylate (1.79 mmol, intermediate 2), 346 mg 4-(1H-1,2,4-triazol-1-yl)phenol (2.15 mmol, CAS 68337-15-5) and 1.17 g cesium carbonate (3.58 mmol) in 10 mL DMF was stirred for 6 h at 90° C. The mixture was poured into an aqueous solution of bicarbonate carbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with water, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 250 mg of the title compound (98% purity, 40% yield).

[1520] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.40 (s, 9H), 1.53 (dtd, 2H), 1.92 (m, 2H), 3.18 (m, 2H), 3.67 (m, 2H), 4.63 (m, 1H), 7.15 (m, 2H), 7.75 (m, 2H), 8.18 (s, 1H), 9.16 (s, 1H).

[1521] LC-MS (Method 2): R.sub.t=1.16 min; MS (ESIpos): m/z=245.5 [M+H].sup.+

Intermediate 4

4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]piperidine

[1522] ##STR00054##

[1523] To a solution of 250 mg tert-butyl 4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]piperidine-1-carboxylate (726 μmol, intermediate 3) in 10 mL dichloromethane was added 1.1 mL trifluoroacetic acid (15 mmol) and the mixture was stirred for 2 h at rt. The mixture was concentrated under reduced pressure and the residue was diluted with toluene. The solvent was evaporated to give 200 mg TFA salt of the title compound (98% purity, 111% yield).

[1524] LC-MS (Method 2): R.sub.t=0.74 min; MS (ESIpos): m/z=245.2 [M+H].sup.+

Intermediate 5

tert-butyl 4-[4-(2-oxopyrrolidin-1-yl)phenoxy]piperidine-1-carboxylate

[1525] ##STR00055##

[1526] A mixture of 500 mg tert-butyl 4-[(methanesulfonyl)oxy]piperidine-1-carboxylate (1-79 mmol, intermediate 2), 381 mg 1-(4-hydroxyphenyl)pyrrolidin-2-one (2.15 mmol, CAS 7517-07-9) and 1.17 g cesium carbonate (3.58 mmol) in 10 mL DMF was stirred for 5 h at 90° C. The mixture was poured into an aqueous solution of bicarbonate and extracted with ethyl acetate (2×). The combined organic phases were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 310 mg of the title compound (98% purity, 46% yield). 1H NMR (DMSO-d6, 400 MHz): δ=7.49-7.57 (m, 2H), 6.91-7.03 (m, 2H), 4.43-4.59 (m, 1H), 3.73-3.82 (m, 2H), 3.55-3.69 (m, 2H), 3.09-3.23 (m, 2H), 2.41-2.48 (m, 2H), 1.95-2.12 (m, 2H), 1.81-1.93 (m, 2H), 1.44-1.54 (m, 2H), 1.40 ppm (s, 9H).

[1527] LC-MS (Method 2): R.sub.t=1.19 min; MS (ESIpos): m/z=362 [M+H].sup.+

Intermediate 6

1-{4-[(piperidin-4-yl)oxy]phenyl}pyrrolidin-2-one

[1528] ##STR00056##

[1529] To a solution of 310 mg tert-butyl 4-[4-(2-oxopyrrolidin-1-yl)phenoxy]piperidine-1-carboxylate (860 μmol, intermediate 5) in 10 mL dichloromethane was added 1.3 mL trifluoroacetic acid (17 mmol) and the mixture was stirred for 2 h at rt. The mixture was concentrated under reduced pressure and the residue was diluted with toluene. The solvent was evaporated to give 300 mg TFA salt of the title compound (98% purity, 120% yield).

[1530] LC-MS (Method 2): R.sub.t=0.79 min; MS (ESIpos): m/z=261.2 [M+H].sup.+

Intermediate 7

tert-butyl 4-[4-(morpholin-4-yl)phenoxy]piperidine-1-carboxylate

[1531] ##STR00057##

[1532] A mixture of 750 mg tert-butyl 4-bromopiperidine-1-carboxylate (2.84 mmol, CAS 180695-79-8), 509 mg 4-(morpholin-4-yl)phenol (2.84 mmol, CAS 6291-23-2) and 1.85 g cesium carbonate (5.68 mmol) in 20 mL DMF was stirred for 6 h at 90° C. and 5 h at 100° C. The mixture was stirred in water and ethyl acetate. The organic phase was washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 80 mg of the title compound (80% purity, 6% yield).

[1533] .sup.1H NMR (DMSO-d.sub.6) δ: 6.86 (s, 4H), 4.33-4.46 (m, 1H), 3.68-3.75 (m, 4H), 3.56-3.66 (m, 2H), 3.08-3.21 (m, 2H), 2.93-3.01 (m, 4H), 1.78-1.89 (m, 2H), 1.43-1.52 (m, 2H), 1.36-1.41 (m, 9H). LC-MS (Method 2): R.sub.t=1.32 min; MS (ESIpos): m/z=363.3 [M+H].sup.+

Intermediate 8

4-{4-[(piperidin-4-yl)oxy]phenyl}morpholine

[1534] ##STR00058##

[1535] To a solution of 12 mg tert-butyl 4-[4-(morpholin-4-yl)phenoxy]piperidine-1-carboxylate (33 μmol, intermediate 7) in 3 mL dichloromethane was added 51 μL trifluoroacetic acid (660 μmol) and the mixture was stirred for 2 h at rt. The mixture was concentrated under reduced pressure and the residue was diluted with toluene. The solvent was evaporated to give 10 mg of title compound (85% purity, 98% yield).

[1536] LC-MS (Method 2): R.sub.t=0.88 min; MS (ESIpos): m/z=263.8 [M+H].sup.+

Intermediate 9

tert-butyl 4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}piperidine-1-carboxylate

[1537] ##STR00059##

[1538] A mixture of 500 mg tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.79 mmol, intermediate 2), 352 mg 2-(trifluoromethyl)pyrimidin-5-ol (2.15 mmol, CAS 100991-09-1) and 1.17 g cesium carbonate (3.58 mmol) in 10 mL DMF was stirred for 5 h at 90° C. The mixture was poured into an aqueous solution of bicarbonate carbonate and extracted with ethyl acetate (2×). The combined organic phases were washed with brine, dried and concentrated under reduced pressure to give 470 mg of the title compound (80% purity, 60% yield).

[1539] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.40 (s, 9H); 1.53-1.65 (m, 2H); 1.94-2.02 (m, 2H); 3.14-3.26 (m, 2H); 3.62-3.73 (m, 2H); 4.87-4.97 (m, 1H); 8.81 (s, 2H).

[1540] LC-MS (Method 2): R.sub.t=1.29 min; MS (ESIpos): m/z=292.4 [M+H].sup.+

Intermediate 10

5-[(piperidin-4-yl)oxy]-2-(trifluoromethyl)pyrimidine

[1541] ##STR00060##

[1542] To a solution of 470 mg tert-butyl 4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}piperidine-1-carboxylate (1.35 mmol, intermediate 9) in 15 mL dichloromethane was added 2.1 mL trifluoroacetic acid (27 mmol) and the mixture was stirred for 2 h at rt. The mixture was concentrated under reduced pressure and the residue was diluted with toluene. The solvent was evaporated to give 400 mg of title compound (80% purity, 96% yield).

[1543] LC-MS (Method 2): R.sub.t=0.89 min; MS (ESIpos): m/z=248.1 [M+H].sup.+

Intermediate 11

tert-butyl 4-[4-(difluoromethoxy)phenoxy]piperidine-1-carboxylate

[1544] ##STR00061##

[1545] To 500 μL 4-(difluoromethoxy)phenol (3.9 mmol, CAS 87789-47-7) in 15 mL DMF at 0° C. was added 343 mg sodium hydride (60% in mineral oil, 8.58 mmol) and the mixture was stirred for 30 min. at 0° C. A solution of 1.49 g of tert-butyl 4-[(methanesulfonyl)oxy]piperidine-1-carboxylate (5.07 mmol, intermediate 2) in 15 mL DMF was added dropwise and the mixture was stirred for 65 h at 80° C. The mixture was cooled down to rt, water was added and concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: water (0.2 vol. % ammonia 32%)/acetonitrile-gradient) to give 633 mg of the title compound (100% purity, 47% yield).

[1546] .sup.1H NMR (DMSO-d.sub.6) δ: 7.06-7.17 (m, 1H), 6.97-7.05 (m, 1H), 6.87-7.34 (m, 3H), 4.43-4.58 (m, 1H), 3.56-3.72 (m, 2H), 3.05-3.26 (m, 2H), 1.82-1.95 (m, 2H), 1.43-1.57 (m, 2H), 1.35-1.43 (m, 9H).

[1547] LC-MS (Method 2): R.sub.t=1.42 min; MS (ESIpos): m/z=288 [M+H].sup.+

Intermediate 12

4-[4-(difluoromethoxy)phenoxy]piperidine, salt with hydrochloric acid

[1548] ##STR00062##

[1549] To a solution of 694 mg tert-butyl 4-[4-(difluoromethoxy)phenoxy]piperidine-1-carboxylate (2.02 mmol, intermediate 11) in 35 mL methanol was added 5.1 mL hydrogen chloride (4.0 M in dioxane, 20 mmol) and the mixture was stirred for 4 h at rt. The mixture was concentrated under reduced pressure and dried in vacuum to give 566 mg of the title compound (100% purity, 100% yield).

[1550] LC-MS (Method 2): R.sub.t=1.02 min; MS (ESIpos): m/z=244.2 [M+H].sup.+

Intermediate 13

tert-butyl 4-methyl-4-(4-nitrophenoxy)piperidine-1-carboxylate

[1551] ##STR00063##

[1552] To a suspension of 92.9 mg sodium hydride (60% in mineral oil, 2.32 mmol) in 2.5 mL THF at 0° C. was added 250 mg tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1.16 mmol, CAS 406235-30-1) solved in 5 mL THF and the mixture was stirred for 15 min. at 0° C. 46 mg 1-fluoro-4-nitrobenzene (1.74 mmol, CAS 350-46-9) solved in 2 mL THF was added dropwise and the mixture was stirred for 6 h at 70° C. After cooling to rt, water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-10%) to give 290 mg of the title compound (95% purity, 71% yield).

[1553] .sup.1H NMR (DMSO-d.sub.6) δ: 8.12-8.19 (m, 2H); 7.20-7.32 (m, 2H); 3.51-3.69 (m, 2H); 3.00-3.28 (m, 2H); 1.90-2.04 (m, 2H); 1.57-1.73 (m, 2H); 1.42-1.45 (m, 3H); 1.36-1.41 (m, 9H).

Intermediate 14

4-methyl-4-(4-nitrophenoxy)piperidine, salt with trifluoroacetic acid

[1554] ##STR00064##

[1555] To a solution of 275 mg tert-butyl 4-methyl-4-(4-nitrophenoxy)piperidine-1-carboxylate (818 μmol, intermediate 13) in 5.3 mL dichloromethane was added 630 μL trifluoroacetic acid (8.2 mmol) and the mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure and the residue was diluted with toluene. The solvent was evaporated to give 280 mg TFA salt of the title compound (95% purity, 138% yield).

[1556] .sup.1H NMR (DMSO-d.sub.6) δ: 8.41-8.61 (m, 1H), 8.16-8.24 (m, 2H), 7.26-7.34 (m, 2H), 3.02-3.26 (m, 4H), 2.12-2.22 (m, 2H), 1.81-1.94 (m, 2H), 1.41-1.48 (m, 3H).

[1557] LC-MS (Method 2): R.sub.t=1.00 min; MS (ESIpos): m/z=237.2 [M+H].sup.+

Intermediate 15

tert-butyl 4-[4-(methanesulfonyl)phenoxy]piperidine-1-carboxylate

[1558] ##STR00065##

[1559] To a suspension of 100 mg tert-butyl 4-hydroxypiperidine-1-carboxylate (497 μmol, CAS 109384-19-2), 94.1 mg 4-(methanesulfonyl)phenol (547 μmol, CAS 14763-60-1) and 143 mg triphenylphosphine (547 μmol) was added 110 μL diisopropyl azodicarboxylate (550 μmol) at 0° C. The mixture was stirred overnight at rt. After that, water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phases were filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-70%). The impure product was purified by flash chromatography again (silica, dichloromethane/methanol gradient 0-20%). The impure product was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 76 mg of the title compound (99% purity, 43% yield).

[1560] .sup.1H NMR (DMSO-d.sub.6) δ: 7.75-7.92 (m, 2H), 7.15-7.26 (m, 2H), 4.66-4.81 (m, 1H), 3.60-3.72 (m, 2H), 3.09-3.25 (m, 5H), 1.87-1.97 (m, 2H), 1.48-1.62 (m, 2H), 1.36-1.45 (m, 9H).

[1561] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=300.1 [M+H].sup.+

Intermediate 16

4-[4-(methanesulfonyl)phenoxy]piperidine

[1562] ##STR00066##

[1563] To a solution of 70 mg tert-butyl 4-[4-(methanesulfonyl)phenoxy]piperidine-1-carboxylate (197 μmol, intermediate 15) in 2 mL dichloromethane was added 380 μL trifluoroacetic acid (4.9 mmol) and the mixture was stirred for 1.5 h at rt. To the mixture was added a solution of sat. sodium bicarbonate and extracted with dichloromethane (3×). The combined organic phases were filtered (using a waterresistant filter) and concentrated under reduced pressure to give 20 mg of the title compound (95% purity, 38% yield).

[1564] .sup.1H NMR (DMSO-d.sub.6) δ: 7.74-7.83 (m, 2H), 7.11-7.22 (m, 2H), 4.50-4.62 (m, 1H), 3.10-3.19 (m, 3H), 2.94 (dt, J=12.8, 4.1 Hz, 2H), 2.54-2.63 (m, 2H), 1.88-1.99 (m, 2H), 1.40-1.53 (in, 2H).

TABLE-US-00002 TABLE 2 Compounds in table 2 were prepared in analogy to intermediate 15. Inter- mediate Structure IUPAC-Name Starting Materials Analytics 17 [00067] tert-butyl 4-[4- (2- methoxyethoxy) phenoxy] piperidine-1- carboxylate tert-butyl 4- hydroxypiperidine-1- carboxylate (CAS 109384-19-2) and 4-(2- methoxyethoxy)phenol (CAS 51980-60-0) .sup.1H NMR (DMSO-d.sub.6) δ: 6.81-6.96 (m, 4H), 4.31-4.47 (m, 1H), 3.98-4.03 (m, 2H), 3.60-3.68 (m, 4H), 3.27-3.31 (m, 3H), 3.06-3.19 (m, 2H), 1.79-1.91 (m, 2H), 1.42-1.51 (m, 2H), 1.36-1.42 (s, 9H). 18 [00068] tert-butyl 4-[4- (dimethylamino) phenoxy] piperidine-1- carboxylate tert-butyl 4- hydroxypiperidine-1- carboxylate (CAS 109384-19-2) and 4- (dimethylamino) phenol (CAS 619-60-3) .sup.1H NMR (DMSO-d.sub.6) δ: 6.80-6.89 (m, 2H), 6.64-6.72 (m, 2H), 4.24-4.39 (m, 1H), 3.62 (ddd, 2H), 3.04-3.22 (m, 2H), 2.76-2.82 (m, 6H), 1.77-1.89 (m, 2H), 1.46 (dtd, 2H), 1.40 (s, 9H). 19 [00069] tert-butyl 4-(4- methoxyphenoxy) piperidine-1- carboxylate tert-butyl 4- hydroxypiperidine-1- carboxylate (CAS 109384-19-2) and 4- methoxyphenol (CAS 150-76-5) .sup.1H NMR (DMSO-d.sub.6) δ: 6.80-6.94 (m, 4H), 4.39 (tt, J = 7.9, 3.7 Hz, 1H), 3.58- 3.72 (m, 5H), 3.04- 3.28 (m, 2H), 1.79- 1.93 (m, 2H), 1.43- 1.52 (m, 2H), 1.38- 1.42 (s, 9H). 20 [00070] tert-butyl 4-{4- [(propan-2- yl)oxy]phenoxy} piperidine-1- carboxylate tert-butyl 4- hydroxypiperidine-1- carboxylate (CAS 109384-19-2) and 4- isopropoxyphenol (CAS 7495-77-4) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.22 (d, 6H), 1.40 (s, 9H), 1.47 (dtd, 2H), 1.79- 1.91 (m, 2H), 3.14 (br t, 2H), 3.58- 3.71 (m, 2H), 4.38 (tt, 1H), 4.42-4.52 (m, 1H), 6.78-6.84 (m, 2H), 6.85-6.90 (m, 2H).

TABLE-US-00003 TABLE 3 synthesis in analogy to intermediate 16. Inter- Starting mediate Structure IUPAC-Name Materials Analytics 21 [00071] 4-[4-(2- methoxyethoxy) phenoxy] piperidine tert-butyl 4-[4-(2- methoxyethoxy) phenoxy]piperidine-1- carboxylate (intermediate 17) .sup.1H NMR (DMSO-d.sub.6) δ: 6.81-6.94 (m, 4H), 4.30-4.39 (m, 1H), 3.97-4.05 (m, 2H), 3.58-3.65 (m, 2H), 3.00-3.09 (m, 2H), 2.70-2.81 (m, 2H), 1.85-2.00 (m, 2H), 1.46-1.61 (m, 2H), 1.16-1.19 (m, 3H). 22 [00072] N,N-dimethyl-4- [(piperidin-4- yl)oxy]aniline tert-butyl 4-[4- (dimethylamino) phenoxy]piperidine-1- carboxylate (intermediate 18) .sup.1H NMR (DMSO-d.sub.6) δ: 6.77-6.89 (m, 2H), 6.65-6.71 (m, 2H), 4.69-4.86 (m, 2H), 4.19-4.34 (m, 1H), 2.99-3.12 (m, 2H), 2.78-2.83 (m, 6H), 2.70-2.78 (m, 2H), 1.85-1.96 (m, 2H), 1.49-1.61 (m, 2H). 23 [00073] 4-(4- methoxyphenoxy) piperidine tert-butyl 4-(4- methoxyphenoxy) piperidine-1- carboxylate (intermediate 19) .sup.1H NMR (DMSO-d.sub.6) δ: 6.80-6.97 (m, 4H), 4.30-4.44 (m, 1H), 3.69 (s, 3H), 3.04- 3.14 (m, 2H), 2.76- 2.88 (m, 2H), 1.89- 2.00 (m, 2H), 1.53- 1.67 (m, 2H). 24 [00074] 4-{4-[(propan-2- yl)oxy]phenoxy} piperidine, salt with trifluoroacetic acid tert-butyl 4-(4- isopropoxyphenoxy) piperidine-1- carboxylate (intermediate 20) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.39-8.70 (m, 2 H), 6.88-6.94 (m, 2 H), 6.81-6.87 (m, 2 H), 4.42-4.54 (m, 2 H), 3.23 (br dd, 2 H), 2.99-3.14 (m, 2 H), 2.03 (d quin, 2 H), 1.77 (ddt, 2 H), 1.22 (d, 6 H). LC-MS (Method 2): R.sub.t = 1.11 min; MS (ESIpos): m/z = 236.2 [M + H].sup.+

Intermediate 25

7-bromo-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1565] ##STR00075##

[1566] To a solution of 50 g 7-bromo-2H-3,1-benzoxazine-2,4(1H)-dione (207 mmol, CAS 76561-16-5) and 72 mL N,N-diisopropylethylamine (413 mmol) in 400 mL dimethylacetamide was added 39 mL iodomethane (620 mmol) at rt and the mixture was stirred overnight. The reaction was cooled to 0° C. and 200 mL water was slowly added. The solid that precipitated from this procedure was collected by filtration, washed with water and dried in an oven at 50° C. 48.1 g of the title compound was obtained (91% yield).

[1567] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 3.46 (s, 3H); 7.52 (dd, 1H); 7.70 (d, 1H); 7.90 (d, 1H).

Intermediate 26

7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1568] ##STR00076##

[1569] A solution of 40 g 7-bromo-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (156 mmol, intermediate 25) in 320 mL THF was slowly treated with 170 mL triethylamine (1.2 mol) followed by the addition of 25 mL ethyl cyanoacetate (234 mmol) at rt. The reaction was heated at 60° C. and stirred at that temperature over night. Further 25 mL ethyl cyanoacetate (234 mmol) were added and the reaction was stirred at 70° C. for further 5 h. After cooling to rt, water was added and THF was evaporated in vacuum. The mixture was acidified to pH=1 by addition of hydrochloric acid (2 M) and extracted with ethyl acetate 3 times. The combined organic layers were evaporated in vacuum and the residue was stirred first with hexane, decanted and then stirred with a small amount ethyl acetate/hexane. The residue was filtered and 46 g of the title material was obtained in two crops (106% yield).

[1570] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 3.51 (s, 3H); 6.67 (bs, 1H); 7.46 (dd, 1H); 7.71 (d, 1H); 7.96 (d, 1H).

Intermediate 27

7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1571] ##STR00077##

[1572] A mixture of 16 g 7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (57 mmol, intermediate 26) and 100 mL phosphoric trichloride (1.05 mol) was stirred at 90° C. overnight. After cooling to rt, hexane was added and the reaction was filtered. The solid was washed with sat. sodium bicarbonate solution and water. The obtained residue was dried in an oven at 50° C. overnight to give 13.2 g of the title compound (77% yield).

[1573] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 3.64 (s, 3H); 7.66 (dd, 1H); 7.94-7.98 (m, 2H).

Intermediate 28

7-methoxy-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1574] ##STR00078##

[1575] To a solution of 420 g potassium carbonate in 300 mL DMF was added 235 g 7-methoxy-2H-3,1-benzoxazine-2,4(1H)-dione (1.22 mol, CAS 128076-63-1) and 259 g iodomethane (1.82 mol, 113 ml). The mixture was stirred at 20° C. for 12 h. The reaction was monitored by LC-MS until complete consumption of 7-methoxy-2H-3,1-benzoxazine-2,4(1H)-dione. The reaction mixture was added to ice water (2000 ml), stirred for 0.5 h and filtered and concentrated under vacuum to give 218 g of the title compound (87% yield) as yellow solid.

[1576] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.92 (d, 3H); 6.91 (dd, 1H); 6.83 (d, 1H); 3.93 (s, 3H); 3.45 (s, 3H).

Intermediate 29

4-hydroxy-7-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1577] ##STR00079##

[1578] To a solution of 218 g 7-methoxy-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (intermediate 28) and 159 g ethyl cyanoacetate in 2 L DMF was added 264 g potassium tert-butoxide. The mixture was stirred at 120° C. for 12 h. The reaction mixture was poured into 1000 mL water, extracted with ethyl acetate, the aqueous phase was adjusted pH=2˜3 with 6 M hydrochloric acid (400 ml) and stirred for 1 h at 0° C., then filtered and dried over sodium sulfate and evaporated in vacuum to give 130 g of the title compound (48% yield) as a yellow solid.

[1579] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.03 (d, 1H); 6.96-6.92 (m, 2H); 3.93 (s, 3H); 3.54 (s, 3H).

Intermediate 30

7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1580] ##STR00080##

[1581] A solution of 50 g 4-hydroxy-7-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (intermediate 29) in 430 mL phosphoric trichloride was stirred at 110° C. for 12 h. The solvent was removed in vacuum and to the residue was added 500 mL ice water and stirred for 12 h. The reaction mixture was filtered and concentrated under vacuum to give 47.5 g of the title compound (88% yield) as a brown solid.

[1582] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.97 (d, 1H); 7.11 (dd, 1H); 7.05 (d, 1H); 3.99 (s, 3H); 3.64 (s, 3H).

Intermediate 31

4-chloro-7-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1583] ##STR00081##

[1584] To a solution of 15 g 7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (intermediate 30) in 350 mL dichloromethane at −40° C. was added 117 g boron tribromide (45.0 ml). Then the mixture was stirred at 20° C. for 12 h. The conversion was checked by LC-MS to indicate ˜10% of left starting material. The residue was poured into 6 L ice water and filtered.

[1585] To the reaction mixture was added 1.5 L sat. aqueous sodium bicarbonate solution and the mixture was stirred for 2 h, then the mixture was filtered and dried over sodium sulfate. The solvent was removed in vacuum and to the resulting residue was added 500 mL DMSO. The mixture was stirred for 3 h, then filtered and washed with water (100 ml, 3X), the product was dried in vacuum to give 3.34 g of the title compound (24% yield) as a light brown solid.

[1586] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 11.28 (brs, 1H); 7.89 (d, 1H); 6.94 (dd, 1H); 6.85 (s, 1H); 3.55 (s, 3H).

Intermediate 32

7-fluoro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1587] ##STR00082##

[1588] To a solution of 5 g 7-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione (26.2 mmol, CAS 321-50-6) and 9.1 mL N,N-diisopropylethylamine (52 mmol) in 400 mL DMF was added 4.9 mL iodomethane (79 mmol) and was stirred overnight at rt. To the mixture was added ice water. The solid that precipitated from this procedure was collected by filtration, washed with water and hexane and dried in vacuum to give 3.75 g of the title compound (95% purity, 70% yield).

[1589] .sup.1H NMR (DMSO-d.sub.6) δ: 8.08 (dd, 1H), 7.40 (dd, 1H), 7.19 (td, 1H), 3.44 (s, 3H).

[1590] LC-MS (Method 1): R.sub.t=0.79 min; MS (ESIpos): m/z=196.1 [M+H].sup.+

Intermediate 33

7-fluoro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1591] ##STR00083##

[1592] A suspension of 3.7 g 7-fluoro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (18 mmol, intermediate 32) in 40 mL 2-methyltetrahydrofuran was slowly treated with 20 mL triethylamine (144 mmol) followed by the addition of 7.7 mL ethyl cyanoacetate (72 mmol) and was refluxed for 73 h. After cooling to rt, the solvent was evaporated in vacuum, water and ethyl acetate was added and the mixture was acidified to pH=1 by addition of hydrochloric acid (2 M). The solid that precipitated from this procedure was collected by filtration, washed with water and hexane and dried in vacuum to give 3.09 g of the title compound (100% purity, 73% yield).

[1593] .sup.1H NMR (DMSO-d.sub.6) δ: 8.11 (dd, 1H), 7.37 (dd, 1H), 7.16 (td, 1H), 3.49 (s, 3H).

[1594] LC-MS (Method 1): R.sub.t=0.68 min; MS (ESIneg): m/z=217.1 [M−H].sup.−

Intermediate 34

4-chloro-7-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1595] ##STR00084##

[1596] A mixture of 3 g 7-fluoro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (13.7 mmol, intermediate 33) and 20 mL phosphoric trichloride (208 mmol) was stirred for 67 h at 70° C. and 4 h at 90° C. After cooling to rt, dichloro methane and ice water were added and the mixture was extracted with dichloromethane (3×). The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure to give 2.46 g of the title compound (96% purity, 73% yield).

[1597] .sup.1H NMR (DMSO-d.sub.6) δ: 8.15 (dd, 1H), 7.67 (dd, 1H), 7.35-7.42 (m, 1H), 3.63 (s, 3H).

[1598] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIneg): m/z=235.1 [M−H].sup.−

Intermediate 35

7-chloro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1599] ##STR00085##

[1600] To a solution of 2 g 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (9.82 mmol, CAS 40928-13-0) and 3.4 mL N,N-diisopropylethylamine (20 mmol) in 15 mL DMF was added 1.9 mL iodomethane (29 mmol) and was stirred overnight at rt. To the mixture was added ice water. The solid that precipitated from this procedure was collected by filtration, washed with water and hexane and dried in vacuum to give 2.50 g of the title compound (98% purity, 118% yield).

[1601] .sup.1H NMR (DMSO-d.sub.6) δ: 8.00 (d, 1H), 7.59 (d, 1H), 7.39 (dd, 1H), 3.46 (s, 3H).

[1602] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=212.1 [M+H].sup.+

Intermediate 36

7-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1603] ##STR00086##

[1604] A suspension of 2.5 g 7-chloro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (11.6 mmol, intermediate 35) in 25 mL 2-methyltetrahydrofuran was slowly treated with 13 mL triethylamine (93 mmol) followed by the addition of 4.9 mL ethyl cyanoacetate (46 mmol) and was refluxed for 65 h. After cooling to rt, the solvent was evaporated in vacuum, water/ethyl acetate (1:1) was added and the mixture was acidified to pH=1 by addition of hydrochloric acid (2 M). The solid that precipitated from this procedure was collected by filtration, washed with water, ethyl acetate and hexane and dried in vacuum to give 2.55 g of the title compound (100% purity, 94% yield).

[1605] .sup.1H NMR (DMSO-d.sub.6) δ: 8.05 (d, 1H), 7.59 (d, 1H), 7.34 (dd, 1H), 3.52 (s, 3H).

[1606] LC-MS (Method 2): R.sub.t=0.57 min; MS (ESIneg): m/z=233.1 [M−H].sup.−

Intermediate 37

4,7-dichloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1607] ##STR00087##

[1608] A mixture of 2.48 g 7-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (10.6 mmol, intermediate 36) and 15 mL phosphoric trichloride (160 mmol) was stirred overnight at 90° C. After cooling to rt, dichloromethane (20 ml) and ice water (500 ml) were added and the mixture was extracted with dichloromethane (3×). The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure to give 2.46 g of the title compound (95% purity, 87% yield).

[1609] .sup.1H NMR (DMSO-d.sub.6) δ: 8.07 (d, 1H), 7.85 (d, 1H), 7.55 (dd, 1H), 3.65 (s, 3H).

[1610] LC-MS (Method 1): R.sub.t=1.10 min; MS (ESIpos): m/z=253.1 [M+H].sup.+

Intermediate 38

1,7-dimethyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1611] ##STR00088##

[1612] To a solution of 4.78 g 7-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (27 mmol, CAS 63480-11-5) and 9.4 mL N,N-diisopropylethylamine (54 mmol) in 45 mL DMF was added 5.1 mL iodomethane (81 mmol) and was stirred overnight at rt. To the mixture was added ice water (300 ml). The solid that precipitated from this procedure was collected by filtration, washed with water and hexane and dried in vacuum to give 4.92 g of the title compound (95% purity, 91% yield).

[1613] .sup.1H NMR (DMSO-d.sub.6) δ: 7.89 (d, 1H), 7.29 (s, 1H), 7.15-7.19 (m, 1H), 3.45 (s, 3H), 2.46 (s, 3H).

[1614] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=192.1 [M+H].sup.+

Intermediate 39

4-hydroxy-1,7-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1615] ##STR00089##

[1616] A suspension of 4.8 g 1,7-dimethyl-2H-3,1-benzoxazine-2,4(1H)-dione (25.1 mmol, intermediate 38) in 65 mL 2-methyltetrahydrofuran was slowly treated with 28 mL triethylamine (200 mmol) followed by the addition of 11 mL ethyl cyanoacetate (100 mmol) and was stirred for 113 h at 80° C. After cooling to rt, the solvent was evaporated in vacuum, water/ethyl acetate (200 ml, 1:1) was added and the mixture was acidified to pH=1 by addition of hydrochloric acid (2 M). The solid that precipitated from this procedure was collected by filtration, washed with water, ethyl acetate and hexane and dried in vacuum to give 5.55 g of the title compound (98% purity, 101% yield).

[1617] .sup.1H NMR (DMSO-d.sub.6) δ: 7.97 (d, 1H), 7.38 (s, 1H), 7.16 (dd, 1H), 3.54 (s, 3H), 2.46 (s, 3H).

[1618] LC-MS (Method 1): R.sub.t=0.72 min; MS (ESIpos): m/z=215.2 [M+H].sup.+

Intermediate 40

4-chloro-1,7-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1619] ##STR00090##

[1620] A mixture of 5.45 g 4-hydroxy-1,7-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (24.9 mmol, intermediate 39) and 35 mL phosphoric trichloride (370 mmol) was stirred overnight at 90° C. After cooling to rt, ice water (400 ml) was added and the mixture was extracted with dichloromethane (3×). The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was stirred in dichloromethane and ethanol, the precipitate was collected by filtration, washed with dichloromethane and dried in vacuum. 2.4 g of the title compound were obtained (31% yield, 74% purity).

[1621] .sup.1H NMR (DMSO-d.sub.6) δ: 7.90-7.99 (m, 1H), 7.51-7.62 (m, 1H), 7.31-7.35 (m, 1H), 3.61-3.68 (m, 3H), 2.52-2.54 (m, 3H).

[1622] LC-MS (Method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=233.2 [M+H].sup.+

Intermediate 41

methyl [1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]acetate

[1623] ##STR00091##

[1624] To a suspension of 500 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (2.29 mmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill) and 1.2 mL N,N-diisopropylethylamine (6.9 mmol) in 10 mL 2-propanol was added 431 mg methyl (piperidin-4-yl)acetate (2.74 mmol, CAS 168986-49-0) and the reaction was stirred for 2 h at 90° C. After this time, water was added, the precipitate was collected by filtration, washed with ethanol and dried in vacuum to give 620 mg of the title compound (80% yield).

[1625] .sup.1H NMR (DMSO-d.sub.6) δ: 7.78-7.87 (m, 1H), 7.68-7.77 (m, 1H), 7.50-7.58 (m, 1H), 7.27-7.36 (m, 1H), 3.69-3.79 (m, 2H), 3.60-3.66 (m, 3H), 3.51-3.60 (m, 3H), 3.36-3.43 (m, 2H), 2.35-2.41 (m, 2H), 1.95-2.13 (m, 1H), 1.79-1.87 (m, 2H), 1.45-1.58 (m, 2H).

[1626] LC-MS (Method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=341 [M+H].sup.+

Intermediate 42

[1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]acetic acid

[1627] ##STR00092##

[1628] To 617 mg methyl [1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]acetate (1.82 mmol, intermediate 41) in 50 mL THF and 12 mL ethanol was added 11 mL lithium hydroxide (1.0 M, 11 mmol) and the mixture was stirred for 3 h at rt. The reaction was diluted with water and adjusted to pH=3-4 with hydrogen chloride (4M). The organic solvents were evaporated, the precipitate was collected by filtration, washed with water and dried in vacuum to give 538 mg of the title compound (95% purity, 86% yield).

[1629] .sup.1H NMR (DMSO-d.sub.6) δ: 12.29 (br s, 1H), 7.65-7.90 (m, 2H), 7.46-7.64 (m, 1H), 7.24-7.38 (m, 1H), 3.69-3.80 (m, 2H), 3.57 (s, 3H), 3.38-3.44 (m, 2H), 2.24-2.31 (m, 2H), 1.94-2.11 (m, 1H), 1.81-1.90 (m, 2H), 1.41-1.59 (m, 2H).

[1630] LC-MS (Method 1): R.sub.t=0.89 min; MS (ESIpos): m/z=326 [M+H].sup.+

Intermediate 43

(rac)-tert-butyl 4-[(methanesulfonyl)oxy]azepane-1-carboxylate

[1631] ##STR00093##

[1632] To a solution of 2 g (rac)-tert-butyl 4-hydroxyazepane-1-carboxylate (9.29 mmol, CAS 478832-21-2) and 2.8 mL triethylamine (20 mmol) in 28 mL THF at 0° C. was added slowly 790 μL methanesulfonyl chloride (10 mmol) and the reaction was stirred for 6 h at 0° C. The mixture was poured into an aqueous solution of bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with water and brine, dried and concentrated under reduced pressure to give 2 g of the title compound (95% purity, 70% yield).

[1633] .sup.1H NMR (DMSO-d.sub.6) δ: 4.74-4.85 (m, 1H), 3.28-3.43 (m, 4H), 3.13-3.19 (m, 3H), 1.93-2.03 (m, 1H), 1.73-1.90 (m, 4H), 1.56-1.68 (m, 1H), 1.36-1.43 (m, 9H).

Intermediate 44

(rac)-tert-butyl 4-[4-(trifluoromethoxy)phenoxy]azepane-1-carboxylate

[1634] ##STR00094##

[1635] To a solution of 300 mg (rac)-tert-butyl 4-[(methanesulfonyl)oxy]azepane-1-carboxylate (971 μmol, intermediate 43) and 633 mg cesium carbonate (1.94 mmol) in 10 mL DMF was added 170 μL 4-(trifluoromethoxy)phenol (1.2 mmol, CAS 828-27-3) and the reaction was stirred for 6 h at 90° C. The mixture was poured into an aqueous solution of bicarbonate and extracted with ethyl acetate (2×). The combined organic phases were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-20%) to give 260 mg of the title compound (95% purity, 68% yield).

[1636] .sup.1H NMR (DMSO-d.sub.6) δ: 7.23-7.33 (m, 2H), 6.96-7.04 (m, 2H), 4.44-4.59 (m, 1H), 3.35-3.47 (m, 2H), 3.23-3.32 (m, 1H), 1.92-2.05 (m, 1H), 1.69-1.88 (m, 4H), 1.54-1.65 (m, 1H), 1.38-1.43 (m, 9H).

Intermediate 45

(rac)-4-[4-(trifluoromethoxy)phenoxy]azepane

[1637] ##STR00095##

[1638] To a solution of 255 mg (rac)-tert-butyl 4-[4-(trifluoromethoxy)phenoxy]azepane-1-carboxylate (655 μmol, intermediate 44) in 4.2 mL dichloromethane was added 500 μL trifluoroacetic acid (6.5 mmol) and the mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure and the residue was diluted with toluene. The solvent was evaporated to give 307 mg TFA salt of the title compound (95% purity, 164% yield).

[1639] .sup.1H NMR (DMSO-d.sub.6) δ: 7.25-7.34 (m, 2H), 6.99-7.09 (m, 2H), 4.67-4.76 (m, 1H), 3.08-3.32 (m, 4H), 2.10-2.22 (m, 1H), 1.97-2.07 (m, 2H), 1.80-1.94 (m, 2H), 1.66-1.78 (m, 1H).

[1640] LC-MS (Method 1): R.sub.t=1.26 min; MS (ESIpos): m/z=376.5 [M+H].sup.+

Intermediate 46

(rac)-tert-butyl 4-(4-bromophenoxy)azepane-1-carboxylate

[1641] ##STR00096##

[1642] To a solution of 1 g (rac)-tert-butyl 4-[(methanesulfonyl)oxy]azepane-1-carboxylate (3.24 mmol, intermediate 43) and 2.11 g cesium carbonate (6.48 mmol) in 33 mL DMF was added 708 mg 4-bromophenol (3.89 mmol, CAS 106-41-2) and the reaction was stirred for 3 h at 90° C. The mixture was poured into an aqueous solution of bicarbonate and extracted with ethyl acetate (2×). The combined organic phases were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-15%) to give 540 mg of the title compound (95% purity, 43% yield).

[1643] .sup.1H NMR (DMSO-d.sub.6) δ: 7.35-7.49 (m, 2H), 6.85-6.94 (m, 2H), 4.40-4.59 (m, 1H), 3.34-3.46 (m, 2H), 3.21-3.31 (m, 1H), 1.89-2.03 (m, 1H), 1.66-1.85 (m, 4H), 1.52-1.64 (m, 1H), 1.40 (s, 9H).

Intermediate 47

(rac)-4-(4-bromophenoxy)azepane

[1644] ##STR00097##

[1645] To a solution of 535 mg tert-butyl (rac)-4-(4-bromophenoxy)azepane-1-carboxylate (1.37 mmol, intermediate 46) in 8.8 mL dichloromethane was added 1.1 mL trifluoroacetic acid (14 mmol) and the mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure and the residue was diluted with toluene. The solvent was evaporated to give 550 mg TFA salt of the title compound (95% purity, 141% yield).

[1646] .sup.1H NMR (DMSO-d.sub.6) δ: 7.39-7.56 (m, 2H), 6.86-6.99 (m, 2H), 4.57-4.78 (m, 1H), 3.05-3.30 (m, 4H), 1.63-2.22 (m, 6H).

[1647] LC-MS (Method 2): R.sub.t=1.19 min; MS (ESIpos): m/z=270.4 [M+H].sup.+

Intermediate 48

4-chloro-6-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1648] ##STR00098##

[1649] A mixture of 2.7 g 4-hydroxy-6-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (11.7 mmol, intermediate 68) and 11 mL phosphoric trichloride (120 mmol) was stirred for 10 h at 90° C. After cooling to rt, ice water (2000 ml) w as added carefully and the mixture was adjusted to pH=10 with sodium carbonate. The precipitate was collected by filtration to obtain 2.6 g of a crude solid. This solid was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 700 mg of the title compound (23% yield).

[1650] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 3.66 (s, 3H); 3.89 (s, 3H); 7.42 (d, 1H); 7.56 (dd, 1H); 7.70 (d, 1H).

[1651] LC-MS (Method 2): R.sub.t=0.80 min; MS (ESIpos): m/z=249.3 [M+H].sup.+

Intermediate 49

4,6-dichloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1652] ##STR00099##

[1653] Intermediate 49 was isolated as a by-product of the synthesis of intermediate 48. After flash chromatography (silica, dichloromethane/methanol gradient 0-3%) 180 mg of the title compound (6% yield) were obtained.

[1654] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 4.00 (s, 3H); 7.51 (d, 1H); 7.75 (dd, 1H); 8.06 (d, 1H).

Intermediate 50

4-[4-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1655] ##STR00100##

[1656] To a solution of 800 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (3.00 g, 3.29 mmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III) and 1.7 mL N,N-diisopropylethylamine (9.9 mmol) in 17 mL 2-propanol was added 455 mg (piperidin-4-yl)methanol (3.95 mmol, CAS 6457-49-4) and the reaction was stirred for 2 h at 90° C. After this time, water was added and the precipitate was collected by filtration, washed with ethanol and dried in vacuum to give 920 mg of the title compound (95% purity, 89% yield).

[1657] .sup.1H NMR (DMSO-d.sub.6) δ: 7.78-7.88 (m, 1H), 7.70-7.78 (m, 1H), 7.52-7.60 (m, 1H), 7.28-7.40 (m, 1H), 4.54-4.64 (m, 1H), 3.70-3.85 (m, 2H), 3.28-3.44 (m, 7H), 1.79-1.92 (m, 2H), 1.61-1.76 (m, 1H), 1.36-1.54 (m, 2H).

[1658] LC-MS (Method 1): R.sub.t=0.84 min; MS (ESIpos): m/z=298 [M+H].sup.+

Intermediate 51

8-fluoro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1659] ##STR00101##

[1660] To a suspension of 5 g 8-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione (26.2 mmol, CAS 174463-53-7) in 200 mL DMF at 0° C. was added 2.4 mL iodomethane (39 mmol) and 1.45 g sodium hydride (60% in mineral oil, 39.3 mmol) and the mixture was stirred overnight at rt. After that time, water and ethyl acetate was added and the mixture was extracted with ethyl acetate (2×). The combined organic phases were washed with brine and water, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-25%) to give 2.40 g of the title compound (95% purity, 45% yield).

[1661] .sup.1H NMR (DMSO-d.sub.6) δ: 7.83-7.96 (m, 1H), 7.70-7.80 (m, 1H), 7.27-7.42 (m, 1H), 3.57-3.68 (m, 3H).

Intermediate 52

8-fluoro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1662] ##STR00102##

[1663] A suspension of 2.4 g 8-fluoro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (11.7 mmol, intermediate 51) in 27 mL THF was slowly treated with 13 mL triethylamine (93 mmol) followed by the addition of 1.9 mL ethyl cyanoacetate (18 mmol) and was stirred for 24 h at 70° C. After cooling to rt, the solvent was evaporated in vacuum, ethyl acetate and water were added and the mixture was acidified to pH=1 by addition of hydrochloric acid (2 N). The solid that precipitated from this procedure was collected by filtration, washed with water and ethyl acetate and dried in vacuum to give 2.4 g of the title compound (95% purity, 89% yield).

[1664] .sup.1H NMR (DMSO-d.sub.6) δ: 7.83-7.98 (m, 1H), 7.53-7.68 (m, 1H), 7.26 (td, 1H), 3.62-3.81 (m, 3H).

[1665] LC-MS (Method 2): R.sub.t=0.49 min; MS (ESIpos): m/z=219.3 [M+H].sup.+

Intermediate 53

4-chloro-8-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1666] ##STR00103##

[1667] A suspension of 1.8 g 8-fluoro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (7.84 mmol, intermediate 52) and 7.3 mL phosphoric trichloride (78 mmol) was stirred for 20 h at 90° C. After cooling to rt, ice water was added carefully and the mixture was adjusted to pH=10 with sodium carbonate. The precipitate was collected by filtration to give 1.5 g of the title compound (95% purity, 77% yield).

[1668] .sup.1H NMR (DMSO-d.sub.6) δ: 7.91-8.02 (m, 1H), 7.74-7.87 (m, 1H), 7.44-7.53 (m, 1H), 3.76-3.84 (m, 3H).

[1669] LC-MS (Method 2): R.sub.t=0.97 min; MS (ESIpos): m/z=237.3 [M+H].sup.+

Intermediate 54

8-bromo-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1670] ##STR00104##

[1671] To a suspension of 90 g 8-bromo-2H-3,1-benzoxazine-2,4(1H)-dione (372 mmol, CAS 331646-98-1) and 130 mL N,N-diisopropylethylamine (740 mmol) in 720 mL dimethylacetamide was added 69 mL iodomethane (1.1 mol) and the mixture was stirred overnight at rt. After that time, water was added and the precipitate was collected by filtration, washed with ethanol and hexane to give 86 g of the title compound (90% yield).

[1672] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 3.64 (s, 3H); 7.26 (t, 1H); 8.00 (dd, 1H); 8.09 (dd, 1H).

[1673] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=256.1 [M+H].sup.+

Intermediate 55

8-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1674] ##STR00105##

[1675] A suspension of 40 g 8-bromo-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (156 mmol, intermediate 54) in 320 mL THF was slowly treated with 170 mL triethylamine (1.2 mol) followed by the addition of 50 mL ethyl cyanoacetate (470 mmol) and was stirred for 24 h at 70° C. After cooling to rt, the solvent was evaporated in vacuum, water was added and the mixture was acidified to pH=1 by addition of hydrochloric acid (2 N). The mixture was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, dried and concentrated under reduced pressure. The residue was stirred in cyclopentyl methyl ether, the solid that precipitated from this procedure was collected by filtration to give 38.6 g of the title compound (89% yield).

[1676] .sup.1H NMR (DMSO-d.sub.6) δ: 8.22-8.98 (m, 1H), 7.83-8.08 (m, 2H), 7.12-7.29 (m, 1H), 3.62-3.74 (m, 3H).

Intermediate 56

8-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1677] ##STR00106##

[1678] A suspension of 35.6 g 8-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (127 mmol, intermediate 55) and 120 mL phosphoric trichloride (1.3 mol) was stirred for 134 h at 90° C. After cooling to rt, hexane was added and the precipitate was collected by filtration. The solid was stirred with an aqueous solution of sodium carbonate, filtered, washed with ethyl acetate and dried in vacuum. The impure product was solved in dichloromethane, the organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was stirred in dichloromethane, the precipitate was collected by filtration and dried in vacuum to give 6.12 g of the title compound (16% yield).

[1679] .sup.1H NMR (DMSO-d.sub.6) δ: 8.08-8.31 (m, 2H); 7.35-7.44 (m, 1H); 3.74-3.87 (m, 3H).

Intermediate 57

8-chloro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1680] ##STR00107##

[1681] To a solution of 4 g 8-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (19.2 mmol, CAS 63497-60-9) and 6.7 mL N,N-diisopropylethylamine (38 mmol) in 33 mL DMF was added 3.6 mL iodomethane (58 mmol) and was stirred overnight at rt. To the mixture was added ice water (300 ml). The solid that precipitated from this procedure was collected by filtration, washed with water and hexane and dried in vacuum to give 4.4 g of the title compound (90% purity, 97% yield).

[1682] .sup.1H NMR (DMSO-d.sub.6) δ: 7.98 (dd, 1H); 7.92 (dd, 1H); 7.34 (t, 1H); 3.64 (s, 3H).

[1683] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=212.1 [M+H].sup.+

Intermediate 58

8-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1684] ##STR00108##

[1685] A suspension of 4.35 g 8-chloro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (18.5 mmol, intermediate 57) in 45 mL 2-methyltetrahydrofuran was slowly treated with 21 mL triethylamine (150 mmol) followed by the addition of 9.7 mL ethyl cyanoacetate (74 mmol) and was stirred for 138 h at 80° C. After cooling to rt, the solvent was evaporated in vacuum, water/ethyl acetate (200 ml, 1:1) was added and the mixture was acidified to pH=1 by addition of hydrochloric acid (2 M). The solid that precipitated from this procedure was collected by filtration, washed with water, ethyl acetate and hexane and dried in vacuum to give 3.87 g of the title compound (99% purity, 88% yield).

[1686] .sup.1H NMR (DMSO-d.sub.6) δ: 8.02 (dd, 1H); 7.75 (dd, 1H); 7.25 (t, 1H); 3.68 (s, 3H).

[1687] LC-MS (Method 1): R.sub.t=0.74 min; MS (ESIneg): m/z=233.2 [M−H].sup.−

Intermediate 59

4,8-dichloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1688] ##STR00109##

[1689] A mixture of 3.8 g 8-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (16.2 mmol, intermediate 58) and 23 mL phosphoric trichloride (240 mmol) was stirred overnight at 90° C. After cooling to rt, ice water (400 ml) was added and the mixture was extracted with dichloromethane (3×). The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was stirred in dichloromethane/ethanol (1:1, 50 ml), the precipitate was collected by filtration and dried in vacuum to give 1.66 g of the title compound (38% yield, 94% purity).

[1690] .sup.1H NMR (DMSO-d.sub.6) δ: 8.09 (dd, 1H); 8.00 (dd, 1H); 7.48 (t, 1H); 3.81 (s, 3H).

[1691] LC-MS (Method 1): R.sub.t=1.08 min; MS (ESIpos): m/z=253.1 [M+H].sup.+

Intermediate 60

6-bromo-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1692] ##STR00110##

[1693] To a solution of 65 g 6-bromo-2H-3,1-benzoxazine-2,4(1H)-dione (269 mmol, CAS 4692-98-2) and 94 mL N,N-diisopropylethylamine (540 mmol) in 520 mL dimethylacetamide was added 50 mL iodomethane (810 mmol) at rt and was stirred overnight. To the reaction was added 2000 mL water. The solid that precipitated from this procedure was collected by filtration, washed with water, ethanol and hexane and dried in an oven at 50° C. 53.7 g of the title compound were obtained (78% yield).

[1694] .sup.1H NMR (DMSO-d.sub.6) δ: 7.95-8.12 (m, 2H), 7.37-7.49 (m, 1H), 3.46 (s, 3H).

[1695] LC-MS (Method 1): R.sub.t=0.93 min; MS (ESIneg): m/z=253.3 [M−H].sup.−

Intermediate 61

6-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1696] ##STR00111##

[1697] A suspension of 53.7 g 6-bromo-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (210 mmol, intermediate 60) in 430 mL THF was slowly treated with 230 mL triethylamine (1.7 mol) followed by the addition of 67 mL ethyl cyanoacetate (630 mmol) and was stirred overnight at 70° C. After cooling to rt, the solvent was evaporated in vacuum, water was added and the mixture was acidified to pH=1 by addition of hydrochloric acid. The mixture was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was stirred in hexane/ethyl acetate, the solid that precipitated from this procedure was collected by filtration to give 61 g of the title compound.

[1698] .sup.1H NMR (DMSO-d.sub.6) δ: 8.12-8.19 (m, 1H); 7.82-7.88 (m, 1H); 7.43-7.51 (m, 1H); 4.01 (s, 3H).

[1699] LC-MS (Method 1): R.sub.t=0.70 min; MS (ESIneg): m/z=277.4 [M−H].sup.−

Intermediate 62

6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1700] ##STR00112##

[1701] A mixture of 58 g 6-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (208 mmol, intermediate 61) and 200 mL phosphoric trichloride (2.1 mol) was stirred overnight at 90° C. After cooling to rt, hexane was added and the precipitate was collected by filtration. The solid was stirred with an aqueous solution of sodium carbonate, filtered, washed with ethyl acetate and dried in vacuum. The impure product was stirred in ethanol/acetonitrile (1:1, 200 ml), the precipitate was collected by filtration and dried in vacuum to give 40.4 g of the title compound (65% yield).

[1702] .sup.1H NMR (DMSO-d.sub.6) δ: 8.11-8.19 (m, 1H); 7.97-8.11 (m, 1H); 7.65-7.72 (m, 1H); 3.65 (s, 3H).

[1703] LC-MS (Method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=297.2 [M+H].sup.+

Intermediate 63

4-chloro-6-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1704] ##STR00113##

[1705] To a solution of 15 g 4-chloro-6-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (CAS 1598417-48-1, intermediate 48) in 300 mL dichloromethane at −40° C. was added 75.5 g boron tribromide (29.1 ml). Then the mixture was stirred at 25° C. for 8 h. Full conversion was checked by LC-MS. 150 mL methanol were carefully added at −30° C. After stirring at rt the solvent was removed in vacuum and the residue was stirred with DMSO. The residue was filtered, the collected solid was washed with water and dried in vacuum to generate 6.79 g (48% yield) of the title compound as yellow solid.

[1706] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 10.15 (s, 1H); 7.59 (d, 1H); 7.38-7.33 (m, 2H); 3.62 (s, 3H).

Intermediate 64

8-bromo-1,6-dimethyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1707] ##STR00114##

[1708] To a solution of 10 g 8-bromo-6-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (39.1 mmol, CAS 177970-27-3) and 14 mL N,N-diisopropylethylamine (78 mmol) in 100 mL dimethylacetamide was added 7.3 mL iodomethane (120 mmol) at rt and was stirred overnight. To the reaction was added 2000 mL water. The solid that precipitated from this procedure was collected by filtration, washed with water, ethanol and hexane and dried in vacuum. 7.2 g of the title compound were obtained (95% purity, 65% yield).

[1709] .sup.1H NMR (DMSO-d.sub.6) δ: 7.91-7.99 (m, 1H), 7.79-7.85 (m, 1H), 3.63 (s, 3H), 2.34 (s, 3H).

Intermediate 65

8-bromo-4-hydroxy-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1710] ##STR00115##

[1711] A suspension of 7.2 g 8-bromo-1,6-dimethyl-2H-3,1-benzoxazine-2,4(1H)-dione (25.3 mmol, intermediate 64) in 150 mL THF was slowly treated with 28 mL triethylamine (200 mmol) followed by the addition of 4.1 mL ethyl cyanoacetate (38 mmol) and was stirred for 8 h at 70° C. After cooling to rt, ethyl acetate and water were added and the mixture was acidified to pH=1 by addition of hydrochloric acid (2 N). The mixture was extracted with ethyl acetate (2×). The combined organic phases were washed with brine and water, dried and concentrated under reduced pressure. The residue was stirred in ethyl acetate, the solid that precipitated from this procedure was collected by filtration to give 4.49 g of the title compound (95% purity, 57% yield).

[1712] .sup.1H NMR (DMSO-d.sub.6) δ: 7.71-7.90 (m, 2H), 3.55-3.71 (m, 3H), 2.26-2.38 (m, 3H).

[1713] LC-MS (Method 2): R.sub.t=0.61 min; MS (ESIpos): m/z=294.0 [M+H].sup.+

Intermediate 66

8-bromo-4-chloro-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1714] ##STR00116##

[1715] A mixture of 4.49 g 8-bromo-4-hydroxy-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (15.3 mmol, intermediate 65) and 14 mL phosphoric trichloride (150 mmol) was stirred for 10 h at 90° C. After cooling to rt, ice water (1500 ml) was added carefully and the mixture was adjusted to pH=10 with sodium carbonate. The mixture was extracted with dichloromethane (3×). The combined organic phases were washed with water, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-1%) to give 2.9 g of the title compound (95% purity, 58% yield).

[1716] .sup.1H NMR (DMSO-d.sub.6) δ: 8.01-8.11 (m, 1H), 7.89-7.94 (m, 1H), 3.78 (s, 3H), 2.41 (s, 3H).

[1717] LC-MS (Method 2): R.sub.t=1.19 min; MS (ESIpos): m/z=311.3 [M+H].sup.+

Intermediate 67

6-methoxy-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[1718] ##STR00117##

[1719] To a solution of 4.6 g 6-methoxy-2H-3,1-benzoxazine-2,4(1H)-dione (22.6 mmol, CAS 37795-77-0) and 7.9 mL N,N-diisopropylethylamine (45 mmol) in 42 mL dimethylacetamide was added 4.2 mL iodomethane (68 mmol) at rt and was stirred overnight. To the reaction was added 1000 mL water. The solid that precipitated from this procedure was collected by filtration, washed with water, ethanol and hexane and dried in vacuum. 4.3 g of the title compound were obtained (87% yield).

[1720] .sup.1H NMR (DMSO-d.sub.6) δ ppm 3.45 (s, 3H); 3.84 (s, 3H); 7.39-7.49 (m, 3H).

Intermediate 68

4-hydroxy-6-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1721] ##STR00118##

[1722] A suspension of 4.3 g 6-methoxy-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (19.7 mmol, intermediate 67) in 45 mL THF was slowly treated with 22 mL triethylamine (160 mmol) followed by the addition of 3.2 mL ethyl cyanoacetate (30 mmol) and was stirred for 24 h at 70° C. After cooling to rt, ethyl acetate and water were added and the mixture was acidified to pH=1 by addition of hydrochloric acid (2 N). The resulting precipitate was collected by filtration to give 2.7 g of the title compound (57% yield).

[1723] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 3.53 (s, 3H); 3.83 (s, 3H); 7.38 (dd, 1H); 7.47-7.51 (m, 1H); 7.57 (d, 1H).

[1724] LC-MS (Method 2): R.sub.t=0.48 min; MS (ESIpos): m/z=231.3 [M+H].sup.+

EXPERIMENTAL SECTION—EXAMPLES

Example 1

1-methyl-4-[4-(4-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1725] ##STR00119##

[1726] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.5 mmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 105 mg 4-(4-methylphenoxy)piperidine (0.55 mmol, CAS 63843-49-2) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 146 mg of the title compound (81% yield, 95% purity).

[1727] .sup.1H NMR (DMSO-d.sub.6) δ: 7.85-7.91 (m, 1H), 7.69-7.78 (m, 1H), 7.53-7.62 (m, 1H), 7.31-7.39 (m, 1H), 7.05-7.14 (m, 2H), 6.87-6.97 (m, 2H), 4.59-4.86 (m, 1H), 3.69-3.82 (m, 2H), 3.49-3.61 (m, 5H), 2.11-2.26 (m, 5H), 1.80-1.98 (m, 2H).

[1728] LC-MS (Method 1): R.sub.t=1.36 min; MS (ESIpos): m/z=374 [M+H].sup.+

Example 2

1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1729] ##STR00120##

[1730] A solution of 5.0 g 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (21.7 mmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 6.57 g 4-[4-(trifluoromethoxy)phenoxy]piperidine (23.9 mmol, CAS 287952-67-4) and 6.1 mL triethylamine (43.5 mmol) in 300 mL 2-propanol was stirred for 5 h at 90° C. After this time, water and ethyl acetate were added and the reaction was extracted with further ethyl acetate.

[1731] The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. Upon evaporation a precipitate was generated and collected by filtration. The resulting solid was dried to obtain 8.1 g of the title compound (80% yield, 95% purity).

[1732] .sup.1H NMR (DMSO-d.sub.6) δ: 7.87 (dd, 1H), 7.69-7.78 (m, 1H), 7.53-7.61 (m, 1H), 7.26-7.39 (m, 3H), 7.11-7.20 (m, 2H), 4.70-4.86 (m, 1H), 3.70-3.83 (m, 2H), 3.49-3.64 (m, 5H), 2.13-2.26 (m, 2H), 1.83-2.00 (m, 2H).

[1733] LC-MS (Method 2): R.sub.t=1.39 min; MS (ESIpos): m/z=444.5 [M+H].sup.+

Example 3

1-methyl-4-[4-(3-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1734] ##STR00121##

[1735] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.5 mmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 117 mg 4-(3-methylphenoxy)piperidine (0.52 mmol, CAS 63843-46-9) and 0.12 mL triethylamine (0.87 mmol) in 4.4 mL 2-propanol was stirred for 5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 23 mg of the title compound were obtained (95% purity, 14% yield).

[1736] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.92 (m, 1H), 7.70-7.79 (m, 1H), 7.53-7.62 (m, 1H), 7.31-7.39 (m, 1H), 7.14-7.23 (m, 1H), 6.73-6.90 (m, 3H), 4.66-4.82 (m, 1H), 3.69-3.85 (m, 2H), 3.49-3.61 (m, 5H), 2.25-2.31 (m, 3H), 2.14-2.25 (m, 2H), 1.84-2.00 (m, 2H).

[1737] LC-MS (Method 2): R.sub.t=1.34 min; MS (ESIpos): m/z=374.5 [M+H].sup.+

Example 4

4-[4-(3-methoxyphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1738] ##STR00122##

[1739] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (434 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 108 mg 4-(3-methoxyphenoxy)piperidine (521 μmol, CAS 162402-37-1) and 0.12 mL triethylamine (0.87 mmol) in 7.5 mL 2-propanol was stirred for 2.5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 94 mg of the title compound were obtained (95% purity, 53% yield).

[1740] .sup.1H NMR (DMSO-d.sub.6) δ: 7.83-7.91 (m, 1H), 7.69-7.77 (m, 1H), 7.52-7.62 (m, 1H), 7.30-7.39 (m, 1H), 7.15-7.26 (m, 1H), 6.49-6.67 (m, 3H), 4.76 (tt, 1H), 3.70-3.81 (m, 5H), 3.51-3.62 (m, 5H), 2.13-2.25 (m, 2H), 1.84-1.99 (m, 2H).

[1741] LC-MS (Method 2): R.sub.t=1.26 min; MS (ESIpos): m/z=390.5 [M+H].sup.+

Example 5

1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile

[1742] ##STR00123##

[1743] A suspension of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 97.3 mg 4-phenoxypiperidine (549 μmol, CAS 3202-33-3) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 142 mg of the title compound (82% yield, 95% purity).

[1744] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.94 (m, 1H), 7.70-7.77 (m, 1H), 7.53-7.61 (m, 1H), 7.26-7.39 (m, 3H), 7.01-7.13 (m, 2H), 6.88-6.98 (m, 1H), 4.68-4.84 (m, 1H), 3.71-3.84 (m, 2H), 3.50-3.62 (m, 5H), 2.14-2.25 (m, 2H), 1.85-2.00 (m, 2H).

[1745] LC-MS (Method 1): R.sub.t=1.28 min; MS (ESIpos): m/z=360 [M+H].sup.+

Example 6

4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1746] ##STR00124##

[1747] A suspension of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 107 mg 4-(4-fluorophenoxy)piperidine (549 μmol, CAS 3202-34-4) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 135 mg of the title compound (74% yield, 95% purity).

[1748] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.91 (m, 1H), 7.69-7.76 (m, 1H), 7.53-7.62 (m, 1H), 7.29-7.38 (m, 1H), 6.98-7.22 (m, 4H), 4.61-4.83 (m, 1H), 3.70-3.82 (m, 2H), 3.47-3.63 (m, 5H), 2.13-2.27 (m, 2H), 1.81-1.99 (m, 2H).

[1749] LC-MS (Method 1): R.sub.t=1.29 min; MS (ESIpos): m/z=378 [M+H].sup.+

Example 7

4-[4-(3-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1750] ##STR00125##

[1751] A suspension of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 127 mg 4-(3-fluorophenoxy)piperidine hydrogen chloride salt (1:1) (549 μmol, CAS 3202-36-6) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 127 mg of the title compound (70% yield, 95% purity).

[1752] .sup.1H NMR (DMSO-d.sub.6) δ: 7.87 (dd, 1H), 7.70-7.79 (m, 1H), 7.57 (d, 1H), 7.27-7.40 (m, 2H), 6.84-7.02 (m, 2H), 6.70-6.80 (m, 1H), 4.72-4.90 (m, 1H), 3.71-3.83 (m, 2H), 3.47-3.63 (m, 5H), 2.13-2.27 (m, 2H), 1.83-1.99 (m, 2H).

[1753] LC-MS (Method 1): R.sub.t=1.31 min; MS (ESIpos): m/z=378 [M+H].sup.+

Example 8

4-[4-(4-bromophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1754] ##STR00126##

[1755] A suspension of 111 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (508 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 130 mg 4-(4-bromophenoxy)piperidine (508 μmol, CAS 74130-05-5) and 0.28 mL triethylamine (2.0 mmol) in 15 mL 2-propanol was stirred for 4 h at 90° C. and 48 h at rt. After this time, water and ethyl acetate were added and the reaction was stirred for some time. The solid was collected by filtration. The impure product was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-2%) to give 66 mg of the title compound (98% purity, 29% yield).

[1756] .sup.1H NMR (DMSO-d.sub.6) δ: 7.81-7.92 (m, 1H), 7.70-7.77 (m, 1H), 7.53-7.62 (m, 1H), 7.41-7.51 (m, 2H), 7.34 (td, 1H), 6.98-7.09 (m, 2H), 4.68-4.86 (m, 1H), 3.69-3.83 (m, 2H), 3.50-3.61 (m, 5H), 2.12-2.26 (m, 2H), 1.78-2.02 (m, 2H).

[1757] LC-MS (Method 2): R.sub.t=1.37 min; MS (ESIpos): m/z=439 [M+H].sup.+

Example 9

4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1758] ##STR00127##

[1759] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 107 mg 4-(3-chlorophenoxy)piperidine (503 μmol, CAS 97840-40-9) and 0.13 mL triethylamine (910 μmol) in 6.3 mL 2-propanol was stirred for 5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 270 mg of the title compound were obtained (95% purity, 142% yield).

[1760] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.97 (m, 1H), 7.67-7.80 (m, 1H), 7.52-7.65 (m, 1H), 7.26-7.42 (m, 2H), 7.12-7.21 (m, 1H), 6.97-7.06 (m, 2H), 4.76-4.92 (m, 1H), 3.71-3.85 (m, 2H), 3.48-3.66 (m, 5H), 2.14-2.27 (m, 2H), 1.80-1.97 (m, 2H).

[1761] LC-MS (Method 2): R.sub.t=1.35 min; MS (ESIpos): m/z=394.5 [M+H].sup.+

Example 10

4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1762] ##STR00128##

[1763] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 107 mg 4-(4-chlorophenoxy)piperidine (503 μmol, CAS 97839-99-1) and 0.13 mL triethylamine (910 μmol) in 6.3 mL 2-propanol was stirred for 5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 175 mg of the title compound were obtained (95% purity, 92% yield).

[1764] .sup.1H NMR (DMSO-d.sub.6) δ: 7.83-7.92 (m, 1H), 7.69-7.77 (m, 1H), 7.51-7.61 (m, 1H), 7.39 (s, 3H), 7.02-7.15 (m, 2H), 4.68-4.82 (m, 1H), 3.69-3.84 (m, 2H), 3.46-3.63 (m, 5H), 2.13-2.31 (m, 2H), 1.82-1.99 (m, 2H).

[1765] LC-MS (Method 2): R.sub.t=1.37 min; MS (ESIpos): m/z=394.5 [M+H].sup.+

Example 11

4-[4-(2-methoxyphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1766] ##STR00129##

[1767] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (434 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 108 mg 4-(2-methoxyphenoxy)piperidine (521 μmol, CAS 28033-32-1) and 0.12 mL triethylamine (0.87 mmol) in 7.5 mL 2-propanol was stirred for 2.5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 102 mg of the title compound were obtained (95% purity, 57% yield).

[1768] .sup.1H NMR (DMSO-d.sub.6) δ: 7.84-7.92 (m, 1H), 7.70-7.79 (m, 1H), 7.52-7.62 (m, 1H), 7.31-7.38 (m, 1H), 7.07-7.13 (m, 1H), 6.84-7.03 (m, 3H), 4.56-4.73 (m, 1H), 3.75-3.85 (m, 5H), 3.47-3.62 (m, 5H), 2.10-2.25 (m, 2H), 1.81-2.00 (m, 2H).

[1769] LC-MS (Method 2): R.sub.t=1.22 min; MS (ESIpos): m/z=390.5 [M+H].sup.+

Example 12

ethyl 4-{[1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]oxy}benzoate

[1770] ##STR00130##

[1771] To a solution of 50 mg 4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (176 μmol, intermediate 1) and 100 μL ethyl 4-fluorobenzoate (710 μmol, CAS 451-46-7) in 2.0 mL DMF at 0° C. was added 33 mg sodium hydride (60% in mineral oil, 829 μmol) and the mixture was stirred for 5 h at 80° C. The mixture was cooled down to rt, water was added and the reaction was extracted with ethyl acetate (3×). The combined organic layers were filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: water (0.2 vol. % ammonia 32%)/acetonitrile-gradient) to give 27.3 mg of the title compound (90% purity, 32% yield).

[1772] 1H-NMR (400 MHz, DMSO-d6): 5 [ppm]=1.31 (t, 3H), 1.88-2.02 (m, 2H), 2.24 (ddd, 2H), 3.51-3.64 (m, 5H), 3.71-3.82 (m, 2H), 4.28 (q, 2H), 4.90 (tt, 1H), 7.11-7.21 (m, 2H), 7.28-7.40 (m, 1H), 7.51-7.62 (m, 1H), 7.74 (ddd, 1H), 7.83-7.96 (m, 3H).

[1773] LC-MS (Method 3): R.sub.t=1.32 min; MS (ESIpos): m/z=432 [M+H].sup.+

Example 13

1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1774] ##STR00131##

[1775] A suspension of 50 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (229 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 77 mg 4-[4-(trifluoromethyl)phenoxy]piperidine hydrogen chloride salt (1:1) (274 μmol, CAS 287952-09-4) and 0.12 mL N,N-diisopropylethylamine (690 μmol) in 1 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 77.9 mg of the title compound (76% yield, 95% purity).

[1776] .sup.1H NMR (DMSO-d.sub.6) δ: 7.83-7.92 (m, 1H), 7.70-7.82 (m, 1H), 7.63-7.70 (m, 2H), 7.53-7.61 (m, 1H), 7.29-7.38 (m, 1H), 7.18-7.28 (m, 2H), 4.85-5.02 (m, 1H), 3.70-3.86 (m, 2H), 3.52-3.68 (m, 5H), 2.15-2.30 (m, 2H), 1.87-2.04 (m, 2H).

[1777] LC-MS (Method 1): R.sub.t=1.39 min; MS (ESIpos): m/z=429 [M+H].sup.+

Example 14

1-methyl-4-[4-(2-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1778] ##STR00132##

[1779] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (434 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 117 mg 4-(2-methylphenoxy)piperidine (521 μmol, CAS 63843-42-5) and 0.12 mL triethylamine (0.87 mmol) in 4.4 mL 2-propanol was stirred for 6 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 75 mg of the title compound were obtained (95% purity, 44% yield).

[1780] .sup.1H NMR (DMSO-d.sub.6) δ: 7.84-7.92 (m, 1H), 7.68-7.78 (m, 1H), 7.51-7.63 (m, 1H), 7.28-7.40 (m, 1H), 7.12-7.21 (m, 2H), 7.01-7.10 (m, 1H), 6.81-6.89 (m, 1H), 4.72-4.89 (m, 1H), 3.69-3.89 (m, 2H), 3.50-3.66 (m, 5H), 2.13-2.28 (m, 5H), 1.83-2.04 (m, 2H).

[1781] LC-MS (Method 2): R.sub.t=1.36 min; MS (ESIpos): m/z=374.5 [M+H].sup.+

Example 15

1-methyl-2-oxo-4-{4-[3-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1782] ##STR00133##

[1783] A suspension of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 135 mg 4-[3-(trifluoromethyl)phenoxy]piperidine (549 μmol, CAS 337912-66-0) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 1 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 167 mg of the title compound (81% yield, 95% purity).

[1784] .sup.1H NMR (DMSO-d.sub.6) δ: 7.85-7.95 (m, 1H), 7.70-7.82 (m, 1H), 7.49-7.62 (m, 2H), 7.26-7.40 (m, 4H), 4.85-5.00 (m, 1H), 3.69-3.85 (m, 2H), 3.50-3.64 (m, 5H), 2.22 (ddd, 2H), 1.87-2.02 (m, 2H).

[1785] LC-MS (Method 1): R.sub.t=1.40 min; MS (ESIpos): m/z=428 [M+H].sup.+

Example 16

4-[4-(2-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1786] ##STR00134##

[1787] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (434 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 110 mg 4-(2-chlorophenoxy)piperidine (521 μmol, CAS 245057-65-2) and 0.12 mL triethylamine (0.87 mmol) in 7.5 mL 2-propanol was stirred for 3.5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 75 mg of the title compound were obtained (95% purity, 42% yield).

[1788] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.92 (m, 1H), 7.68-7.79 (m, 1H), 7.51-7.61 (m, 1H), 7.41-7.50 (m, 1H), 7.26-7.38 (m, 3H), 6.93-7.03 (m, 1H), 4.80-4.98 (m, 1H), 3.73-3.89 (m, 2H), 3.51-3.62 (m, 5H), 2.16-2.29 (m, 2H), 1.86-2.06 (m, 2H).

[1789] LC-MS (Method 2): R.sub.t=1.32 min; MS (ESIpos): m/z=394.4 [M+H].sup.+

Example 17

1-methyl-2-oxo-4-{4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1790] ##STR00135##

[1791] A suspension of 157 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (716 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 175 mg 4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]piperidine (716 μmol, intermediate 4) and 0.4 mL triethylamine (2.9 mmol) in 15 mL 2-propanol was stirred for 2 h at 90° C. and 48 h at rt. After this time, water and ethyl acetate were added and the reaction was stirred for some time. The solid was collected by filtration to give 210 mg of the title compound (98% purity, 67% yield).

[1792] .sup.1H NMR (DMSO-d.sub.6) δ: 9.15-9.23 (m, 1H), 8.19-8.28 (m, 1H), 7.85-7.94 (m, 1H), 7.70-7.83 (m, 3H), 7.55-7.62 (m, 1H), 7.30-7.40 (m, 1H), 7.18-7.30 (m, 2H), 4.77-4.91 (m, 1H), 3.71-3.85 (m, 2H), 3.51-3.65 (m, 5H), 2.19-2.29 (m, 2H), 1.87-2.05 (m, 2H).

[1793] LC-MS (Method 2): R.sub.t=1.05 min; MS (ESIpos): m/z=427.6 [M+H].sup.+

Example 18

1-methyl-2-oxo-4-{4-[4-(2-oxopyrrolidin-1-yl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1794] ##STR00136##

[1795] A suspension of 185 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (845 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 220 mg 1-{4-[(piperidin-4-yl)oxy]phenyl}pyrrolidin-2-one (845 μmol, intermediate 6) and 0.47 mL triethylamine (3.4 mmol) in 15 mL 2-propanol was stirred for 2 h at 90° C. and overnight at rt. After this time, water and ethyl acetate were added and the reaction was stirred for some time. The solid was collected by filtration to give 310 mg of the title compound (98% purity, 81% yield).

[1796] .sup.1H NMR (DMSO-d.sub.6) δ: 7.85-7.97 (m, 1H), 7.68-7.78 (m, 1H), 7.51-7.62 (m, 3H), 7.30-7.39 (m, 1H), 6.97-7.10 (m, 2H), 4.65-4.84 (m, 1H), 3.71-3.87 (m, 4H), 3.47-3.63 (m, 5H), 2.43-2.48 (m, 2H), 2.15-2.26 (m, 2H), 2.00-2.10 (m, 2H), 1.85-1.97 (m, 2H).

[1797] LC-MS (Method 2): R.sub.t=1.08 min; MS (ESIpos): m/z=443.6 [M+H].sup.+

Example 19

4-{4-[4-(1H-imidazol-1-yl)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1798] ##STR00137##

[1799] A suspension of 45 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (205 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 50.0 mg 4-[4-(1H-imidazol-1-yl)phenoxy]piperidine (205 μmol, CAS 397277-13-3) and 0.11 mL triethylamine (820 μmol) in 8 mL 2-propanol was stirred for 4 h at 90° C. After this time, water and ethyl acetate were added and the reaction was stirred for some time. The solid was collected by filtration to give 57 mg of the title compound (90% purity, 59% yield).

[1800] .sup.1H NMR (DMSO-d.sub.6) δ: 8.12-8.17 (m, 1H), 7.82-7.90 (m, 1H), 7.71-7.77 (m, 1H), 7.64-7.67 (m, 1H), 7.53-7.60 (m, 3H), 7.32-7.39 (m, 1H), 7.15-7.25 (m, 2H), 7.08 (t, 1H), 4.76-4.91 (m, 1H), 3.72-3.84 (m, 2H), 3.53-3.65 (m, 5H), 2.18-2.28 (m, 2H), 1.88-2.01 (m, 2H).

[1801] LC-MS (Method 2): R.sub.t=1.06 min; MS (ESIpos): m/z=426.8 [M+H].sup.+

Example 20

1-methyl-4-{4-[4-(morpholin-4-yl)phenoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1802] ##STR00138##

[1803] A suspension of 8.3 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (38.1 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 10.0 mg 4-{4-[(piperidin-4-yl)oxy]phenyl}morpholine (38 μmol, intermediate 8) and 21 μL triethylamine (150 μmol) in 3 mL 2-propanol was stirred for 4 h at 90° C. After this time, water and ethyl acetate were added and the reaction was stirred for some time. The solid was collected by filtration to give 5 mg of the title compound (95% purity, 28% yield).

[1804] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.96 (m, 1H), 7.66-7.79 (m, 1H), 7.49-7.63 (m, 1H), 7.28-7.39 (m, 1H), 6.80-6.99 (m, 4H), 4.51-4.69 (m, 1H), 3.67-3.85 (m, 6H), 3.48-3.61 (m, 5H), 2.94-3.04 (m, 4H), 2.10-2.22 (m, 2H), 1.82-1.96 (m, 2H).

[1805] LC-MS (Method 2): R.sub.t=1.17 min; MS (ESIpos): m/z=445.8 [M+H].sup.+

Example 21

1-methyl-4-{4-[4-(3-methyl-2-oxo-1,3-diazinan-1-yl)phenoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1806] ##STR00139##

[1807] A suspension of 100 mg 4-[4-(4-bromophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (217 μmol, example 8), 50 mg 1-methyltetrahydropyrimidin-2(1H)-one (433 μmol, CAS 10166-54-8), 66 mg potassium carbonate (477 μmol), 8.3 mg copper(I)iodide (43 μmol) and 93 μL N,N′-dimethylethane-1,2-diamine (870 μmol) in 5 mL toluene was stirred for 30 h at 110° C. Water was added and the reaction was extracted with ethyl acetate (3×). The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%). 20 mg of the title compound were obtained (99% purity, 19% yield).

[1808] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.92 (m, 1H), 7.66-7.78 (m, 1H), 7.52-7.62 (m, 1H), 7.30-7.44 (m, 1H), 7.08-7.21 (m, 2H), 6.89-7.01 (m, 2H), 4.64-4.81 (m, 1H), 3.70-3.84 (m, 2H), 3.51-3.63 (m, 7H), 2.83 (s, 3H), 2.16-2.24 (m, 2H), 1.86-2.05 (m, 4H).

[1809] LC-MS (Method 2): R.sub.t=1.08 min; MS (ESIpos): m/z=472.6 [M+H].sup.+

Example 22

1-methyl-4-{4-[4-(3-methyl-2-oxoimidazolidin-1-yl)phenoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1810] ##STR00140##

[1811] A suspension of 80 mg 4-[4-(4-bromophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (173 μmol, example 8), 35 mg 1-methylimidazolidin-2-one (347 μmol, CAS 694-32-6), 53 mg potassium carbonate (381 μmol), 6.6 mg copper(I)iodide (35 μmol) and 75 μL N,N′-dimethylethane-1,2-diamine (690 μmol) in 5 mL toluene was stirred for 10 h at 110′C. Water was added and the reaction was extracted with ethyl acetate (3×). The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%). 5 mg of the title compound were obtained (91% purity, 6% yield).

[1812] .sup.1H NMR (DMSO-d.sub.6) δ: 7.83-7.96 (m, 1H), 7.67-7.77 (m, 1H), 7.52-7.60 (m, 1H), 7.41-7.51 (m, 2H), 7.28-7.37 (m, 1H), 6.95-7.08 (m, 2H), 4.62-4.73 (m, 1H), 3.69-3.83 (m, 4H), 3.49-3.62 (m, 5H), 3.36-3.46 (m, 2H), 2.74 (s, 3H), 2.10-2.26 (m, 2H), 1.82-1.97 (m, 2H).

[1813] LC-MS (Method 2): R.sub.t=1.09 min; MS (ESIpos): m/z=458.6 [M+H].sup.+

Example 23

1-methyl-2-oxo-4-{4-[4-(2-oxopiperidin-1-yl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1814] ##STR00141##

[1815] A suspension of 80 mg 4-[4-(4-bromophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (173 μmol, example 8), 34 mg piperidin-2-one (347 μmol, CAS 675-20-7), 53 mg potassium carbonate (381 μmol), 6.6 mg copper(I)iodide (35 μmol) and 75 μL N,N′-dimethylethane-1,2-diamine (690 μmol) in 5 mL toluene was stirred for 10 h at 110° C.

[1816] Water was added and the reaction was extracted with ethyl acetate (3×). The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%). 5 mg of the title compound were obtained (91% purity, 6% yield).

[1817] .sup.1H NMR (CHLOROFORM-d) δ: 7.78-7.87 (m, 1H), 7.61-7.70 (m, 1H), 7.34-7.42 (m, 1H), 7.25-7.27 (m, 1H), 7.15-7.22 (m, 2H), 6.92-7.03 (m, 2H), 4.56-4.73 (m, 1H), 3.83-3.98 (m, 2H), 3.69 (s, 3H), 3.56-3.66 (m, 4H), 2.49-2.64 (m, 2H), 2.20-2.33 (m, 2H), 2.04-2.15 (m, 2H), 1.87-2.02 (m, 4H).

[1818] LC-MS (Method 2): R.sub.t=1.09 min; MS (ESIpos): m/z=457.6 [M+H].sup.+

Example 24

1-methyl-4-{4-[4-(4-methyl-2-oxopiperazin-1-yl)phenoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1819] ##STR00142##

[1820] A suspension of 100 mg 4-[4-(4-bromophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (217 μmol, example 8), 50 mg 4-methylpiperazin-2-one (433 μmol, CAS 34770-60-0), 66 mg potassium carbonate (477 μmol), 8.3 mg copper(I)iodide (43 μmol) and 93 μL N,N′-dimethylethane-1,2-diamine (870 μmol) in 5 mL toluene was stirred for 30 h at 110′C. Water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation the residue was stirred in ethyl acetate, the solid was collected by filtration and dried in vacuum to give 26 mg of the title compound (24% yield, 95% purity).

[1821] .sup.1H NMR (DMSO-d.sub.6) δ: 7.84-7.97 (m, 1H), 7.69-7.79 (m, 1H), 7.52-7.63 (m, 1H), 7.29-7.38 (m, 1H), 7.14-7.26 (m, 2H), 7.01-7.09 (m, 2H), 4.70-4.82 (m, 1H), 3.70-3.85 (m, 2H), 3.50-3.65 (m, 7H), 3.02-3.13 (m, 2H), 2.68-2.74 (m, 2H), 2.28 (s, 3H), 2.15-2.25 (m, 2H), 1.86-2.00 (m, 2H).

[1822] LC-MS (Method 2): R.sub.t=0.99 min; MS (ESIpos): m/z=472.8 [M+H].sup.+

Example 25

1-methyl-4-{4-[4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1823] ##STR00143##

[1824] Example 25 was obtained as a side product from the synthesis of example 22. Purification was performed by analogous chromatography and 11 mg were obtained (14% yield, 97% purity).

[1825] .sup.1H NMR (CHLOROFORM-d) δ: 7.79-7.91 (m, 1H), 7.61-7.70 (m, 1H), 7.48-7.55 (m, 2H), 7.35-7.41 (m, 1H), 7.26 (br s, 1H), 6.97-7.05 (m, 2H), 6.47-6.55 (m, 1H), 6.28-6.33 (m, 1H), 4.65 (dt, 1H), 3.83-3.97 (m, 2H), 3.70 (s, 3H), 3.56-3.66 (m, 2H), 3.34 (s, 3H), 2.21-2.34 (m, 2H), 2.03-2.17 (m, 2H).

[1826] LC-MS (Method 2): R.sub.t=1.04 min; MS (ESIpos): m/z=456.5 [M+H].sup.+

Example 26

4-{[1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]oxy}-N,N-dimethylbenzamide

[1827] ##STR00144##

[1828] To a suspension of 50.0 mg 4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (176 μmol, intermediate 1) and 118 mg 4-fluoro-N,N-dimethylbenzamide (706 μmol, CAS 24167-56-4) in 3 mL DMF at 0° C. was added 33 mg sodium hydride (60% in mineral oil, 829 μmol) and the mixture was stirred for 17 h at 80° C. After that time, water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were filtered over a hydrophobic filter and concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 1.3 mg of the title compound (100% purity, 2% yield).

[1829] .sup.1H NMR (DMSO-d.sub.6) δ: 7.85-7.93 (m, 1H), 7.71-7.82 (m, 1H), 7.55-7.65 (m, 1H), 7.30-7.45 (m, 3H), 7.02-7.11 (m, 2H), 4.73-4.91 (m, 1H), 3.73-3.84 (m, 2H), 3.51-3.64 (m, 5H), 2.91-3.03 (m, 6H), 2.17-2.29 (m, 2H), 1.86-2.01 (m, 2H).

[1830] LC-MS (Method 2): R.sub.t=1.04 min; MS (ESIpos): m/z=456.5 [M+H].sup.+

Example 27

4-{4-[(1,3-benzoxazol-4-yl)oxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1831] ##STR00145##

[1832] To a suspension of 100 mg 4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (353 μmol, intermediate 1), 91 mg 1,3-benzoxazol-4-ol (671 μmol, CAS 89590-22-7) and 185 mg triphenylphosphin (706 μmol) in 4 mL THF was added 140 μL diisopropyl azodicarboxylate (710 μmol) at 0° C. The mixture was stirred 48 h at rt. After that, the reaction was concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-100%). The impure product was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient). The impure product was purified by preparative TLC (dichloromethane/ethanol; 95:5) to give 12 mg of the title compound (8% yield, 90% purity).

[1833] .sup.1H NMR (DMSO-d.sub.6) δ: 8.65-8.70 (m, 1H), 7.90 (d, 1H), 7.71-7.78 (m, 1H), 7.55-7.61 (m, 1H), 7.32-7.40 (m, 3H), 7.06-7.14 (m, 1H), 5.15-5.28 (m, 1H), 3.76-3.88 (m, 2H), 3.54-3.66 (m, 5H), 2.23-2.31 (m, 2H), 1.96-2.08 (m, 2H).

[1834] LC-MS (Method 1): R.sub.t=1.17 min; MS (ESIpos): m/z=401 [M+H].sup.+

Example 28

1-methyl-2-oxo-4-(4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}piperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile

[1835] ##STR00146##

[1836] A suspension of 292 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.33 mmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 330 mg 5-[(piperidin-4-yl)oxy]-2-(trifluoromethyl)pyrimidine (1.33 mmol, intermediate 10) and 740 μL triethylamine (5.3 mmol) in 15 mL 2-propanol was stirred for 2 h at 90° C. and 24 h at rt. After this time, water and ethyl acetate were added and the reaction was stirred for some time. The solid was collected by filtration to give 70 mg of the title compound (95% purity, 12% yield).

[1837] .sup.1H NMR (DMSO-d.sub.6) δ: 8.87-8.92 (m, 2H), 7.85-7.91 (m, 1H), 7.69-7.79 (m, 1H), 7.54-7.61 (m, 1H), 7.31-7.41 (m, 1H), 5.06-5.18 (m, 1H), 3.69-3.87 (m, 2H), 3.51-3.66 (m, 5H), 2.24-2.33 (m, 2H), 1.95-2.11 (m, 2H).

[1838] LC-MS (Method 2): R.sub.t=1.19 min; MS (ESIpos): m/z=430.5 [M+H].sup.+

Example 29

4-{4-[(1,2-benzoxazol-6-yl)oxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1839] ##STR00147##

[1840] To a suspension of 100 mg 4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (353 μmol, intermediate 1), 91 mg 1,2-benzoxazol-6-ol (671 μmol, CAS 65685-55-4) and 185 mg triphenylphosphine (706 μmol) in 4 mL THF was added 140 μL diisopropyl azodicarboxylate (710 μmol). The mixture was stirred 48 h at rt. After that, the reaction was concentrated under reduced pressure. Water was added and the mixture was extracted with dichloromethane. The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). The impure product was stirred in ethanol, the solid was collected by filtration to give 41 mg of the title compound (23% yield, 80% purity).

[1841] .sup.1H NMR (DMSO-d.sub.6) δ: 10.63 (s, 1H), 7.84-7.94 (m, 1H), 7.74 (ddd, 1H), 7.49-7.63 (m, 2H), 7.29-7.40 (m, 1H), 6.46-6.76 (m, 2H), 4.75-4.92 (m, 1H), 3.70-3.84 (m, 2H), 3.51-3.67 (m, 5H), 2.15-2.31 (m, 2H), 1.87-2.02 (m, 2H).

[1842] LC-MS (Method 2): R.sub.t=0.67 min; MS (ESIpos): m/z=401 [M+H].sup.+

Example 30

4-[4-(4-{[dimethyl(oxo)-λ.SUP.6.-sulfanylidene]amino}phenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1843] ##STR00148##

[1844] 24 mg 1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile (67 μmol, example 5), 37 mg (s-methanesulfonimidoyl)methane (401 μmol, CAS 1520-31-6), 5.7 mg 3,6-di-tert-butyl-10-phenyl-9-(2,4,6-trimethylphenyl)acridinium tetrafluoroborate (10 μmol) and 2.1 mg (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (13 μmol) were dissolved in 800 μL 1,2-dichloroethane. The solution was degassed with argon for some time. The vial was placed in a water bath (to keep the temperature below 35,C) and was subsequently irradiated by two 40 W Kessil LED Aquarium lights (40 W each, 4 cm distance) for 24 h. The solvent was evaporated and the crude material was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 3.5 mg of the title compound (11% yield, 93% purity).

[1845] .sup.1H NMR (DMSO-d.sub.6) δ: 7.85-7.91 (m, 1H), 7.69-7.81 (m, 1H), 7.53-7.62 (m, 1H), 7.30-7.40 (m, 1H), 6.82-6.93 (m, 4H), 4.55-4.67 (m, 1H), 3.71-3.83 (m, 2H), 3.46-3.61 (m, 5H), 3.10-3.19 (m, 6H), 2.12-2.25 (m, 2H), 1.83-1.94 (m, 2H).

[1846] LC-MS (Method 2): R.sub.t=0.98 min; MS (ESIpos): m/z=451.5 [M+H].sup.+

Example 31

4-[4-(2-methoxy-4-methylphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1847] ##STR00149##

[1848] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (434 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 115 mg 4-(2-methoxy-4-methylphenoxy)piperidine (521 μmol, CAS 883543-21-3) and 0.12 mL triethylamine (0.87 mmol) in 7.5 mL 2-propanol was stirred for 4 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 68 mg of the title compound were obtained (95% purity, 37% yield).

[1849] .sup.1H NMR (DMSO-d.sub.6) δ: 7.81-7.91 (m, 1H), 7.70-7.79 (m, 1H), 7.52-7.62 (m, 1H), 7.30-7.38 (m, 1H), 6.90-7.01 (m, 1H), 6.75-6.87 (m, 1H), 6.64-6.72 (m, 1H), 4.47-4.62 (m, 1H), 3.73-3.83 (m, 5H), 3.55-3.59 (m, 3H), 3.45-3.55 (m, 2H), 2.25 (s, 3H), 2.13 (ddd, 2H), 1.82-1.95 (m, 2H).

[1850] LC-MS (Method 2): R.sub.t=1.29 min; MS (ESIpos): m/z=404.5 [M+H].sup.+

Example 32

4-[4-(4-cyanophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1851] ##STR00150##

[1852] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 111 mg 4-[(piperidin-4-yl)oxy]benzonitrile (549 μmol, CAS 224178-67-0) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 159 mg of the title compound (86% yield, 95% purity).

[1853] .sup.1H NMR (DMSO-d.sub.6) δ: 7.86-7.89 (m, 1H), 7.71-7.81 (m, 3H), 7.55-7.62 (m, 1H), 7.29-7.39 (m, 1H), 7.19-7.27 (m, 2H), 4.87-4.99 (m, 1H), 3.70-3.84 (m, 2H), 3.53-3.64 (m, 5H), 2.18-2.28 (m, 2H), 1.89-2.02 (m, 2H).

[1854] LC-MS (Method 1): R.sub.t=1.19 min; MS (ESIpos): m/z=385 [M+H].sup.+

Example 33

4-[4-(2-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1855] ##STR00151##

[1856] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 107 mg 4-(2-fluorophenoxy)piperidine (549 μmol, CAS 3623-02-7) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 145 mg of the title compound (75% yield, 90% purity).

[1857] .sup.1H NMR (DMSO-d.sub.6) δ: 7.80-7.93 (m, 1H), 7.66-7.78 (m, 1H), 7.52-7.59 (m, 1H), 7.07-7.40 (m, 4H), 6.92-7.03 (m, 1H), 4.71-4.85 (m, 1H), 3.73-3.85 (m, 2H), 3.47-3.63 (m, 5H), 2.17-2.27 (m, 2H), 1.86-2.07 (m, 2H).

[1858] LC-MS (Method 1): R.sub.t=1.28 min; MS (ESIpos): m/z=378 [M+H].sup.+

Example 34

4-[4-(2-cyanophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1859] ##STR00152##

[1860] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 111 mg 2-[(piperidin-4-yl)oxy]benzonitrile (549 μmol, CAS 900572-37-4) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 163 mg of the title compound (88% yield, 95% purity).

[1861] .sup.1H NMR (DMSO-d.sub.6) δ: 7.86-7.93 (m, 1H), 7.64-7.79 (m, 3H), 7.55-7.60 (m, 1H), 7.41-7.48 (m, 1H), 7.32-7.39 (m, 1H), 7.06-7.18 (m, 1H), 4.94-5.05 (m, 1H), 3.72-3.85 (m, 2H), 3.53-3.68 (m, 5H), 2.20-2.31 (m, 2H), 1.90-2.06 (m, 2H).

[1862] LC-MS (Method 1): R.sub.t=1.18 min; MS (ESIpos): m/z=385 [M+H].sup.+

Example 35

4-{[1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]oxy}benzamide

[1863] ##STR00153##

[1864] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 121 mg 4-[(piperidin-4-yl)oxy]benzamide (549 μmol, CAS 609781-30-8) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 166 mg of the title compound (86% yield, 95% purity).

[1865] .sup.1H NMR (DMSO-d.sub.6) δ: 7.81-7.92 (m, 4H), 7.71-7.78 (m, 1H), 7.55-7.62 (m, 1H), 7.30-7.38 (m, 1H), 7.16-7.25 (m, 1H), 7.03-7.11 (m, 2H), 4.80-4.92 (m, 1H), 3.70-3.84 (m, 2H), 3.51-3.65 (m, 5H), 2.16-2.28 (m, 2H), 1.86-2.01 (m, 2H).

[1866] LC-MS (Method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=403 [M+H].sup.+

Example 36

1-methyl-2-oxo-4-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1867] ##STR00154##

[1868] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 135 mg 4-[2-(trifluoromethyl)phenoxy]piperidine (549 μmol, CAS 824390-04-7) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried at 100° C. in vacuum to give 166 mg of the title compound (87% yield, 95% purity).

[1869] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.90 (m, 1H), 7.68-7.78 (m, 1H), 7.51-7.67 (m, 3H), 7.28-7.49 (m, 2H), 7.02-7.17 (m, 1H), 4.90-5.11 (m, 1H), 3.67-3.81 (m, 2H), 3.48-3.65 (m, 5H), 2.12-2.28 (m, 2H), 1.87-2.06 (m, 2H).

[1870] LC-MS (Method 1): R.sub.t=1.37 min; MS (ESIpos): m/z=428 [M+H].sup.+

Example 37

4-[4-(4-cyclopropylphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1871] ##STR00155##

[1872] 30 mg 4-[4-(4-bromophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (68 μmol, example 8) and 6.0 mg di-μ-iodobis(tri-tert-butylphosphino)dipalladium(l) (7.0 μmol, CAS 166445-62-1) were sealed in a vessel and flushed with argon. 1.1 mL toluene was added and the mixture was stirred at rt. 410 μL bromo(cyclopropyl)zinc (0.50 M, 210 μmol, CAS 126403-68-7) was added dropwise. The mixture was stirred at rt for 1 h. The mixture was filtered via a silica column. The column was washed with dichloromethane and dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (instrument: Waters Autopurificationsystem; column: X-Bridge C18 5μ 50×50 mm; eluent A: water (0.1 vol. % formic acid 99%), eluent B: acetonitrile; gradient: 0.00-0.50 min. 36% B (40->100 mL/min), 0.51-13 min. 36-56% B (100 mL/min), DAD scan: 210-400 nm) to give 4.1 mg of the title compound (88% purity, 13% yield).

[1873] .sup.1H NMR (400 MHz, ACETONITRILE-d.sub.3) δ ppm 0.52-0.64 (m, 2H); 0.78-0.97 (m, 3H); 1.22-1.30 (m, 4H); 1.80-1.89 (m, 1H); 3.49-3.61 (m+s, 7H); 3.75-3.84 (m, 2H); 4.63 (tt, 1H); 6.85-6.92 (m, 2H); 6.99-7.07 (m, 2H); 7.25-7.31 (m, 1H); 7.44-7.50 (m, 1H); 7.67 (ddd, 1H); 7.89 (dd, 1H).

Example 38

1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1874] ##STR00156##

[1875] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 131 mg 4-[3-(trifluoromethoxy)phenoxy]piperidine (503 μmol, CAS 459819-38-6) and 0.13 mL triethylamine (910 μmol) in 6.3 mL 2-propanol was stirred for 4 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 120 mg of the title compound were obtained (95% purity, 56% yield).

[1876] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.92 (m, 1H), 7.70-7.80 (m, 1H), 7.53-7.62 (m, 1H), 7.41-7.47 (m, 1H), 7.30-7.39 (m, 1H), 7.04-7.15 (m, 2H), 6.90-7.01 (m, 1H), 4.78-4.91 (m, 1H), 3.72-3.82 (m, 2H), 3.51-3.63 (m, 5H), 2.16-2.27 (m, 2H), 1.84-2.01 (m, 2H).

[1877] LC-MS (Method 2): R.sub.t=1.40 min; MS (ESIpos): m/z=444.5 [M+H].sup.+

Example 39

4-{4-[4-(difluoromethoxy)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1878] ##STR00157##

[1879] A suspension of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 73 mg 4-[4-(difluoromethoxy)phenoxy]piperidine hydrogen chloride salt (1:1) (261 μmol, intermediate 12) and 0.11 mL N,N-diisopropylethylamine (650 μmol) in 1.3 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with water and ethanol. The resulting solid was dried to give 88 mg of the title compound (95% yield, 100% purity).

[1880] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.95 (m, 1H), 7.70-7.80 (m, 1H), 7.52-7.62 (m, 1H), 6.87-7.45 (m, 6H), 4.65-4.82 (m, 1H), 3.70-3.84 (m, 2H), 3.48-3.63 (m, 5H), 2.11-2.26 (m, 2H), 1.85-1.98 (m, 2H).

[1881] LC-MS (Method 1): R.sub.t=1.29 min; MS (ESIpos): m/z=426.4 [M+H].sup.+

Example 40

1-methyl-4-[4-methyl-4-(4-nitrophenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1882] ##STR00158##

[1883] A solution of 239 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.04 mmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 270 mg 4-methyl-4-(4-nitrophenoxy)piperidine (1.14 mmol, intermediate 14) and 0.29 mL triethylamine (2.1 mmol) in 14 mL 2-propanol was stirred for 5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, DMSO was added and the reaction was stirred for some time. The residue was collected by filtration to give 125 mg of the title compound (95% purity, 27% yield).

[1884] .sup.1H NMR (DMSO-d.sub.6) δ: 8.14-8.26 (m, 2H), 7.86-7.94 (m, 1H), 7.70-7.78 (m, 1H), 7.53-7.60 (m, 1H), 7.28-7.40 (m, 3H), 3.52-3.75 (m, 7H), 2.20-2.30 (m, 2H), 2.04-2.15 (m, 2H), 1.56 (s, 3H).

[1885] LC-MS (Method 2): R.sub.t=1.27 min; MS (ESIpos): m/z=419.4 [M+H].sup.+

Example 41

4-[4-(4-aminophenoxy)-4-methylpiperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1886] ##STR00159##

[1887] 100 mg 1-methyl-4-[4-methyl-4-(4-nitrophenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile (227 μmol, example 40) and 10 mg palladium (94.0 μmol, 10% on activated car) were solved in 10 mL methanol and 10 mL dichloromethane. The mixture was stirred at rt under hydrogen atmosphere for 6 h. The reaction was filtered via kieselgur. After evaporation of the solvent 96 mg of the title compound were obtained (95% purity, 103% yield).

[1888] .sup.1H NMR (DMSO-d.sub.6) δ: 7.85-7.95 (m, 1H), 7.70-7.79 (m, 1H), 7.60 (br d, J=1.0 Hz, 1H), 7.29-7.38 (m, 1H), 6.47-6.87 (m, 4H), 3.74-3.92 (m, 2H), 3.50-3.64 (m, 5H), 1.82-2.03 (m, 4H), 1.19-1.27 (m, 3H).

[1889] LC-MS (Method 2): R.sub.t=1.08 min; MS (ESIpos): m/z=389.4 [M+H].sup.+

Example 42

4-[4-(4-bromophenoxy)-4-methylpiperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1890] ##STR00160##

[1891] To a mixture of 80 mg 4-[4-(4-aminophenoxy)-4-methylpiperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (206 μmol, example 41) in 630 μL tribromomethane (7.2 mmol) at 100° C. was added dropwise a solution of 55 μL 3-m ethylbutyl nitrite (410 μmol) in 180 μL tribromomethane (2.1 mmol). The reaction was stirred for 4 h at 100° C. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica, dichloromethane/methanol gradient 0-1%) to give 33 mg of the title compound (95% purity, 34% yield).

[1892] .sup.1H NMR (DMSO-d.sub.6) δ: 7.86-7.92 (m, 1H), 7.71-7.77 (m, 1H), 7.42-7.63 (m, 3H), 7.28-7.37 (m, 1H), 7.00-7.15 (m, 2H), 3.50-3.89 (m, 8H), 1.85-2.17 (m, 6H).

[1893] LC-MS (Method 2): R.sub.t=1.40 min; MS (ESIpos): m/z=453.3 [M+H].sup.+

Example 43

4-{4-[4-(methanesulfonyl)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1894] ##STR00161##

[1895] A suspension of 13 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (58.7 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 18 mg 4-[4-(methanesulfonyl)phenoxy]piperidine (70.5 μmol, intermediate 16) and 41 μL N,N-diisopropylethylamine (230 μmol) in 250 μL 2-propanol was stirred for 4 h at rt. The mixture was concentrated under reduced pressure. The residue was solved in dichloromethane and concentrated under reduced pressure again. The residue was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 23 mg of the title compound (99% purity, 89% yield).

[1896] .sup.1H NMR (DMSO-d.sub.6) δ: 7.80-7.92 (m, 3H), 7.69-7.78 (m, 1H), 7.52-7.61 (m, 1H), 7.22-7.39 (m, 3H), 4.88-5.00 (m, 1H), 3.70-3.85 (m, 2H), 3.50-3.66 (m, 5H), 3.17 (s, 3H), 2.18-2.31 (m, 2H), 1.87-2.04 (m, 2H).

[1897] LC-MS (Method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=438.4 [M+H].sup.+

Example 44

4-{4-[4-(2-methoxyethoxy)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1898] ##STR00162##

[1899] A suspension of 51 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (232 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 70 mg 4-[4-(2-methoxyethoxy)phenoxy]piperidine (279 μmol, intermediate 21) and 160 μL N,N-diisopropylethylamine (930 μmol) in 1 mL 2-propanol was stirred for 2 h at rt. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water-gradient) to give 29 mg of the title compound (99% purity, 29% yield).

[1900] .sup.1H NMR (DMSO-d.sub.6) δ: 7.80-7.91 (m, 1H), 7.68-7.77 (m, 1H), 7.57 (dd, 1H), 7.34 (td, 1H), 6.93-7.01 (m, 2H), 6.84-6.91 (m, 2H), 4.53-4.70 (m, 1H), 3.98-4.07 (m, 2H), 3.70-3.81 (m, 2H), 3.61-3.66 (m, 2H), 3.48-3.60 (m, 5H), 3.28 (s, 3H), 2.17 (ddd, 2H), 1.83-1.95 (m, 2H).

[1901] LC-MS (Method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=434.8 [M+H].sup.+

Example 45

4-{4-[4-(dimethylamino)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1902] ##STR00163##

[1903] A suspension of 66 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (303 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 80 mg N,N-dimethyl-4-[(piperidin-4-yl)oxy]aniline (363 μmol, intermediate 22) and 0.21 mL N,N-diisopropylethylamine (1.2 mmol) in 1.3 mL 2-propanol was stirred for 3 h at rt. After this time, water was added and the reaction was extracted with ethyl acetate (3×). The combined organic phases were filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 25 mg of the title compound were obtained (98% purity, 20% yield).

[1904] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.94 (m, 1H), 7.66-7.78 (m, 1H), 7.52-7.63 (m, 1H), 7.29-7.38 (m, 1H), 6.86-6.98 (m, 2H), 6.67-6.77 (m, 2H), 4.49-4.62 (m, 1H), 3.70-3.87 (m, 2H), 3.46-3.62 (m, 5H), 2.81 (s, 6H), 2.09-2.22 (m, 2H), 1.82-1.97 (m, 2H).

[1905] LC-MS (Method 2): R.sub.t=1.27 min; MS (ESIpos): m/z=403.3 [M+H].sup.+

Example 46

4-[4-(4-methoxyphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1906] ##STR00164##

[1907] A suspension of 44 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (201 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 50 mg 4-(4-methoxyphenoxy)piperidine (241 μmol, intermediate 23) and 0.14 mL N,N-diisopropylethylamine (800 μmol) in 870 μL 2-propanol was stirred for 2 h at rt. After this time, water was added and the reaction was extracted with ethyl acetate (2×). The combined organic phases were filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water-gradient). 12 mg of the title compound were obtained (97% purity, 15% yield).

[1908] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.93 (m, 1H), 7.68-7.76 (m, 1H), 7.53-7.62 (m, 1H), 7.31-7.39 (m, 1H), 6.82-7.02 (m, 4H), 4.54-4.68 (m, 1H), 3.66-3.83 (m, 5H), 3.46-3.60 (m, 5H), 2.12-2.25 (m, 2H), 1.79-1.97 (m, 2H).

[1909] LC-MS (Method 1): R.sub.t=1.24 min; MS (ESIpos): m/z=390.6 [M+H].sup.+

Example 47

1-methyl-2-oxo-4-(4-{4-[(propan-2-yl)oxy]phenoxy}piperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile

[1910] ##STR00165##

[1911] A solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 129 mg 4-{4-[(propan-2-yl)oxy]phenoxy}piperidine (549 μmol, intermediate 24) and 320 μL N,N-diisopropylethylamine (1.8 mmol) in 2 mL 2-propanol was stirred for 4 h at rt. After this time, water (50 ml) was added and the reaction was stirred for 1 h. The solid was collected by filtration, washed with water and dried under reduced pressure at 60° C. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 38.2 mg of the title compound were obtained (99% purity, 20% yield).

[1912] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (dd, 1H), 7.74 (ddd, 1H), 7.57 (dd, 1H), 7.34 (td, 1H), 6.91-7.00 (m, 2H), 6.82-6.90 (m, 2H), 4.56-4.67 (m, 1H), 4.48 (dt, 1H), 3.70-3.82 (m, 2H), 3.48-3.61 (m, 5H), 2.17 (ddd, 2H), 1.81-1.98 (m, 2H), 1.23 (d, 6H).

[1913] LC-MS (Method 1): R.sub.t=1.34 min; MS (ESIpos): m/z=418.3 [M+H].sup.+

Example 48

1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carboxamide

[1914] ##STR00166##

[1915] A mixture of 580 mg 1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (1.24 mmol, example 2), 70 mg palladium(II)diacetate (311 μmol) and 734 mg N-[(1E)-ethylidene]hydroxylamine (12.4 mmol, CAS 107-29-9) in 9.3 mL ethanol was stirred for 9 h at 80° C. Water was added and the reaction was extracted with ethyl acetate (2×). The organic phase was washed with brine and dried over sodium sulfate. After evaporation the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 530 mg of the title compound (95% purity, 88% yield).

[1916] .sup.1H NMR (DMSO-d.sub.6) δ: 7.83-8.03 (m, 1H), 7.59-7.74 (m, 2H), 7.40-7.58 (m, 2H), 7.24-7.36 (m, 3H), 7.06-7.19 (m, 2H), 4.58-4.70 (m, 1H), 3.59 (s, 3H), 3.34-3.45 (m, 2H), 3.07-3.22 (m, 2H), 2.09-2.20 (m, 2H), 1.78-1.93 (m, 2H).

[1917] LC-MS (Method 2): R.sub.t=1.27 min; MS (ESIpos): m/z=462.5 [M+H].sup.+

Example 49

4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide

[1918] ##STR00167##

[1919] A mixture of 50 mg 4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (121 μmol, example 9), 7 mg palladium(II)diacetate (30 μmol) and 71 mg N-[(1E)-ethylidene]hydroxylamine (1.2 mmol, CAS 107-29-9) in 5 mL ethanol was stirred for 6 h at 80° C. Water was added and the reaction was extracted with ethyl acetate (2×). The organic phase was washed with brine and dried over sodium sulfate. After evaporation the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 20 mg of the title compound (95% purity, 38% yield).

[1920] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.79-1.90 (m, 2H); 2.07-2.18 (m, 2H); 3.11-3.21 (m, 2H); 3.34-3.42 (m, 2H); 3.58 (s, 3H); 4.67 (dt, 1H); 6.97-7.01 (m, 2H); 7.10-7.12 (m, 1H); 7.28-7.33 (m, 2H); 7.53 (s, 2H); 7.59-7.65 (m, 1H); 7.68 (s, 1H); 7.91 (dd, 1H).

Example 50

4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide

[1921] ##STR00168##

[1922] A mixture of 50 mg 4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (121 μmol, example 10), 7 mg palladium(II)diacetate (30 μmol) and 71 mg N-[(1E)-ethylidene]hydroxylamine (1.2 mmol, CAS 107-29-9) in 5 mL ethanol was stirred for 4 h at 80° C. Water was added and the reaction was extracted with ethyl acetate (2×). The organic phase was washed with brine and dried over sodium sulfate. After evaporation the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 30 mg of the title compound (95% purity, 57% yield).

[1923] .sup.1H NMR (DMSO-d.sub.6) δ: 7.85-7.99 (m, 1H), 7.57-7.73 (m, 2H), 7.43-7.57 (m, 2H), 7.25-7.38 (m, 3H), 7.00-7.09 (m, 2H), 4.53-4.70 (m, 1H), 3.50-3.65 (m, 3H), 3.34-3.41 (m, 2H), 3.09-3.22 (m, 2H), 2.06-2.19 (m, 2H), 1.76-1.89 (m, 2H).

[1924] LC-MS (Method 2): R.sub.t=1.20 min; MS (ESIpos): m/z=412.5 [M+H].sup.+

Example 51

ethyl 4-{[1-(3-carbamoyl-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]oxy}benzoate

[1925] ##STR00169##

[1926] To a solution of 56 mg ethyl 4-{[1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]oxy}benzoate (130 μmol, example 12) in 2.0 mL ethanol were added 39 mg N-[(1E)-ethylidene]hydroxylamine (651 μmol, CAS 107-29-9) and 7 mg palladium(II)diacetate (33 μmol). The mixture was stirred for 3 h at 80° C. Water was added and the reaction was extracted with ethyl acetate (3×). The combined organic layers were filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 36.1 mg of the title compound (100% purity, 62% yield). 1H-NMR (400 MHz, DMSO-d6): 5 [ppm]=1.30 (t, 3H), 1.79-2.00 (m, 2H), 2.10-2.22 (m, 2H), 3.11-3.24 (m, 2H), 3.34-3.46 (m, 2H), 3.58 (s, 3H), 4.27 (q, 2H), 4.73 (dt, 1H), 7.08-7.15 (m, 2H), 7.27-7.35 (m, 1H), 7.48 (d, 1H), 7.50-7.54 (m, 1H), 7.59-7.66 (m, 1H), 7.68 (br d, 1H), 7.85-7.94 (m, 3H).

[1927] LC-MS (Method 3): R.sub.t=1.22 min; MS (ESIpos): m/z=450 [M+H].sup.+

Example 52

4-{4-[4-(difluoromethoxy)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide

[1928] ##STR00170##

[1929] A mixture of 50 mg 4-{4-[4-(difluoromethoxy)phenoxy]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (118 μmol, example 39), 7 mg palladium(II)diacetate (29 μmol) and 70 mg N-[(1E)-ethylidene]hydroxylamine (1.2 mmol, CAS 107-29-9) in 1 mL ethanol was stirred for 6 h at 80° C. Water was added and the re action was extracted with ethyl acetate (2×). The organic phase was washed with brine and dried over sodium sulfate. After evaporation the residue was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 28.8 mg of the title compound (100% purity, 55% yield).

[1930] .sup.1H NMR (DMSO-d.sub.6) δ: 7.91 (dd, 1H); 7.68 (s, 1H); 7.59-7.65 (m, 1H); 7.52 (d, 1H); 7.47 (br d, 1H); 6.90-7.35 (m, 6H); 4.53-4.62 (m, 1H); 3.58 (s, 3H); 3.36-3.42 (m, 2H); 3.09-3.19 (m, 2H); 2.07-2.17 (m, 2H); 1.79-1.90 (m, 2H).

[1931] LC-MS (Method 2): R.sub.t=1.15 min; MS (ESIpos): m/z=444.4 [M+H].sup.+

Example 53

1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile

[1932] ##STR00171##

[1933] A suspension of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 126 mg 4-(phenylsulfanyl)piperidine hydrogen chloride salt (1:1) (549 μmol, CAS 101798-66-7) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2.0 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried to give 141 mg of the title compound (78% yield, 95% purity).

[1934] .sup.1H NMR (DMSO-d.sub.6) δ: 7.80-7.85 (m, 1H), 7.68-7.76 (m, 1H), 7.53-7.61 (m, 1H), 7.42-7.49 (m, 2H), 7.24-7.41 (m, 4H), 3.72-3.82 (m, 2H), 3.62-3.72 (m, 1H), 3.54-3.61 (m, 3H), 3.42-3.53 (m, 2H), 2.05-2.18 (m, 2H), 1.71-1.86 (m, 2H).

[1935] LC-MS (Method 1): R.sub.t=1.35 min; MS (ESIpos): m/z=376 [M+H].sup.+

Example 54

7-bromo-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile

[1936] ##STR00172##

[1937] A suspension of 100 mg 7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (336 μmol, intermediate 27), 71.5 mg 4-phenoxypiperidine (403 μmol, CAS 3202-33-3) and 0.18 mL N,N-diisopropylethylamine (1.0 mmol) in 2.0 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried to give 123 mg of the title compound (79% yield, 95% purity).

[1938] .sup.1H NMR (DMSO-d.sub.6) δ: 7.72-7.83 (m, 2H), 7.47-7.51 (m, 1H), 7.26-7.35 (m, 2H), 7.02-7.09 (m, 2H), 6.89-6.98 (m, 1H), 4.68-4.88 (m, 1H), 3.70-3.81 (m, 2H), 3.49-3.61 (m, 5H), 2.12-2.26 (m, 2H), 1.85-1.99 (m, 2H).

[1939] LC-MS (Method 1): R.sub.t=1.40 min; MS (ESIpos): m/z=438 [M+H].sup.+

Example 55

7-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile

[1940] ##STR00173##

[1941] A suspension of 100 mg 7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (336 μmol, intermediate 27), 93 mg 4-(phenylsulfanyl)piperidine hydrogen chloride salt (1:1) (403 μmol, CAS 101798-66-7) and 0.18 mL N,N-diisopropylethylamine (1.0 mmol) in 2.0 mL 2-propanol was stirred for 2 h at 90° C. After this ti me, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried to give 141 mg of the title compound (87% yield, 95% purity).

[1942] .sup.1H NMR (DMSO-d.sub.6) δ: 7.67-7.80 (m, 2H), 7.43-7.51 (m, 3H), 7.32-7.40 (m, 2H), 7.23-7.32 (m, 1H), 3.63-3.81 (m, 3H), 3.41-3.58 (m, 5H), 2.04-2.17 (m, 2H), 1.73-1.86 (m, 2H).

[1943] LC-MS (Method 1): R.sub.t=1.46 min; MS (ESIpos): m/z=454 [M+H].sup.+

Example 56

7-bromo-4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1944] ##STR00174##

[1945] A suspension of 64 mg 7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (213 μmol, intermediate 27), 50 mg 4-(4-fluorophenoxy)piperidine hydrogen chloride salt (256 μmol, CAS 3202-34-4) and 0.11 mL N,N-diisopropylethylamine (640 μmol) in 1.3 mL 2-propanol was stirred for 2 h at 90° C. After this ti me, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried to give 80 mg of the title compound (78% yield, 95% purity).

[1946] .sup.1H NMR (DMSO-d.sub.6) δ: 7.72-7.82 (m, 2H), 7.49 (dd, J=8.9, 1.8 Hz, 1H), 7.01-7.20 (m, 4H), 4.62-4.78 (m, 1H), 3.69-3.80 (m, 2H), 3.47-3.61 (m, 5H), 2.07-2.23 (m, 2H), 1.78-2.02 (m, 2H).

[1947] LC-MS (Method 1): R.sub.t=1.40 min; MS (ESIpos): m/z=458 [M+H].sup.+

Example 57

7-bromo-4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1948] ##STR00175##

[1949] A suspension of 200 mg 7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (672 μmol, intermediate 27), 157 mg 4-(4-chlorophenoxy)piperidine (739 μmol, CAS 97839-99-1) and 190 μL triethylamine (1.3 mmol) in 9.3 mL 2-propanol was stirred for 5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, ethyl acetate was added and the reaction was stirred for some time. The residue was collected by filtration to give 116 mg of the title compound (95% purity, 35% yield).

[1950] .sup.1H NMR (DMSO-d.sub.6) δ: 7.69-7.84 (m, 2H), 7.43-7.55 (m, 1H), 7.27-7.38 (m, 2H), 7.01-7.11 (m, 2H), 4.69-4.83 (m, 1H), 3.67-3.81 (m, 2H), 3.47-3.62 (m, 5H), 2.11-2.26 (m, 2H), 1.82-1.98 (m, 2H).

[1951] LC-MS (Method 2): R.sub.t=1.48 min; MS (ESIpos): m/z=472 [M+H].sup.+

Example 58

7-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1952] ##STR00176##

[1953] A solution of 150 mg 7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (504 μmol, intermediate 27), 145 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (555 μmol, CAS 287952-67-4) and 0.14 mL triethylamine (1.0 mmol) in 2-propanol was stirred for 3 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 175 mg of the title compound were obtained (95% purity, 63% yield).

[1954] .sup.1H NMR (DMSO-d.sub.6) δ: 7.72-7.85 (m, 2H), 7.45-7.54 (m, 1H), 7.27-7.33 (m, 2H), 7.09-7.21 (m, 2H), 4.78 (tt, 1H), 3.67-3.83 (m, 2H), 3.47-3.63 (m, 5H), 2.13-2.26 (m, 2H), 1.84-1.99 (m, 2H).

[1955] LC-MS (Method 2): R.sub.t=1.50 min; MS (ESIpos): m/z=523 [M+H].sup.+

Example 59

7-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1956] ##STR00177##

[1957] A suspension of 174 mg 7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (584 μmol, intermediate 27), 172 mg 4-[4-(trifluoromethyl)phenoxy]piperidine (701 μmol, CAS 28033-37-6) and 0.31 mL N,N-diisopropylethylamine (1.8 mmol) in 3.5 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried to give 267 mg of the title compound (86% yield, 95% purity).

[1958] .sup.1H NMR (DMSO-d.sub.6) δ: 7.73-7.82 (m, 2H), 7.63-7.73 (m, 2H), 7.44-7.55 (m, 1H), 7.19-7.30 (m, 2H), 4.83-5.00 (m, 1H), 3.69-3.82 (m, 2H), 3.50-3.62 (m, 5H), 2.16-2.28 (m, 2H), 1.87-2.00 (m, 2H).

[1959] LC-MS (Method 1): R.sub.t=1.49 min; MS (ESIpos): m/z=508 [M+H].sup.+

Example 60

7-bromo-4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1960] ##STR00178##

[1961] A solution of 200 mg 7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (672 μmol, intermediate 27), 157 mg 4-(3-chlorophenoxy)piperidine (739 μmol, CAS 97840-40-9) and 0.19 mL triethylamine (1.3 mmol) in 9.3 mL 2-propanol was stirred for 5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 250 mg of the title compound were obtained (95% purity, 75% yield).

[1962] .sup.1H NMR (DMSO-d.sub.6) δ: 7.70-7.84 (m, 2H), 7.45-7.54 (m, 1H), 7.28-7.39 (m, 1H), 7.12-7.19 (m, 1H), 6.98-7.06 (m, 2H), 4.78-4.95 (m, 1H), 3.69-3.81 (m, 2H), 3.49-3.64 (m, 5H), 2.13-2.26 (m, 2H), 1.83-1.97 (m, 2H).

[1963] LC-MS (Method 2): R.sub.t=1.47 min; MS (ESIpos): m/z=472 [M+H].sup.+

Example 61

7-bromo-1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1964] ##STR00179##

[1965] A solution of 300 mg 7-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.01 mmol, intermediate 27), 290 mg 4-[3-(trifluoromethoxy)phenoxy]piperidine (1.11 mmol, CAS 459819-38-6) and 0.28 mL triethylamine (2.0 mmol) in 14 mL 2-propanol was stirred for 5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 370 mg of the title compound were obtained (95% purity, 76% yield).

[1966] .sup.1H NMR (DMSO-d.sub.6) δ: 7.73-7.82 (m, 2H), 7.37-7.52 (m, 2H), 7.05-7.15 (m, 2H), 6.94 (dt, 1H), 4.78-4.90 (m, 1H), 3.68-3.81 (m, 2H), 3.48-3.61 (m, 5H), 2.15-2.25 (m, 2H), 1.80-2.00 (m, 2H).

[1967] LC-MS (Method 2): R.sub.t=1.49 min; MS (ESIpos): m/z=523 [M+H].sup.+

Example 62

7-hydroxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1968] ##STR00180##

[1969] A suspension of 100 mg 4-chloro-7-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (426 μmol, intermediate 31), 111 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (426 μmol, CAS 287952-67-4) and 120 μL triethylamine (850 μmol) in 5 mL 2-propanol was stirred for 2 h at 90° C. After this time, water and ethyl acetate were added and the reaction was stirred for some time. The solid was collected by filtration. The impure product was stirred in dichloromethane/methanol for some time. The residue was collected by filtration to give 100 mg of the title compound (95% purity, 49% yield).

[1970] .sup.1H NMR (DMSO-d.sub.6) δ: 10.80 (br s, 1H), 7.67-7.75 (m, 1H), 7.24-7.40 (m, 2H), 7.06-7.23 (m, 2H), 6.70-6.85 (m, 2H), 4.69-4.83 (m, 1H), 3.64-3.81 (m, 2H), 3.46-3.56 (m, 5H), 2.12-2.24 (m, 2H), 1.80-1.95 (m, 2H).

[1971] LC-MS (Method 1): R.sub.t=1.27 min; MS (ESIpos): m/z=460 [M+H].sup.+

Example 63

7-fluoro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1972] ##STR00181##

[1973] A suspension of 120 mg 4-chloro-7-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (487 μmol, intermediate 34), 157 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (584 μmol, CAS 287952-67-4) and 250 μL triethylamine (1.5 mmol) in 3 mL 2-propanol was stirred for 4 h at 90° C. After this time, water was added and the reaction was stirred for some time. The solid was collected by filtration, washed with water, ethanol and hexane and dried. 216 mg of the title compound was obtained (99% purity, 95% yield).

[1974] .sup.1H NMR (DMSO-d.sub.6) δ: 7.93 (dd, 1H), 7.46 (dd, 1H), 7.28-7.34 (m, 2H), 7.12-7.23 (m, 3H), 4.78 (dt, 1H), 3.70-3.80 (m, 2H), 3.50-3.60 (m, 5H), 2.20 (ddd, 2H), 1.86-1.97 (m, 2H).

[1975] LC-MS (Method 1): R.sub.t=1.44 min; MS (ESIpos): m/z=462 [M+H].sup.+

Example 64

7-chloro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1976] ##STR00182##

[1977] A suspension of 120 mg 4,7-dichloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (450 μmol, intermediate 37), 164 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (541 μmol, CAS 287952-67-4) and 240 μL triethylamine (1.4 mmol) in 3 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The solid was collected by filtration, washed with water and hexane and dried. 198 mg of the title compound was obtained (99% purity, 83% yield).

[1978] .sup.1H NMR (DMSO-d.sub.6) δ: 7.86 (d, 1H), 7.66 (d, 1H), 7.37 (dd, 1H), 7.27-7.34 (m, 2H), 7.11-7.17 (m, 2H), 4.78 (dt, 1H), 3.71-3.80 (m, 2H), 3.49-3.60 (m, 5H), 2.16-2.25 (m, 2H), 1.86-1.97 (m, 2H).

[1979] LC-MS (Method 2): R.sub.t=1.49 min; MS (ESIpos): m/z=478 [M+H].sup.+

Example 65

4-[4-(4-chlorophenoxy)piperidin-1-yl]-7-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[1980] ##STR00183##

[1981] 30 mg 7-bromo-4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (64 μmol, example 57), 5.5 mg (2′-amino[biphenyl]-2-yl)(methanesulfonato-kappaO)palladium-di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxy [biphenyl]-2-yl)phosphine (1:1) (6.4 μmol, CAS 1536473-72-9), 3.1 mg di-tert-butyl[3,6-dimethoxy-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphine (6.4 μmol, CAS 1160861-53-9) and 29 mg cesium carbonate (89 μmol) were sealed in a vessel and flushed with argon. 1.0 mL toluene and 26 μL methanol were added and the mixture was stirred overnight at 60° C. The mixture was filtered via a silica column. The column was washed with dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 2.4 mg of the title compound (95% purity, 8% yield).

[1982] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.59-7.70 (m, 1H), 7.07-7.15 (m, 2H), 6.79-6.87 (m, 2H), 6.66-6.76 (m, 2H), 4.44-4.56 (m, 1H), 3.76 (s, 3H), 3.55-3.66 (m, 2H), 3.33-3.44 (m, 5H), 2.00-2.09 (m, 2H), 1.79-1.84 (m, 2H).

Example 66

7-methoxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1983] ##STR00184##

mg 7-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydro-quinoline-3-carbonitrile (59 μmol, example 59), 5.1 mg (2′-amino[biphenyl]-2-yl)(methanesulfonato-kappaO)palladium-di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxy [biphenyl]-2-yl)phosphine (1:1) (5.9 μmol, CAS 1536473-72-9), 2.9 mg di-tert-butyl[3,6-dimethoxy-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphine (5.9 μmol, CAS 1160861-53-9) and 27 mg cesium carbonate (83 μmol) were sealed in a vessel and flushed with argon. 1.0 mL toluene and 24 μL methanol were added and the mixture was stirred overnight at 60° C. The mixture was filtered via a silica column. The column was washed with dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 3.6 mg of the title compound (100% purity, 13% yield).

[1984] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.60 (d, 1H), 7.41 (d, 2H), 6.93 (d, 2H), 6.61-6.71 (m, 2H), 4.53-4.65 (m, 1H), 3.72 (s, 3H), 3.53-3.64 (m, 2H), 3.29-3.43 (m, 5H), 2.03 (ddt, Hz, 2H), 1.74-1.82 (m, 2H).

Example 67

1,7-dimethyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[1985] ##STR00185##

[1986] A suspension of 122 mg 4-chloro-1,7-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (514 μmol, intermediate 40), 166 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (617 μmol, CAS 287952-67-4) and 0.27 mL N,N-diisopropylethylamine (1.5 mmol) in 3.0 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with water and ethanol. The resulting solid was dried to give 231 mg of the title compound (100% yield, 98% purity).

[1987] .sup.1H NMR (DMSO-d.sub.6) δ: 7.75 (d, 1H), 7.40 (s, 1H), 7.31 (d, 2H), 7.12-7.19 (m, 3H), 4.77 (dt, 1H), 3.70-3.79 (m, 2H), 3.50-3.59 (m, 5H), 2.47 (s, 3H), 2.16-2.24 (m, 2H), 1.86-1.96 (m, 2H).

[1988] LC-MS (Method 1): R.sub.t=1.49 min; MS (ESIpos): m/z=458.5 [M+H].sup.+

Example 68

7-cyclopropyl-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile

[1989] ##STR00186##

[1990] 30 mg 7-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile (66 μmol, example 55) and 5.8 mg di-μ-iodobis(tri-tert-butylphosphino)dipalladium(I) (6.6 μmol, CAS 166445-62-1) were sealed in a vessel and flushed with argon. 1.1 mL toluene was added and the mixture was stirred at rt. 400 μL bromo(cyclopropyl)zinc (0.50 M, 200 μmol, CAS 126403-68-7) was added dropwise. The mixture was stirred at rt for 1 h. The mixture was filtered via a silica column. The column was washed with dichloromethane and dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient) to give 24.9 mg of the title compound (100% purity, 91% yield).

[1991] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.53-7.68 (m, 1H), 7.33-7.42 (m, 2H), 7.15-7.31 (m, 3H), 6.99-7.11 (m, 1H), 6.78-6.86 (m, 1H), 3.60-3.73 (m, 2H), 3.31-3.45 (m, 3H), 1.91-2.00 (m, 1H), 1.81-1.89 (m, 5H), 1.66-1.80 (m, 2H), 0.96-1.08 (m, 2H), 0.72-0.81 (m, 2H).

[1992] LC-MS (Method 1): R.sub.t=1.47 min; MS (ESIpos): m/z=416 [M+H].sup.+

Example 69

7-butoxy-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile

[1993] ##STR00187##

[1994] 30 mg 7-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile (66 μmol, example 55), 5.5 mg (2′-aminobiphenyl-2-yl)(methanesulfonato-kappaO)palladium-di-tert-butyl[3-methoxy-6-methyl-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphine (1:1) (6.6 μmol, CAS 1445085-55-1), 3.1 mg di-tert-butyl[3-methoxy-6-methyl-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphine (6.6 μmol, CAS 1262046-34-3) and 30 mg cesium carbonate (92 μmol) were sealed in a vessel and flushed with argon. 1.0 mL toluene and 60 μL n-butanol were added and the mixture was stirred overnight at 80° C. The mixture was filtered via a silica column. The column was washed with dichloromethane and dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient) to give 21.5 mg of the title compound (100% purity, 73% yield).

[1995] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.49-7.58 (m, 1H), 7.20-7.37 (m, 2H), 7.02-7.19 (m, 3H), 6.56-6.67 (m, 2H), 3.84-4.00 (m, 2H), 3.49-3.60 (m, 2H), 3.34 (s, 3H), 3.18-3.32 (m, 3H), 1.90 (br d, 2H), 1.51-1.69 (m, 4H), 1.23-1.35 (m, 2H), 0.72-0.81 (m, 3H).

[1996] LC-MS (Method 1): R.sub.t=1.58 min; MS (ESIpos): m/z=448 [M+H].sup.+

Example 70

7-(cyclopropyloxy)-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile

[1997] ##STR00188##

[1998] 30 mg 7-bromo-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile (68 μmol, example 54), 5.7 mg (2′-aminobiphenyl-2-yl)(methanesulfonato-kappaO)palladium-di-tert-butyl[3-methoxy-6-methyl-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphine (1:1) (6.8 μmol, CAS 1445085-55-1), 3.2 mg di-tert-butyl[3-methoxy-6-methyl-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphine (6.8 μmol, CAS 1262046-34-3) and 31 mg cesium carbonate (96 μmol) were sealed in a vessel and flushed with argon. 1.0 mL toluene and 33 μL cyclopropanol were added and the mixture was stirred overnight at 80° C. The mixture was filtered via a silica column. The column was washed with dichloromethane and dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient) to give 23.5 mg of the title compound (100% purity, 83% yield).

[1999] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.49-7.58 (m, 1H), 7.20-7.37 (m, 2H), 7.02-7.19 (m, 3H), 6.56-6.67 (m, 2H), 3.84-4.00 (m, 2H), 3.49-3.60 (m, 2H), 3.34 (s, 3H), 3.18-3.32 (m, 3H), 1.90 (br d, 2H), 1.51-1.69 (m, 4H), 1.23-1.35 (m, 2H), 0.72-0.81 (m, 3H).

[2000] LC-MS (Method 1): R.sub.t=1.58 min; MS (ESIpos): m/z=448 [M+H].sup.+

Example 71

7-methoxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2001] ##STR00189##

[2002] 30 mg 7-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (57 μmol, example 58), 4.9 mg (2′-amino[biphenyl]-2-yl)(methanesulfonato-kappaO)palladium-di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[biphenyl]-2-yl)phosphine (1:1) (5.74 μmol, CAS 1536473-72-9), 2.8 mg di-tert-butyl[3,6-dimethoxy-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphine (5.7 μmol, CAS 1160861-53-9) and 26 mg cesium carbonate (80 μmol) were sealed in a vessel and flushed with argon. 1.0 mL toluene and 23 μL methanol were added and the mixture was stirred overnight at 60° C. The mixture was filtered via a silica column. The column was washed with dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 4.1 mg of the title compound (100% purity, 15% yield).

[2003] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.64 (d, 1H), 7.02-7.12 (m, 2H), 6.86-6.94 (m, 2H), 6.66-6.82 (m, 2H), 4.47-4.60 (m, 1H), 3.76 (s, 3H), 3.56-3.67 (m, 2H), 3.42 (s, 3H), 3.33-3.41 (m, 2H), 2.01-2.10 (m, 2H), 1.79-1.85 (m, 2H).

[2004] LC-MS (Method 2): R.sub.t=1.43 min; MS (ESIpos): m/z=474 [M+H].sup.+

Example 72

4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-7-(oxetan-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2005] ##STR00190##

[2006] 50 mg 7-bromo-4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (106 μmol, example 57), 2.4 mg bis{3,5-difluoro-2-[5-(trifluoromethyl)pyridin-2-yl]phenyl}iridium(I)hexafluorophosphate-4,4′-di-tert-butyl-2,2′-bipyridine (1:1:1) (2.1 μmol, CAS 870987-63-6) and 74 μL 2,6-dimethylpyridine (635 μmol) were dissolved in the reaction vial in 1.9 mL 1,2-dimethoxyethane. In a separate vial the Ni-catalyst was prepared by dissolving 1.2 mg 1,2-dimethoxyethane-dichloronickel (1:1) (5.3 μmol) and 1.4 mg 4,4′-di-tert-butyl-2,2′-bipyridine (5.3 μmol) in 1.9 mL 1,2-dimethoxyethane followed by stirring for 5 min. The catalyst solution was syringed to the sealed reaction vial and was degassed with argon for 5 min., then 39.5 μL 3-bromooxetane (476 μmol, CAS 39267-79-3) and 32.6 μL 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (106 μmol) was added. The vial was placed in a water bath (to keep the temperature below 35° C.) and was subsequently irradiated by two 40 W Kessil LED Aquarium lamps for 16 h. The reaction was quenched with water, extracted with ethyl acetate (3×), dried over sodium sulfate and concentrated in vacuum. The crude material was purificated by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 20 mg of the title compound were obtained (93% purity, 12% yield).

[2007] .sup.1H NMR (DMSO-d.sub.6) δ: 7.84-7.92 (m, 1H), 7.51 (s, 2H), 7.32-7.40 (m, 2H), 7.05-7.12 (m, 2H), 4.93-5.03 (m, 2H), 4.73-4.80 (m, 1H), 4.66-4.72 (m, 2H), 4.36-4.51 (m, 1H), 3.69-3.82 (m, 2H), 3.49-3.62 (m, 5H), 2.15-2.25 (m, 2H), 1.86-1.98 (m, 2H).

[2008] LC-MS (Method 2): R.sub.t=1.30 min; MS (ESIpos): m/z=450.5 [M+H].sup.+

Example 73

4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-7-(oxetan-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2009] ##STR00191##

[2010] 50 mg 7-bromo-4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (106 μmol, example 60), 2.4 mg bis{3,5-difluoro-2-[5-(trifluoromethyl)pyridin-2-yl]phenyl}iridium(I)hexafluorophosphate-4,4′-di-tert-butyl-2,2′-bipyridine (1:1:1) (2.1 μmol, CAS 870987-63-6) and 74 μL 2,6-dimethylpyridine (635 μmol) were dissolved in the reaction vial in 1.9 mL 1,2-dimethoxyethane. In a separate vial the Ni-catalyst was prepared by dissolving 1.2 mg 1,2-dimethoxyethane-dichloronickel (1:1) (5.3 μmol) and 1.4 mg 4,4′-di-tert-butyl-2,2′-bipyridine (5.3 μmol) in 1.9 mL 1,2-dimethoxyethane followed by stirring for 5 min. The catalyst solution was syringed to the sealed reaction vial and was degassed with argon for 5 min., then 39.5 μL 3-bromooxetane (476 μmol, CAS 39267-79-3) and 32.6 μL 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (106 μmol) was added. The vial was placed in a water bath (to keep the temperature below 35° C.) and was subsequently irradiated by two 40 W Kessil LED Aquarium lamps for 16 h. The reaction was quenched with water, extracted with ethyl acetate (3×), dried over sodium sulfate and concentrated in vacuum. The crude material was purificated by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 14 mg of the title compound were obtained (95% purity, 9% yield).

[2011] .sup.1H NMR (DMSO-d.sub.6) δ: 7.88 (d, 1H), 7.41-7.51 (m, 2H), 7.25-7.39 (m, 1H), 7.12-7.21 (m, 1H), 6.97-7.06 (m, 2H), 4.95-5.03 (m, 2H), 4.77-4.91 (m, 1H), 4.64-4.74 (m, 2H), 4.36-4.52 (m, 1H), 3.70-3.85 (m, 2H), 3.50-3.62 (m, 5H), 2.14-2.26 (m, 2H), 1.84-2.01 (m, 2H).

[2012] LC-MS (Method 2): R.sub.t=1.30 min; MS (ESIpos): m/z=450.5 [M+H].sup.+

Example 74

4-[4-(3-chlorophenoxy)piperidin-1-yl]-7-(2-methoxyethyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2013] ##STR00192##

[2014] 50 mg 7-bromo-4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (106 μmol, example 60), 2.4 mg bis{3,5-difluoro-2-[5-(trifluoromethyl)pyridin-2-yl]phenyl}iridium(I)hexafluorophosphate-4,4′-di-tert-butyl-2,2′-bipyridine (1:1:1) (2.1 μmol, CAS 870987-63-6) and 74 μL 2,6-dimethylpyridine (635 μmol) were dissolved in the reaction vial in 1.9 mL 1,2-dimethoxyethane. In a separate vial the Ni-catalyst was prepared by dissolving 1.2 mg 1,2-dimethoxyethane-dichloronickel (1:1) (5.3 μmol) and 1.4 mg 4,4′-di-tert-butyl-2,2′-bipyridine (5.3 μmol) in 1.9 mL 1,2-dimethoxyethane followed by stirring for 5 min. The catalyst solution was syringed to the sealed reaction vial and was degassed with argon for 5 min., then 44.7 μL 1-bromo-2-methoxyethane (476 μmol, CAS 6482-24-2) and 32.6 μL 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (106 μmol) was added. The vial was placed in a water bath (to keep the temperature below 35° C.) and was subsequently irradiated by two 40 W Kessil LED Aquarium lamps for 16 h. The reaction was quenched with water, extracted with ethyl acetate (3×), dried over sodium sulfate and concentrated in vacuum. The crude material was purificated by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 20 mg of the title compound were obtained (95% purity, 13% yield).

[2015] .sup.1H NMR (DMSO-d.sub.6) δ: 7.74-7.79 (m, 1H), 7.41-7.45 (m, 1H), 7.27-7.36 (m, 1H), 7.19-7.25 (m, 1H), 7.12-7.18 (m, 1H), 6.98-7.05 (m, 2H), 4.73-4.89 (m, 1H), 3.70-3.80 (m, 2H), 3.50-3.64 (m, 7H), 3.22-3.27 (m, 3H), 2.97 (t, 2H), 2.19 (ddd, 2H), 1.84-1.96 (m, 2H).

[2016] LC-MS (Method 2): R.sub.t=1.40 min; MS (ESIpos): m/z=452.5 [M+H].sup.+

Example 75

4-[4-(4-chlorophenoxy)piperidin-1-yl]-7-(2-methoxyethyl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2017] ##STR00193##

[2018] 50 mg 7-bromo-4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (106 μmol, example 57), 2.4 mg bis{3,5-difluoro-2-[5-(trifluoromethyl)pyridin-2-yl]phenyl}iridium(I)hexafluorophosphate-4,4′-di-tert-butyl-2,2′-bipyridine (1:1:1) (2.1 μmol, CAS 870987-63-6) and 74 μL 2,6-dimethylpyridine (635 μmol) were dissolved in the reaction vial in 1.9 mL 1,2-dimethoxyethane. In a separate vial the Ni-catalyst was prepared by dissolving 1.2 mg 1,2-dimethoxyethane-dichloronickel (1:1) (5.3 μmol) and 1.4 mg 4,4′-di-tert-butyl-2,2′-bipyridine (5.3 μmol) in 1.9 mL 1,2-dimethoxyethane followed by stirring for 5 min. The catalyst solution was syringed to the sealed reaction vial and the solution was degassed with argon for 5 min., then 44.7 μL 1-bromo-2-methoxyethane (476 μmol, CAS 6482-24-2) and 32.6 μL 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (106 μmol) was added. The vial was placed in a water bath (to keep the temperature below 35° C.) and was subsequently irradiated by two 40 W Kessil LED Aquarium lamps for 16 h. The reaction was quenched with water, extracted with ethyl acetate (3×), dried over sodium sulfate and concentrated in vacuum. The crude material was purificated by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 9 mg of the title compound were obtained (95% purity, 6% yield).

[2019] .sup.1H NMR (DMSO-d.sub.6) δ: 7.63-7.75 (m, 1H), 7.09-7.41 (m, 4H), 6.91-7.07 (m, 2H), 4.60-4.76 (m, 1H), 3.37-3.75 (m, 9H), 3.16 (s, 3H), 2.88 (br t, 2H), 2.04-2.18 (m, 2H), 1.73-1.88 (m, 2H).

[2020] LC-MS (Method 2): R.sub.t=1.37 min; MS (ESIpos): m/z=452.4 [M+H].sup.+

Example 76

7-(2-methoxyethyl)-1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2021] ##STR00194##

[2022] 60 mg 7-bromo-1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (115 μmol, example 61), 2.6 mg bis{3,5-difluoro-2-[5-(trifluoromethyl)pyridin-2-yl]phenyl}iridium(I)hexafluorophosphate-4,4′-di-tert-butyl-2,2′-bi-pyridine (1:1:1) (2.3 μmol, CAS 870987-63-6) and 80 μL 2,6-dimethylpyridine (689 μmol) were dissolved in the reaction vial in 2.1 mL 1,2-dimethoxyethane. In a separate vial the Ni-catalyst was prepared by dissolving 1.3 mg 1,2-dimethoxyethane-dichloronickel (1:1) (5.7 μmol) and 1.5 mg 4,4′-di-tert-butyl-2,2′-bipyridine (5.7 μmol) in 2.1 mL 1,2-dimethoxyethane followed by stirring for 5 min. The catalyst solution was syringed to the sealed reaction vial and the solution was degassed with argon for 5 min., then 49 μL 1-bromo-2-methoxyethane (517 μmol, CAS 6482-24-2) and 35 μL 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (115 μmol) was added. The vial was placed in a water bath (to keep the temperature below 35° C.) and was subsequently irradiated by two 40 W Kessil LED Aquarium lamps for 16 h. The reaction was quenched with water, extracted with ethyl acetate (3×), dried over sodium sulfate and concentrated in vacuum. The crude material was purificated by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 21 mg of the title compound were obtained (95% purity, 13% yield).

[2023] .sup.1H NMR (DMSO-d.sub.6) δ: 7.73-7.81 (m, 1H), 7.39-7.46 (m, 2H), 7.18-7.28 (m, 1H), 7.02-7.14 (m, 2H), 6.90-7.00 (m, 1H), 4.76-4.93 (m, 1H), 3.70-3.83 (m, 2H), 3.47-3.67 (m, 7H), 3.20-3.27 (m, 3H), 2.92-3.01 (m, 2H), 2.15-2.24 (m, 2H), 1.86-1.99 (m, 2H).

[2024] LC-MS (Method 2): R.sub.t=1.43 min; MS (ESIpos): m/z=502.5 [M+H].sup.+

Example 77

1-methyl-7-(oxetan-3-yl)-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2025] ##STR00195##

[2026] 60 mg 7-bromo-1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (115 μmol, example 61), 2.6 mg bis{3,5-difluoro-2-[5-(trifluoromethyl)pyridin-2-yl]phenyl}iridium(I)hexafluorophosphate-4,4′-di-tert-butyl-2,2′-bi-pyridine (1:1:1) (2.3 μmol, CAS 870987-63-6) and 80 μL 2,6-dimethylpyridine (689 μmol) were dissolved in the reaction vial in 2.1 mL 1,2-dimethoxyethane. In a separate vial the Ni-catalyst was prepared by dissolving 1.3 mg 1,2-dimethoxyethane-dichloronickel (1:1) (5.7 μmol) and 1.5 mg 4,4′-di-tert-butyl-2,2′-bipyridine (5.7 μmol) in 2.1 mL 1,2-dimethoxyethane followed by stirring for 5 min. The catalyst solution was syringed to the sealed reaction vial and the solution was degassed with argon for 5 min., then 43 μL 3-bromooxetane (517 μmol, CAS 39267-79-3) and 35 μL 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (115 μmol) was added. The vial was placed in a water bath (to keep the temperature below 35° C.) and was subsequently irradiated by two 40 W Kessil LED Aquarium lamps for 16 h. The reaction was quenched with water, extracted with ethyl acetate (3×), dried over sodium sulfate and concentrated in vacuum. The crude material was purificated by flash chromatography (silica, dichloromethane/methanol gradient 0-1%). 26 mg of the title compound were obtained (95% purity, 16% yield).

[2027] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.92 (m, 1H), 7.39-7.51 (m, 3H), 7.06-7.14 (m, 2H), 6.89-6.99 (m, 1H), 4.94-5.08 (m, 2H), 4.77-4.91 (m, 1H), 4.65-4.75 (m, 2H), 4.36-4.49 (m, 1H), 3.71-3.82 (m, 2H), 3.51-3.64 (m, 5H), 2.16-2.27 (m, 2H), 1.83-1.99 (m, 2H).

[2028] LC-MS (Method 2): R.sub.t=1.36 min; MS (ESIpos): m/z=500.5 [M+H].sup.+

Example 78

7-(dimethylphosphoryl)-1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2029] ##STR00196##

[2030] To a suspension of 150 mg 7-bromo-1-methyl-2-oxo-4-{4-[3-(trifluoromethoxy)phenoxy]-piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (287 μmol, example 61), 10 mg (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17 μmol), 3.2 mg palladium(II)diacetate (14 μmol) and 67 mg tripotassium phosphate (316 μmol) in 5 mL DMF was added 26.5 mg dimethylphosphine oxide (316 μmol, CAS 7211-39-4) and the mixture was stirred for 6 h at 130° C. Water was added, and the reaction was extracted with ethyl acetate (2×). The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 95 mg of the title compound (95% purity, 60% yield).

[2031] .sup.1H NMR (DMSO-d.sub.6) δ: 7.93-8.03 (m, 1H), 7.78-7.88 (m, 1H), 7.61-7.73 (m, 1H), 7.40-7.47 (m, 1H), 7.05-7.16 (m, 2H), 6.89-6.99 (m, 1H), 4.79-4.92 (m, 1H), 3.71-3.85 (m, 2H), 3.52-3.67 (m, 5H), 2.15-2.26 (m, 2H), 1.88-1.99 (m, 2H), 1.74 (d, 6H).

[2032] LC-MS (Method 2): R.sub.t=1.19 min; MS (ESIpos): m/z=520.5 [M+H].sup.+

Example 79

7-(dimethylphosphoryl)-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2033] ##STR00197##

[2034] To a suspension of 140 mg 7-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]-piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (268 μmol, example 58), 9.3 mg (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (16 μmol), 3 mg palladium(II)diacetate (13 μmol) and 63 mg tripotassium phosphate (295 μmol) in 6 mL DMF was added 24.7 mg dimethylphosphine oxide (295 μmol, CAS 7211-39-4) and the mixture was stirred for 6 h at 130° C. Water was added, and the reaction was extracted with ethyl acetate (2×). The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-5%). The impure product was stirred in ethyl acetate overnight. The solid that precipitated from this procedure was collected by filtration and dried. 49 mg of the title compound were obtained (95% purity, 33% yield).

[2035] .sup.1H NMR (DMSO-d.sub.6) δ: 7.95-8.06 (m, 1H), 7.76-7.86 (m, 1H), 7.63-7.70 (m, 1H), 7.25-7.39 (m, 2H), 7.11-7.19 (m, 2H), 4.72-4.86 (m, 1H), 3.73-3.84 (m, 2H), 3.52-3.69 (m, 5H), 2.15-2.26 (m, 2H), 1.87-2.03 (m, 2H), 1.74 (d, 6H).

[2036] LC-MS (Method 2): R.sub.t=1.16 min; MS (ESIpos): m/z=520.3 [M+H].sup.+

Example 80

4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-7-(4-methylpiperazin-1-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2037] ##STR00198##

[2038] A suspension of 90 mg 7-bromo-4-[4-(3-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (190 μmol, example 60), 23 mg 1-methylpiperazine (228 μmol, CAS 109-01-3), 15 mg chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (19.0 μmol) and 124 mg cesium carbonate (381 μmol) in 1,4-dioxane was stirred for 4 h at 110° C. Water was added, and the reaction was extracted with ethyl acetate (2×). The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). The impure product was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-1%) to give 5 mg of the title compound (95% purity, 5% yield).

[2039] .sup.1H NMR (DMSO-d.sub.6) δ: 7.58-7.68 (m, 1H), 7.27-7.38 (m, 1H), 7.12-7.19 (m, 1H), 6.94-7.05 (m, 3H), 6.62-6.74 (m, 1H), 4.72-4.87 (m, 1H), 3.62-3.79 (m, 2H), 3.46-3.57 (m, 5H), 3.41-3.46 (m, 4H), 2.42-2.46 (m, 4H), 2.21-2.25 (m, 3H), 2.10-2.20 (m, 2H), 1.78-1.94 (m, 2H).

[2040] LC-MS (Method 2): R.sub.t=1.33 min; MS (ESIpos): m/z=492.4 [M+H].sup.+

Example 81

7-(2-methoxyethoxy)-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2041] ##STR00199##

[2042] A mixture of 100 mg 7-hydroxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (218 μmol, example 62), 200 μL 1-bromo-2-methoxyethane (2.2 mmol, CAS 6482-24-2) and 60 mg potassium carbonate (435 μmol) in 5.0 mL acetonitrile was refluxed for 2 h. Water was added. The mixture was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 75 mg of the title compound (98% purity, 65% yield).

[2043] .sup.1H NMR (DMSO-d.sub.6) δ: 7.74-7.81 (m, 1H), 7.27-7.36 (m, 2H), 7.10-7.19 (m, 2H), 6.91-7.03 (m, 2H), 4.69-4.87 (m, 1H), 4.29 (dd, 2H), 3.65-3.82 (m, 4H), 3.49-3.57 (m, 5H), 3.32 (s, 3H), 2.11-2.26 (m, 2H), 1.83-1.96 (m, 2H).

[2044] LC-MS (Method 2): R.sub.t=1.39 min; MS (ESIpos): m/z=518.5 [M+H].sup.+

Example 82

1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2045] ##STR00200##

[2046] A suspension of 194 mg 7-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (371 μmol, example 58), 63 mg pyrrolidin-2-one (743 μmol, CAS 616-45-5), 160 μL N,N′-dimethylethane-1,2-diamine (1.5 mmol), 14 mg copper(I)iodide (74 μmol) and 113 mg potassium carbonate (817 μmol) in 6.3 mL toluene was stirred overnight at 110° C. The mixture was cooled down to rt, water was added and the mixture was extracted with dichloromethane. The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/ethanol gradient 0-5%). The impure product was stirred in ethanol, the precipitate was collected by filtration and dried in vacuum. 156 mg of the title compound were obtained (76% yield, 95% purity).

[2047] .sup.1H NMR (DMSO-d.sub.6) δ: 7.76-7.90 (m, 2H), 7.63-7.72 (m, 1H), 7.25-7.38 (m, 2H), 7.10-7.20 (m, 2H), 4.68-4.89 (m, 1H), 3.88-4.06 (m, 2H), 3.68-3.82 (m, 2H), 3.46-3.65 (m, 5H), 2.55-2.63 (m, 2H), 2.15-2.28 (m, 2H), 2.06-2.15 (m, 2H), 1.85-2.00 (m, 2H).

[2048] LC-MS (Method 4): R.sub.t=1.31 min; MS (ESIpos): m/z=527 [M+H].sup.+

Example 83

1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile

[2049] ##STR00201##

[2050] A suspension of 219 mg 7-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile (482 μmol, example 55), 82 mg pyrrolidin-2-one (964 μmol, CAS 616-45-5), 210 μL N,N′-dimethylethane-1,2-diamine (1.9 mmol), 18 mg copper(I)iodide (96 μmol) and 147 mg potassium carbonate (1.1 mmol) in 8.2 mL toluene was stirred overnight at 110′C. The mixture was cooled down to rt, water was added and the mixture was extracted with dichloromethane. The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/ethanol gradient 0-5%). The impure product was stirred in ethanol, the precipitate was collected by filtration and dried in vacuum. 180 mg of the title compound were obtained (77% yield, 95% purity).

[2051] .sup.1H NMR (DMSO-d.sub.6) δ: 7.75-7.84 (m, 2H), 7.61-7.72 (m, 1H), 7.44-7.53 (m, 2H), 7.33-7.41 (m, 2H), 7.22-7.31 (m, 1H), 3.89-4.03 (m, 2H), 3.70-3.82 (m, 2H), 3.60-3.70 (m, 1H), 3.42-3.58 (m, 5H), 2.55-2.64 (m, 2H), 2.03-2.17 (m, 4H), 1.73-1.87 (m, 2H).

[2052] LC-MS (Method 4): R.sub.t=1.22 min; MS (ESIpos): m/z=459 [M+H].sup.+

Example 84

4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile

[2053] ##STR00202##

[2054] A suspension of 75 mg 7-bromo-4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (164 μmol, example 56), 28 mg pyrrolidin-2-one (329 μmol, CAS 616-45-5), 71 μL N,N′-dimethylethane-1,2-diamine (660 μmol), 6.3 mg copper(I)iodide (33 μmol) and 50 mg potassium carbonate (362 μmol) in 2.8 mL toluene was stirred overnight at 110′C. The mixture was cooled down to rt, water was added and the mixture was extracted with dichloromethane. The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/ethanol gradient 0-5%). The impure product was stirred in ethanol, the precipitate was collected by filtration and dried in vacuum. 63 mg of the title compound were obtained (79% yield, 95% purity).

[2055] .sup.1H NMR (DMSO-d.sub.6) δ: 7.78-7.94 (m, 2H), 7.62-7.74 (m, 1H), 7.01-7.24 (m, 4H), 4.64-4.75 (m, 1H), 3.97 (t, 2H), 3.69-3.82 (m, 2H), 3.48-3.63 (m, 5H), 2.58-2.62 (m, 2H), 2.05-2.23 (m, 4H), 1.82-1.99 (m, 2H).

[2056] LC-MS (Method 4): R.sub.t=1.16 min; MS (ESIpos): m/z=461 [M+H].sup.+

Example 85

4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile

[2057] ##STR00203##

[2058] A suspension of 154 mg 7-bromo-4-[4-(4-chlorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (164 μmol, example 57), 55 mg pyrrolidin-2-one (651 μmol, CAS 616-45-5), 140 μL N,N′-dimethylethane-1,2-diamine (1.3 mmol), 12 mg copper(I)iodide (65 μmol) and 99 mg potassium carbonate (717 μmol) in 5.6 mL toluene was stirred overnight at 110′C. The mixture was cooled down to rt, water was added and the mixture was extracted with dichloromethane. The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/ethanol gradient 0-5%). The impure product was stirred in ethanol, the precipitate was collected by filtration and dried in vacuum. 125 mg of the title compound were obtained (76% yield, 95% purity).

[2059] .sup.1H NMR (DMSO-d.sub.6) δ: 7.77-7.88 (m, 2H), 7.63-7.70 (m, 1H), 7.31-7.40 (m, 2H), 7.02-7.14 (m, 2H), 4.69-4.86 (m, 1H), 3.91-4.01 (m, 2H), 3.69-3.80 (m, 2H), 3.47-3.62 (m, 5H), 2.55-2.63 (m, 2H), 2.04-2.26 (m, 4H), 1.83-1.97 (m, 2H).

[2060] LC-MS (Method 4): R.sub.t=1.25 min; MS (ESIpos): m/z=477 [M+H].sup.+

Example 86

1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2061] ##STR00204##

[2062] A suspension of 155 mg 7-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (306 μmol, example 59), 52 mg pyrrolidin-2-one (612 μmol, CAS 616-45-5), 130 μL N,N′-dimethylethane-1,2-diamine (1.2 mmol), 12 mg copper(I)iodide (61.2 μmol) and 93 mg potassium carbonate (673 μmol) in 5.2 mL toluene was stirred overnight at 110° C. The mixture was cooled down to rt, water was added and the mixture was extracted with dichloromethane. The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/ethanol gradient 0-5%). The impure product was stirred in ethanol, the precipitate was collected by filtration and dried in vacuum. 105 mg of the title compound were obtained (64% yield, 95% purity).

[2063] .sup.1H NMR (DMSO-d.sub.6) δ: 7.75-7.89 (m, 2H), 7.63-7.73 (m, 3H), 7.20-7.31 (m, 2H), 4.81-4.99 (m, 1H), 3.91-4.03 (m, 2H), 3.69-3.83 (m, 2H), 3.47-3.63 (m, 5H), 2.55-2.63 (m, 2H), 2.19-2.28 (m, 2H), 2.05-2.16 (m, 2H), 1.88-2.00 (m, 2H).

[2064] LC-MS (Method 4): R.sub.t=1.29 min; MS (ESIpos): m/z=511 [M+H].sup.+

Example 87

7-cyclopropyl-1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2065] ##STR00205##

mg 7-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (59 μmol, example 59) and 5.2 mg di-μ-iodobis(tri-tert-butylphosphino)dipalladium(I) (5.9 μmol, CAS 166445-62-1) were sealed in a vessel and flushed with argon. 1.0 mL toluene was added and the mixture was stirred at rt. 360 μL bromo(cyclopropyl)zinc (0.50 M, 210 μmol, CAS 126403-68-7) was added dropwise. The mixture was stirred at rt for 1 h. The mixture was filtered via a silica column. The column was washed with dichloromethane and dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (instrument: Waters Autopurificationsystem; column: YMC Triart C18 5μ 150×50 mm; eluent A: water (0.1 vol. % formic acid 99%), eluent B: acetonitrile; gradient: 0.00-0.50 min. 60% B, (50->100 mL/min), 0.51-13.0 min. 60-84% B (100 mL/min), DAD scan: 210-400 nm) to give 3.0 mg of the title compound (98% purity, 11% yield).

[2066] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.71-7.79 (m, 1H), 7.59-7.67 (m, 2H), 7.09-7.19 (m, 3H), 6.90-6.99 (m, 1H), 4.80 (tt, 1H), 3.72-3.88 (m, 2H), 3.52-3.64 (m, 5H), 2.25 (ddt, 2H), 2.05-2.10 (m, 1H), 1.97-2.04 (m, 2H), 1.08-1.15 (m, 2H), 0.83-0.89 (m, 2H).

[2067] LC-MS (Method 2): R.sub.t=1.52 min; MS (ESIpos): m/z=468 [M+H].sup.+

Example 88

1,7-dimethyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile

[2068] ##STR00206##

[2069] 30 mg 7-bromo-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile (68 μmol, example 54), 21 mg methylboronic acid (342 μmol, CAS 13061-96-6), 28 mg potassium carbonate (205 μmol) and 5.6 mg [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-complex with dichloromethane (6.84 μmol, CAS 95464-05-4) were sealed in a vessel and degassed with argon. 600 μL 1,4-dioxane and 300 μL water (both degassed with argon) were added and the mixture was stirred at 130° C. for 1 h. The mixture was filtered via a water repellent filter. The filter was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 16.5 mg of the title compound (100% purity, 65% yield).

[2070] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.61 (d, 1H), 7.09-7.19 (m, 3H), 6.92-7.01 (m, 1H), 6.76-6.88 (m, 3H), 4.44-4.60 (m, 1H), 3.59-3.70 (m, 2H), 3.33-3.47 (m, 5H), 2.32 (s, 3H), 2.01-2.12 (m, 2H), 1.79-1.85 (m, 2H).

[2071] LC-MS (Method 2): R.sub.t=1.34 min; MS (ESIpos): m/z=374.3 [M+H].sup.+

Example 89

7-methoxy-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile

[2072] ##STR00207##

[2073] 30 mg 7-bromo-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydroquinoline-3-carbonitrile (68 μmol, example 54), 5.9 mg (2′-amino[biphenyl]-2-yl)(methanesulfonato-kappaO)palladium-di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxy[biphenyl]-2-yl)phosphine (1:1) (6.84 μmol, CAS 1536473-72-9), 31 mg potassium carbonate (96 μmol) and 3.3 mg di-tert-butyl[3,6-dimethoxy-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphine (6.8 μmol, CAS 1160861-53-9) were sealed in a vessel and degassed with argon. 1.0 mL toluene and 28 μL methanol were added and the mixture was stirred overnight at 60° C. The mixture was filtered via a silica column. The column was washed with dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 19.2 mg of the title compound (100% purity, 72% yield).

[2074] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.49-7.60 (m, 1H), 6.99-7.12 (m, 2H), 6.56-6.82 (m, 5H), 4.43 (tt, 1H), 3.67 (s, 3H), 3.44-3.59 (m, 2H), 3.24-3.36 (m, 5H), 1.91-2.00 (m, 2H), 1.69-1.75 (m, 2H).

[2075] LC-MS (Method 2): R.sub.t=1.31 min; MS (ESIpos): m/z=390.3 [M+H].sup.+

Example 90

7-methoxy-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile

[2076] ##STR00208##

mg 7-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile (66 μmol, example 55), 5.6 mg (2′-amino[biphenyl]-2-yl)(methanesulfonato-kappaO)palladium-di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxy[biphenyl]-2-yl)phosphine (1:1) (6.6 μmol, CAS 1536473-72-9), 30 mg potassium carbonate (92 μmol) and 3.3 mg di-tert-butyl[3,6-dimethoxy-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphine (6.6 μmol, CAS 1160861-53-9) were sealed in a vessel and degassed with argon. 1.0 mL toluene and 27 μL methanol were added and the mixture was stirred overnight at 60° C. The mixture was filtered via a silica column. The column was washed with dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 8.3 mg of the title compound (98% purity, 30% yield).

[2077] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.72-7.79 (m, 1H), 7.41-7.53 (m, 2H), 7.24-7.39 (m, 3H), 6.81-6.90 (m, 2H), 3.92 (s, 3H), 3.71-3.80 (m, 2H), 3.57 (s, 3H), 3.41-3.55 (m, 3H), 2.09-2.14 (m, 2H), 1.78-1.89 (m, 2H).

[2078] LC-MS (Method 2): R.sub.t=1.36 min; MS (ESIpos): m/z=406.3 [M+H].sup.+

Example 91

4-(4-benzylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2079] ##STR00209##

[2080] To a solution of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (412 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill) and 79 mg 4-benzylpiperidine (453 μmol, CAS 31252-42-3) in 2.5 mL DMSO was added 92 μL triethylamine (660 μmol) and the mixture was stirred for 2 h at 90° C. and overnight at rt. The reaction was filtered and was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 58 mg of the title compound (95% purity, 37% yield).

[2081] .sup.1H NMR (DMSO-d.sub.6) δ: 7.78-7.86 (m, 1H), 7.66-7.77 (m, 1H), 7.52-7.59 (m, 1H), 7.15-7.39 (m, 6H), 3.73 (br d, 2H), 3.56 (s, 3H), 3.32-3.33 (m, 2H), 2.60-2.65 (m, 2H), 1.80-2.01 (m, 1H), 1.67-1.79 (m, 2H), 1.44-1.56 (m, 2H).

[2082] LC-MS (Method 2): R.sub.t=1.36 min; MS (ESIpos): m/z=358.7 [M+H].sup.+

Example 92

4-{4-[(4-fluorophenyl)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2083] ##STR00210##

[2084] A suspension of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 106 mg 4-[(4-fluorophenyl)methyl]piperidine (549 μmol, CAS 92822-02-1) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried to give 155 mg of the title compound (95% yield, 86% purity).

[2085] .sup.1H NMR (DMSO-d.sub.6) δ: 7.67-7.86 (m, 2H), 7.51-7.62 (m, 1H), 7.23-7.38 (m, 3H), 7.06-7.19 (m, 2H), 3.67-3.79 (m, 2H), 3.55 (s, 3H), 3.29 (br s, 2H), 2.62 (d, 2H), 1.78-1.94 (m, 1H), 1.73 (br d, 2H), 1.41-1.57 (m, 2H).

[2086] LC-MS (Method 1): R.sub.t=1.37 min; MS (ESIpos): m/z=376 [M+H].sup.+

Example 93

4-{4-[(1,3-benzothiazol-2-yl)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2087] ##STR00211##

[2088] A solution of 100 mg [1-(3-cyano-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl]acetic acid (307 μmol, intermediate 42), 33 μL 2-aminobenzenethiol (310 μmol, CAS 137-07-5), 220 μL T3P (50% purity in ethyl acetate, 370 μmol) and 110 μL N,N-diisopropylethylamine (0.61 mmol) in 1.0 mL N,N-dimethylacetamide was stirred for 2 h at 100° C. The mixture was cooled down to rt and was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 52.6 mg of the title compound (95% purity, 39% yield).

[2089] .sup.1H NMR (DMSO-d.sub.6) δ: 8.04-8.13 (m, 1H), 7.92-8.00 (m, 1H), 7.80-7.88 (m, 1H), 7.67-7.78 (m, 1H), 7.45-7.60 (m, 2H), 7.38-7.45 (m, 1H), 7.29-7.38 (m, 1H), 3.70-3.86 (m, 2H), 3.58 (s, 3H), 3.37-3.46 (m, 2H), 3.13-3.27 (m, 2H), 2.14-2.29 (m, 1H), 1.91 (br d, 2H), 1.54-1.70 (m, 2H).

[2090] LC-MS (Method 1): R.sub.t=1.29 min; MS (ESIpos): m/z=416 [M+H].sup.+

Example 94

4-{4-[(2-methoxyphenyl)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2091] ##STR00212##

[2092] A suspension of 36 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (162 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 100 mg 4-[(2-methoxyphenyl)methyl]piperidine (487 μmol, CAS 37581-33-2) and 23 μL triethylamine (160 μmol) in 1 mL 2-propanol was stirred for 6 h at 90° C. The mixture was cooled down to rt, diisopropyl ether was added and for 5 min. sonicated. The solid that precipitated from this procedure was collected by filtration and dried. 85 mg of the title compound were obtained (95% purity, 128% yield).

[2093] .sup.1H NMR (DMSO-d.sub.6) δ: 7.77-7.88 (m, 1H), 7.67-7.76 (m, 1H), 7.51-7.61 (m, 1H), 7.27-7.40 (m, 1H), 7.14-7.26 (m, 2H), 6.95-7.05 (m, 1H), 6.84-6.92 (m, 1H), 3.80 (s, 3H), 3.67-3.76 (m, 2H), 3.56 (s, 3H), 2.57-2.65 (m, 2H), 1.81-1.97 (m, 1H), 1.66-1.77 (m, 2H), 1.42-1.57 (m, 2H).

[2094] LC-MS (Method 2): R.sub.t=1.34 min; MS (ESIpos): m/z=388.7 [M+H].sup.+

Example 95

4-{4-[(4-cyanophenyl)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2095] ##STR00213##

[2096] A suspension of 100 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (457 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound Ill), 135 mg 4-[(piperidin-4-yl)methyl]benzonitrile hydrogen chloride salt (1:1) (549 μmol, CAS 333987-04-5) and 0.24 mL N,N-diisopropylethylamine (1.4 mmol) in 2.0 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried. The impure product was purified by preparative TLC (dichloromethane/ethanol; 95:5) to give 117 mg of the title compound (64% yield, 95% purity).

[2097] .sup.1H NMR (DMSO-d.sub.6) δ: 7.69-7.90 (m, 4H), 7.53-7.61 (m, 1H), 7.41-7.52 (m, 2H), 7.26-7.38 (m, 1H), 3.67-3.84 (m, 2H), 3.56 (s, 3H), 3.29 (br s, 2H), 2.69-2.81 (m, 2H), 1.85-2.05 (m, 1H), 1.65-1.78 (m, 2H), 1.43-1.61 (m, 2H).

[2098] LC-MS (Method 1): R.sub.t=1.26 min; MS (ESIpos): m/z=383 [M+H].sup.+

Example 96

1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carboxamide

[2099] ##STR00214##

[2100] A mixture of 50 mg 1-methyl-2-oxo-7-(2-oxopyrrolidin-1-yl)-4-{4-[4-(trifluoromethoxy)-phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (90 μmol, example 82), 5.1 mg palladium(II)diacetate (23 μmol) and 53 mg N-[(1E)-ethylidene]hydroxylamine (0.9 mmol, CAS 107-29-9) in 5 mL ethanol was stirred for 4 h at 80° C. Water was added and the reaction was extracted with ethyl acetate (2×). The organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 34 mg of the title compound (95% purity, 66% yield).

[2101] .sup.1H NMR (DMSO-d.sub.6) δ: 7.80-7.94 (m, 2H), 7.57-7.75 (m, 2H), 7.40-7.49 (m, 1H), 7.24-7.33 (m, 2H), 7.05-7.15 (m, 2H), 4.54-4.72 (m, 1H), 3.89-4.04 (m, 2H), 3.56 (s, 3H), 3.34-3.41 (m, 2H), 3.09-3.20 (m, 2H), 2.53-2.61 (m, 2H), 2.05-2.19 (m, 4H), 1.78-1.92 (m, 2H).

[2102] LC-MS (Method 2): R.sub.t=1.20 min; MS (ESIpos): m/z=545.5 [M+H].sup.+

TABLE-US-00004 TABLE 4 synthetic precedure for compound in analogy to example 96. Starting Example Structure IUPAC-Name Materials Analytics 97 [00215] 4-[4-(4- chlorophenoxy) piperidin-1-yl]- 1-methyl-2- oxo-7-(2- oxopyrrolidin-1- yl)-1,2- dihydroquinoline-3- carboxamide 4-[4-(4- chlorophenoxy) piperidin-1- yl]-1-methyl- 2-oxo-7-(2- oxopyrrolidin- 1-yl)-1,2- dihydroquinoline- 3-carbonitrile (example 85) .sup.1H NMR (DMSO-d.sub.6) δ: 7.77-7.95 (m, 2H), 7.55- 7.72 (m, 2H), 7.38-7.51 (m, 1H), 7.28-7.38 (m, 2H), 6.99-7.10 (m, 2H), 4.53-4.68 (m, 1H), 3.89- 4.03 (m, 2H), 3.58 (s, 3H), 3.08-3.22 (m, 2H), 2.53- 2.60 (m, 4H), 2.05-2.17 (m, 4H), 1.76-1.91 (m, 2H). LC-MS (Method 2): R.sub.t = 1.13 min; MS (ESIpos): m/z = 495.5 [M + H].sup.+ 98 [00216] 7-chloro-1- methyl-2-oxo- 4-{4-[4- (trifluorometho xy)phenoxy] piperidin-1-yl}-1,2- dihydroquinoline-3- carboxamide 7-chloro-1- methyl-2-oxo- 4-{4-[4- (trifluoromethoxy) phenoxy] piperidin-1- yl}-1,2- dihydroquinoline- 3-carbonitrile (example 64) .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.95 (m, 1H), 7.54- 7.61 (m, 1H), 7.22-7.38 (m, 3H), 7.04-7.11 (m, 2H), 4.51-4.71 (m, 1H), 3.54 (s, 3H), 3.28-3.41 (m, 2H), 3.11 (br t, 2H), 2.04- 2.22 (m, 2H), 1.74-1.97 (m, 2H). LC-MS (Method 2): R.sub.t = 1.37 min; MS (ESIpos): m/z = 496.4 [M + H].sup.+ 99 [00217] 7-fluoro-1- methyl-2-oxo- 4-{4-[4- (trifluoromethoxy) phenoxy] piperidin-1-yl}-1,2- dihydroquinoline-3- carboxamide 7-fluoro-1- methyl-2-oxo- 4-{4-[4- (trifluorometh oxy)phenoxy] piperidin-1- yl}-1,2- dihydroquinoline- 3-carbonitrile (example 63) .sup.1H NMR (DMSO-d.sub.6) δ: 7.94 (dd, 1H), 7.68 (s, 1H), 7.45-7.54 (m, 1H), 7.35- 7.42 (m, 1H), 7.29 (d, 2H), 7.05-7.21 (m, 3H), 4.62 (dt, 1H), 3.55 (s, 3H), 3.35-3.43 (m, 2H), 3.08- 3.22 (m, 2H), 2.07-2.19 (m, 2H), 1.77-1.92 (m, 2H). LC-MS (Method 2): R.sub.t = 1.30 min; MS (ESIpos): m/z = 480.5 [M + H].sup.+

Example 100

(rac)-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]azepan-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2103] ##STR00218##

[2104] A solution of 183 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (796 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 300 mg (rac)-4-[4-(trifluoromethoxy)phenoxy]azepane (1.04 mmol, intermediate 45) and 0.22 mL triethylamine (1.6 mmol) in 8 mL 2-propanol was stirred for 7 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%). 192 mg of the title compound were obtained (95% purity, 50% yield).

[2105] .sup.1H NMR (DMSO-d.sub.6) δ: 7.98-8.02 (m, 1H), 7.69-7.78 (m, 1H), 7.55-7.60 (m, 1H), 7.24-7.39 (m, 3H), 7.05-7.12 (m, 2H), 4.74-4.84 (m, 1H), 3.64-3.84 (m, 4H), 3.57 (s, 3H), 2.13-2.28 (m, 2H), 1.78-2.08 (m, 4H).

[2106] LC-MS (Method 2): R.sub.t=1.41 min; MS (ESIpos): m/z=458.5 [M+H].sup.+

[2107] The title compound (192 mg) was separated into enantiomers by preparative chiral HPLC to give enantiomer 1 (50 mg, see example 102) and enantiomer 2 (55 mg, see example 101).

Preparative Chiral HPLC Method

[2108] Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; column: Chiralpak IG 5μ 250×30 mm; eluent A: methanol; isocratic 100% A; flow 50.0 ml/min; UV 254 nm

Analytical Chiral HPLC Method

[2109] Instrument: Agilent HPLC 1260; column: Chiralpak IG 3μ 100×4.6 mm; eluent A: methanol; isocratic 100% A; flow 1.4 ml/min; temperature: 25° C.; DAD 254 nm

Example 101

1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]azepan-1-yl}-1,2-dihydroquinoline-3-carbonitrile, enantiomer 1

[2110] ##STR00219##

[2111] For the preparation of the racemic title compound see example 100. Separation of enantiomers by preparative chiral HPLC (method see example 100) to give 55 mg of the title compound (99% purity, 15% yield).

[2112] Analytical chiral HPLC (method see example 100): R.sub.t=3.41 min.

[2113] Optical rotation:[α].sub.D=+14.5° (c=10 mg/ml, methanol)

[2114] .sup.1H NMR (DMSO-d.sub.6) δ: 7.96-8.04 (m, 1H), 7.68-7.77 (m, 1H), 7.55-7.62 (m, 1H), 7.24-7.40 (m, 3H), 7.04-7.12 (m, 2H), 4.75-4.84 (m, 1H), 3.63-3.88 (m, 4H), 3.57 (s, 3H), 1.78-2.28 (m, 6H).

Example 102

1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]azepan-1-yl}-1,2-dihydroquinoline-3-carbonitrile, enantiomer 2

[2115] ##STR00220##

[2116] For the preparation of the racemic title compound see example 100. Separation of enantiomers by preparative chiral HPLC (method see example 100) to give 50 mg of the title compound (99% purity, 14% yield).

[2117] Analytical chiral HPLC (method see example 100): R.sub.t=2.85 min.

[2118] Optical rotation:[α].sub.D=−14.7°(c=10 mg/ml, methanol)

[2119] .sup.1H NMR (DMSO-d.sub.6) δ: 7.96-8.04 (m, 1H), 7.68-7.81 (m, 1H), 7.52-7.66 (m, 1H), 7.25-7.43 (m, 3H), 7.04-7.15 (m, 2H), 4.74-4.86 (m, 1H), 3.63-3.90 (m, 4H), 3.58 (s, 3H), 1.78-2.28 (m, 6H).

Example 103

(rac)-4-[4-(4-bromophenoxy)azepan-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2120] ##STR00221##

[2121] A solution of 212 mg 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (796 μmol, CAS 150617-68-8, synthesis described in WO2012009649, example 1—compound III), 486 mg (rac)-4-(4-bromophenoxy)azepane (1.26 mmol, intermediate 47) and 0.27 mL triethylamine (1.9 mmol) in 6.3 mL 2-propanol was stirred for 4 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%). The crude product was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 75 mg of the title compound were obtained (95% purity, 16% yield).

[2122] .sup.1H NMR (DMSO-d.sub.6) δ: 7.92-8.07 (m, 1H), 7.70-7.80 (m, 1H), 7.54-7.64 (m, 1H), 7.41-7.50 (m, 2H), 7.30-7.38 (m, 1H), 6.89-7.05 (m, 2H), 4.72-4.82 (m, 1H), 3.61-3.87 (m, 4H), 3.57 (s, 3H), 1.74-2.27 (m, 6H).

[2123] LC-MS (Method 2): R.sub.t=1.42 min; MS (ESIpos): m/z=453.5 [M+H].sup.+

Example 104

(rac)-4-{4-[4-(azetidin-1-yl)phenoxy]azepan-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2124] ##STR00222##

[2125] A mixture of 65 mg (rac)-4-[4-(4-bromophenoxy)azepan-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (137 μmol, example 103), 9.4 mg azetidine (164 μmol, CAS 503-29-7), 89 mg cesium carbonate (273 μmol) and 21.4 mg chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (27.4 μmol, CAS 1310584-14-5) in 400 μL 1,4-dioxane was stirred for 16 h at 110° C. Water was added and the reaction was extracted with ethyl acetate (3×). The combined organic phases were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 10 mg of the title compound (95% purity, 16% yield).

[2126] .sup.1H NMR (DMSO-d.sub.6) δ: 7.97-8.04 (m, 1H), 7.69-7.78 (m, 1H), 7.53-7.62 (m, 1H), 7.30-7.39 (m, 1H), 6.81-6.88 (m, 2H), 6.30-6.42 (m, 2H), 4.47-4.62 (m, 1H), 3.78-3.88 (m, 1H), 3.61-3.78 (m, 7H), 3.55-3.60 (m, 3H), 2.21-2.29 (m, 2H), 1.76-2.19 (m, 6H).

[2127] LC-MS (Method 2): R.sub.t=1.33 min; MS (ESIpos): m/z=229.6 [M+H].sup.+

Example 105

(rac)-1-methyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)phenoxy]azepan-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2128] ##STR00223##

[2129] A mixture of 180 mg (rac)-4-[4-(4-bromophenoxy)azepan-1-yl]-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (387 μmol, example 103), 60 mg (1-methyl-1H-pyrazol-4-yl)boronic acid (454 μmol, CAS 847818-55-7), 185 mg cesium carbonate (567 μmol), 30 mg chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (38 μmol, CAS 1310584-14-5) and 22 mg palladium-triphenylphosphine (1:4) (19 μmol, CAS 14221-01-3) in 3 mL 1,4-dioxane was stirred for 3 h at 110° C. Water was added and the reaction was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 42 mg of the title compound (95% purity, 23% yield).

[2130] .sup.1H NMR (DMSO-d.sub.6) δ: 7.95-8.06 (m, 2H), 7.70-7.77 (m, 2H), 7.52-7.59 (m, 1H), 7.44-7.51 (m, 2H), 7.30-7.38 (m, 1H), 6.94-7.03 (m, 2H), 4.71-4.82 (m, 1H), 3.79-3.91 (m, 4H), 3.63-3.76 (m, 3H), 3.58 (s, 3H), 2.11-2.27 (m, 2H), 1.92-2.08 (m, 3H), 1.77-1.90 (m, 1H).

[2131] LC-MS (Method 2): R.sub.t=1.17 min; MS (ESIpos): m/z=454.6 [M+H].sup.+

Example 106

4-[4-(benzyloxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2132] ##STR00224##

[2133] To a solution of 100 mg 4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (353 μmol, intermediate 1) and 46 μL (bromomethyl)benzene (390 μmol, CAS 100-39-0) in 2 mL DMF at 0° C. was added 28 mg sodium hydride (60% in mineral oil, 706 μmol) and the reaction was stirred for 2 h at rt. After this time, water was added and the mixture was stirred for some time. The residue was collected by filtration and washed with water. The resulting solid was dried under reduced pressure at 60° C. to give 106 mg of the title compound (77% yield, 96% purity).

[2134] 1H-NMR (400 MHz, DMSO-d6): 5 [ppm]=1.75-1.88 (m, 2H), 2.12 (ddd, 2H), 3.40-3.49 (m, 2H), 3.56 (s, 3H), 3.68-3.81 (m, 3H), 4.59 (s, 2H), 7.24-7.42 (m, 6H), 7.56 (d, 1H), 7.73 (ddd, 1H), 7.85 (dd, 1H).

[2135] LC-MS (Method 2): R.sub.t=1.26 min; MS (ESIpos): m/z=374.2 [M+H].sup.+

Example 107

1-methyl-4-{4-[(4-methylphenyl)methoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2136] ##STR00225##

[2137] To a solution of 100 mg 4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (353 μmol, intermediate 1) and 62 μL 1-(bromomethyl)-4-methylbenzene (460 μmol, CAS 104-81-4) in 2 mL DMF at 0° C. was added 28 mg sodium hydride (60% in mineral oil, 706 μmol) and the reaction was stirred for 2 h at rt. After this time, water was added and the mixture was stirred for some time. The residue was collected by filtration and washed with water. The resulting solid was dried under reduced pressure at 60° C. to give 114 mg of the title compound (82% yield, 98% purity).

[2138] 1H-NMR (400 MHz, DMSO-d6): 5 [ppm]=1.72-1.91 (m, 2H), 2.10 (ddd, 2H), 2.30 (s, 3H), 3.43 (ddd, 2H), 3.56 (s, 3H), 3.72 (br dd, 3H), 4.54 (s, 2H), 7.17 (d, 2H), 7.23-7.29 (m, 2H), 7.30-7.39 (m, 1H), 7.55 (d, 1H), 7.69-7.76 (m, 1H), 7.84 (dd, 1H).

[2139] LC-MS (Method 2): R.sub.t=1.34 min; MS (ESIpos): m/z=388.2 [M+H].sup.+

Example 108

1-methyl-4-{4-[(3-methylphenyl)methoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2140] ##STR00226##

[2141] To a solution of 100 mg 4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (353 μmol, intermediate 1) and 52 μL 1-(bromomethyl)-3-methylbenzene 390 μmol, CAS 620-13-3) in 2 mL DMF at 0° C. was added 28 mg sodium hydride (60% in mineral oil, 706 μmol) and the reaction was stirred for 2 h at rt. After this time, water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were filtered and concentrated under reduced pressure. 123 mg of the title compound were obtained (86% yield, 96% purity).

[2142] 1H-NMR (400 MHz, DMSO-d6): 5 [ppm]=1.73-1.89 (m, 2H), 2.11 (ddd, 2H), 2.28-2.35 (m, 3H), 3.44 (ddd, 2H), 3.56 (s, 3H), 3.67-3.80 (m, 3H), 4.55 (s, 2H), 7.10 (d, 1H), 7.14-7.21 (m, 2H), 7.22-7.29 (m, 1H), 7.33 (ddd, 1H), 7.56 (dd, 1H), 7.73 (ddd, 1H), 7.85 (dd, 1H).

[2143] LC-MS (Method 2): R.sub.t=1.35 min; MS (ESIpos): m/z=388.2 [M+H].sup.+

TABLE-US-00005 TABLE 5 synthetic precedure for compound in analogy to example 108. Example Structure IUPAC-Name Starting Materials Analytics 109 [00227] 4-{4-[(4- methoxyphenyl)m ethoxy]piperidin-1- yl}-1-methyl-2- oxo-1,2- dihydroquinoline- 3-carbonitrile 4-(4-hydroxypiperidin- 1-yl)-1-methyl-2-oxo- 1,2-dihydroquinoline- 3-carbonitrile (Intermediate 1) and 1-(chloromethyl)-4- methoxybenzene (CAS 824-94-2) .sup.1H NMR (DMSO-d.sub.6) δ: 7.79-7.89 (m, 1H), 7.68-7.79 (m, 1H), 7.50-7.62 (m, 1H), 7.26-7.38 (m, 3H), 6.87-6.94 (m, 2H), 4.46-4.54 (m, 2H), 3.68-3.77 (m, 6H), 3.54-3.58 (m, 2H), 3.54-3.59 (m, 1H), 3.37-3.50 (m, 2H), 2.05-2.26 (m, 2H), 1.73-1.86 (m, 2H). 110 [00228] 4-{4-[(4- fluorophenyl)methoxy] piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile 4-(4-hydroxypiperidin- 1-yl)-1-methyl-2-oxo- 1,2-dihydroquinoline- 3-carbonitrile (Intermediate 1) and 1-(bromomethyl)-4- fluorobenzene (CAS 459-46-1) .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.73-1.88 (m, 2H), 2.11 (ddd, 2H), 3.40- 3.50 (m, 2H), 3.56 (s, 3H), 3.67-3.83 (m, 3H), 4.57 (s, 2H), 7.13-7.26 (m, 2H), 7.28-7.36 (m, 1H), 7.38-7.46 (m, 2H), 7.55 (d, 1H), 7.73 (ddd, 1H), 7.80- 7.90 (m, 1H). 111 [00229] 4-{4-[(2- fluorophenyl)methoxy] piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile 4-(4-hydroxypiperidin- 1-yl)-1-methyl-2-oxo- 1,2-dihydroquinoline- 3-carbonitrile (Intermediate 1) and 1-(bromomethyl)-2- fluorobenzene (CAS 446-48-0) .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.73-1.89 (m, 2H), 2.06-2.20 (m, 2H), 3.45 (ddd, 2H), 3.56 (s, 3H), 3.66-3.87 (m, 3H),4.64 (s, 2H), 7.12-7.27 (m, 2H), 7.29-7.44 (m, 2H), 7.47-7.60 (m, 2H), 7.73 (ddd, 1H), 7.81-7.88 (m, 1H). 112 [00230] (rac)-1-methyl-2- oxo-4-[4-(1- phenylethoxy) piperidin-1-yl]-1,2- dihydroquinoline- 3-carbonitrile 4-(4-hydroxypiperidin- 1-yl)-1-methyl-2-oxo- 1,2-dihydroquinoline- 3-carbonitrile (Intermediate 1) and (1- bromoethyl)benzene (CAS 585-71-7) .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.37 (d, 3H), 1.64- 1.75 (m, 1H), 1.75- 1.86 (m, 1H), 1.87- 1.95 (m, 1H), 2.06- 2.17 (m, 1H), 3.35- 3.46 (m, 2H), 3.50- 3.60 (m, 4H), 3.62- 3.78 (m, 2H), 4.72 (q, 1H), 7.23-7.43 (m, 6H), 7.55 (d, 1H), 7.72 (ddd, 1H), 7.82 (dd, 1H). 113 [00231] 4-{4-[(3- fluorophenyl)methoxy] piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile 4-(4-hydroxypiperidin- 1-yl)-1-methyl-2-oxo- 1,2-dihydroquinoline- 3-carbonitrile (Intermediate 1) and 1-(bromomethyl)-3- fluorobenzene (CAS 456-41-7) .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.85 (dd, 1 H), 7.73 (ddd, 1 H), 7.56 (dd, 1 H), 7.39- 7.45 (m, 1 H), 7.33 (ddd, 1 H), 7.17- 7.24(m, 2H), 7.07- 7.15 (m, 1 H), 4.62 (s, 2 H), 3.68- 3.83 (m, 3 H), 3.56 (s, 3 H), 3.45 (ddd, 2 H), 2.12 (ddd, 2 H), 1.76-1.91 (m, 2 H). 114 [00232] 1-methyl-4-{4-[(2- methylphenyl) methoxy]piperidin-1- yl}-2-oxo-1,2- dihydroquinoline- 3-carbonitrile 4-(4-hydroxypiperidin- 1-yl)-1-methyl-2-oxo- 1,2-dihydroquinoline- 3-carbonitrile (Intermediate 1) and 1-(bromomethyl)-2- methylbenzene (CAS 89-92-9) .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.85 (dd, 1 H), 7.73 (ddd, 1 H), 7.56 (d, 1 H), 7.30-7.39 (m, 2 H), 7.15- 7.22 (m, 3 H), 4.57 (s, 2 H), 3.66-3.83 (m, 3 H), 3.56 (s, 3 H), 3.45 (ddd, 2 H), 2.32 (s, 3 H), 2.13 (ddd, 2H), 1.77- 1.92 (m, 2 H). 115 [00233] 4-{4-[(3- methoxyphenyl) methoxy]piperidin-1- yl}-1-methyl-2- oxo-1,2- dihydroquinoline- 3-carbonitrile 4-(4-hydroxypiperidin- 1-yl)-1-methyl-2-oxo- 1,2-dihydroquinoline- 3-carbonitrile (Intermediate 1) and 1-(bromomethyl)-3- methoxybenzene (CAS 874-98-6) .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.85 (dd, 1 H), 7.73 (ddd, 1 H), 7.56 (dd, 1 H), 7.33 (ddd, 1 H), 7.23- 7.30 (m, 1 H), 6.89- 6.97 (m, 2H), 6.81-6.88 (m, 1 H), 4.57 (s, 2 H), 3.69-3.79 (m, 6 H), 3.56 (s, 3 H), 3.44 (ddd, 2 H), 2.11 (ddd, 2 H), 1.76-1.87 (m, 2 H).

Example 116

4-{4-[(4-chlorophenoxy)methyl]piperidin-1-yl}-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2144] ##STR00234##

[2145] To a suspension of 100 mg 4-[4-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (336 μmol, intermediate 50), 82 mg 4-chlorophenol (639 μmol, CAS 106-48-9) and 176 mg triphenylphosphine (673 μmol) in 3.8 mL THF was added 130 μL diisopropyl azodicarboxylate (670 μmol). The reaction was stirred for 24 h at rt. The mixture was concentrated under reduced pressure. The residue was stirred in DMSO, the precipitate was collected by filtration and dried in vacuum. 63 mg of the title compound were obtained (44% yield, 95% purity).

[2146] .sup.1H NMR (DMSO-d.sub.6) δ: 7.78-7.90 (m, 1H), 7.66-7.77 (m, 1H), 7.51-7.61 (m, 1H), 7.30-7.38 (m, 3H), 6.94-7.07 (m, 2H), 3.92-3.98 (m, 2H), 3.76-3.86 (m, 2H), 3.58 (s, 3H), 3.39-3.48 (m, 2H), 2.05-2.22 (m, 1H), 1.90-2.00 (m, 2H), 1.54-1.69 (m, 2H).

[2147] LC-MS (Method 1): R.sub.t=1.43 min; MS (ESIpos): m/z=408 [M+H].sup.+

TABLE-US-00006 TABLE 6 examples prepared. Starting Materials, procedure from Example Structure IUPAC-Name example Analytics 117 [00235] 4-{4-[(2- methoxyphenyl) methoxy]piperidin-1- yl}-1-methyl-2- oxo-1,2- dihydroquinoline- 3-carbonitrile In analogy to example 95 with 4- chloro-1-methyl-2- oxo-1,2- dihydroquinoline-3- carbonitrile (CAS 150617-68-8) and 4-[(2- methoxybenzyl)oxy] piperidine (CAS 86928-12-3) and with 1- methylpyrrolidin-2- one as solvent 118 [00236] 1-methyl-2-oxo-4- [4- (phenoxymethyl) piperidin-1-yl]-1,2- dihydroquinoline- 3-carbonitrile in analogy to example 116 with 4- [4- (hydroxymethyl) piperidin-1-yl]-1- methyl-2-oxo-1,2- dihydroquinoline-3- carbonitrile (intermediate 50) and phenol (CAS 108-95-2) .sup.1H NMR (DMSO-d.sub.6) δ: 7.83-7.91 (m, 1H), 7.68-7.78 (m, 1H), 7.51-7.61 (m, 1H), 7.24-7.38 (m, 3H), 6.89-7.02 (m, 3H), 3.89-3.98 (m, 2H), 3.75-3.85 (m, 2H), 3.58 (s, 3H), 3.39- 3.49 (m, 2H), 2.07- 2.25 (m, 1H), 1.93- 2.03 (m, 2H), 1.55- 1.72 (m, 2H). LC-MS (Method 1): R.sub.t = 1.35 min; MS (ESIpos): m/z = 374.4 [M + H].sup.+ 119 [00237] 4-{4-[(3- chlorophenoxy) methyl]piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile in analogy to example 116 with 4- [4- (hydroxymethyl) piperidin-1-yl]-1- methyl-2-oxo-1,2- dihydroquinoline-3- carbonitrile (intermediate 50) and 3-chlorophenol (CAS 108-43-0) .sup.1H NMR (DMSO-d.sub.6) δ: 7.80-7.90 (m, 1H), 7.69-7.78 (m, 1H), 7.50-7.60 (m, 1H), 7.22-7.42 (m, 2H), 7.02-7.10 (m, 1H), 6.92-7.01 (m, 2H), 3.94-4.03 (m, 2H), 3.75-3.86 (m, 2H), 3.57 (s, 3H), 3.37- 3.49 (m, 2H), 2.07- 2.21 (m, 1H), 1.88- 2.03 (m, 2H), 1.54- 1.71 (m, 2H). LC-MS (Method 1): R.sub.t = 1.44 min; MS (ESIpos): m/z = 408 [M + H].sup.+ 120 [00238] 4-{4-[(2- chlorophenoxy) methyl]piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile in analogy to example 116 with 4- [4- (hydroxymethyl) piperidin-1-yl]-1- methyl-2-oxo-1,2- dihydroquinoline-3- carbonitrile (intermediate 50) and 2-chlorophenol (CAS 95-57-8) .sup.1H NMR (DMSO-d.sub.6) δ: 7.85 (dd, J = 8.4, 1.3 Hz, 1H), 7.70-7.77 (m, 1H), 7.55-7.59 (m, 1H), 7.41-7.47 (m, 1H), 7.28-7.37 (m, 2H), 7.14-7.22 (m, 1H), 6.89-7.04 (m, 1H), 4.04 (d, J = 6.3 Hz, 2H), 3.82 (br d, J = 12.7 Hz, 2H), 3.57 (s, 3H), 3.40- 3.51 (m, 2H), 2.12- 2.26 (m, 1H), 2.00 (br dd, J = 10.8, 2.2 Hz, 2H), 1.59-1.76 (m, 2H). LC-MS (Method 1): R.sub.t = 1.40 min; MS (ESIpos): m/z = 408 [M + H].sup.+

Example 121

4-[4-(benzyloxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide

[2148] ##STR00239##

[2149] A solution of 70 mg 4-[4-(benzyloxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (189 μmol, example 106), 11 mg palladium(II)diacetate (47 μmol) and 56 mg N-[(1E)-ethylidene]hydroxylamine (943 μmol, CAS 107-29-9) in 2 mL ethanol was stirred for 3 h at 80° C. Water was added and the reaction was extracted with ethyl acetate (3×). The combined organic layers were filtered and concentrated under reduced pressure. The crude was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 33.5 mg of the title compound (100% purity, 45% yield).

[2150] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, 1H), 7.58-7.68 (m, 2H), 7.51 (dd, 1H), 7.44 (d, 1H), 7.36 (d, 4H), 7.26-7.33 (m, 2H), 4.57 (s, 2H), 3.57 (s, 4H), 3.26-3.40 (m, 2H), 3.03 (ddd, 2H), 1.98-2.11 (m, 2H), 1.65-1.80 (m, 2H).

[2151] LC-MS (Method 3): R.sub.t=1.20 min; MS (ESIpos): m/z=392 [M+H].sup.+

Example 122

1-methyl-4-{4-[(4-methylphenyl)methoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carboxamide

[2152] ##STR00240##

[2153] A solution of 78 mg 1-methyl-4-{4-[(4-methylphenyl)methoxy]piperidin-1-yl}-2-oxo-1,2-dihydroquinoline-3-carbonitrile (201 μmol, example 107), 11 mg palladium(II)diacetate (50 μmol) and 59 mg N-[(1E)-ethylidene]hydroxylamine (1.0 mmol, CAS 107-29-9) in 2 mL ethanol was stirred for 17 h at 80° C. Water was added and the reaction was extracted with ethyl acetate (3×). The combined organic layers were filtered and concentrated under reduced pressure. The crude was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient) to give 10.5 mg of the title compound (100% purity, 13% yield).

[2154] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88 (dd, 1H), 7.58-7.67 (m, 2H), 7.51 (d, 1H), 7.44 (br d, 1H), 7.27-7.34 (m, 1H), 7.22-7.27 (m, 2H), 7.12-7.19 (m, 2H), 4.51 (s, 2H), 3.53-3.59 (m, 4H), 3.30-3.41 (m, 2H), 2.97-3.07 (m, 2H), 2.30 (s, 3H), 1.97-2.07 (m, 2H), 1.65-1.78 (m, 2H).

[2155] LC-MS (Method 3): R.sub.t=1.29 min; MS (ESIpos): m/z=406 [M+H].sup.+

TABLE-US-00007 TABLE 7 in analogy to example 122 Starting Example Structure IUPAC-Name Materials Analytics 123 [00241] 1-methyl-4-{4-[(3- methylphenyl) methoxy]piperidin-1- yl}-2-oxo-1,2- dihydroquinoline- 3-carboxamide 1-methyl-4-{4- [(3- methylbenzyl) oxy]piperidin-1-yl}- 2-oxo-1,2- dihydroquinoline- 3-carbonitrile (example 108) .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.89 (dd, 1 H), 7.59-7.68 (m, 2 H), 7.51 (dd, 1 H), 7.44 (br d, 1 H), 7.27-7.32 (m, 1 H), 7.22-7.27 (m, 1 H), 7.12-7.19 (m, 2 H), 7.09 (d, 1 H), 4.52 (s, 2 H), 3.57 (s, 4 H), 3.28- 3.36 (m, 2 H), 2.93-3.12 (m, 2 H), 2.31 (s, 3 H), 1.97-2.11 (m, 2 H), 1.66- 1.84 (m, 2 H). LC-MS (Method 2): R.sub.t = 1.16 min; MS (ESIpos): m/z = 406.3 [M + H].sup.+ 124 [00242] 1-methyl-4-{4-[(2- methylphenyl) methoxy]piperidin-1- yl}-2-oxo-1,2- dihydroquinoline- 3-carboxamide 1-methyl-4-{4- 1(2- methylbenzyl) oxy]piperidin-1-yl}- 2-oxo-1,2- dihydroquinoline- 3-carbonitrile (example 114) .sup.1H NMR (DMSO-d.sub.6) δ: 7.89 (dd, 1H), 7.59-7.67 (m, 2H), 7.51 (dd, J = 8.6, 0.8 Hz, 1H), 7.42-7.47 (m, 1H), 7.33-7.37 (m, 1H), 7.27-7.32 (m, 1H), 7.15-7.22 (m, 3H), 4.49- 4.62 (m, 2H), 3.52-3.64 (m, 4H), 3.34-3.37 (m, 1H), 3.32 (brs, 1H), 2.96-3.09 (m, 2H), 2.27- 2.35 (m, 3H), 1.97-2.10 (m, 2H), 1.66-1.82 (m, 2H). LC-MS (Method 2): R.sub.t = 1.16 min; MS (ESIpos): m/z = 406.3 [M + H].sup.+ 125 [00243] 4-{4-[(3- methoxyphenyl) methoxy]piperidin-1- yl}-1-methyl-2- oxo-1,2- dihydroquinoline- 3-carboxamide 4-{4-[(3- methoxybenzyl) oxy]piperidin-1- yl}-1-methyl-2- oxo-1,2- dihydroquinoline- 3-carbonitrile (example 115) .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.89 (dd, 1 H), 7.57-7.68 (m, 2 H), 7.48-7.56 (m, 1 H), 7.44 (d, 1 H), 7.21- 7.34 (m, 2 H), 6.90-6.98 (m, 2 H), 6.85 (dt, 1 H), 4.54 (s, 2 H), 3.76 (s, 3 H), 3.57 (s, 4 H), 3.35 (br s, 1 H), 3.32 (brs, 1 H), 2.94-3.10 (m, 2 H), 1.94- 2.12 (m, 2 H), 1.62- 1.85 (m, 2 H). LC-MS (Method 2): R.sub.t = 1.08 min; MS (ESIpos): m/z = 422.3 [M + H].sup.+ 126 [00244] 4-{4-[(2- fluorophenyl)methoxy] piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carboxamide 4-{4-[(2- fluorobenzyl)oxy] piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile (example 111) .sup.1H NMR (DMSO-d.sub.6) δ: 7.85-7.91 (m, 1H), 7.58- 7.69 (m, 2H), 7.47-7.54 (m, 2H), 7.45 (d, 1H), 7.37 (tdd, 1H), 7.27-7.32 (m, 1H), 7.16-7.25 (m, 2H), 4.59-4.66 (m, 2H), 3.54-3.67 (m, 4H), 3.34- 3.37 (m, 1H), 3.29-3.32 (m, 1H), 2.99-3.10 (m, 2H), 2.00-2.11 (m, 2H), 1.68-1.82 (m, 2H). LC-MS (Method 2): R.sub.t = 1.11 min; MS (ESIpos): m/z = 410.2 [M + H].sup.+ 127 [00245] 4-{4-[(4- fluorophenyl)methoxy] piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carboxamide 4-{4-[(4- fluorobenzyl)oxy] piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile (example 110) .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.88 (dd, 1 H), 7.58-7.67 (m, 2 H), 7.51 (dd, 1 H), 7.36- 7.46 (m,3H), 7.26- 7.34 (m, 1 H), 7.14-7.22 (m, 2 H), 4.55 (s, 2 H), 3.57 (s, 4 H), 3.34-3.38 (m, 1 H), 3.28-3.32 (m, 1 H), 3.03 (ddd, 2 H), 1.97-2.09 (m, 2 H), 1.65- 1.81 (m, 2 H). LC-MS (Method 2): R.sub.t = 1.11 min; MS (ESIpos): m/z = 410.2 [M + H].sup.+ 128 [00246] 4-{4-[(3- fluorophenyl)methoxy] piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carboxamide 4-{4-[(3- fluorobenzyl)oxy] piperidin-1-yl}- 1-methyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile (example 113) .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.89 (dd, 1 H), 7.58-7.68 (m, 2 H), 7.49-7.56 (m, 1 H), 7.36-7.47 (m, 2 H), 7.30 (td, 1 H), 7.15-7.25 (m, 2 H), 7.06-7.14 (m, 1 H), 4.59 (s, 2 H), 3.54- 3.64 (m, 4 H), 3.35 (br s, 1 H), 3.27-3.32 (m, 1 H), 2.98-3.10 (m, 2 H), 1.98-2.11 (m, 2H), 1.68- 1.83 (m, 2 H). LC-MS (Method 2): R.sub.t = 1.11 min; MS (ESIpos): m/z = 410.2 [M + H].sup.+

Example 129

8-fluoro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2156] ##STR00247##

[2157] A solution of 100 mg 4-chloro-8-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (423 μmol, intermediate 53), 144 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (549 μmol, CAS 287952-67-4) and 0.12 mL triethylamine (850 μmol) in 2.8 mL 2-propanol was stirred for 3 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%). 71 mg of the title compound were obtained (95% purity, 35% yield).

[2158] .sup.1H NMR (DMSO-d.sub.6) δ: 7.66-7.77 (m, 1H), 7.55-7.66 (m, 1H), 7.25-7.41 (m, 3H), 7.08-7.19 (m, 2H), 4.73-4.84 (m, 1H), 3.66-3.80 (m, 5H), 3.49-3.60 (m, 2H), 2.13-2.28 (m, 2H), 1.81-1.99 (m, 2H).

[2159] LC-MS (Method 2): R.sub.t=1.44 min; MS (ESIpos): m/z=462.3 [M+H].sup.+

Example 130

8-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2160] ##STR00248##

[2161] A suspension of 1.3 g 8-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (4.37 mmol, intermediate 56), 1.37 g 4-[4-(trifluoromethoxy)phenoxy]piperidine (5.24 mmol, CAS 287952-67-4) and 2.3 mL N,N-diisopropylethylamine (340 mmol) in 26 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried to give 2.17 g of the title compound (90% yield, 95% purity).

[2162] .sup.1H NMR (DMSO-d.sub.6) δ: 7.94-8.07 (m, 1H), 7.81-7.90 (m, 1H), 7.20-7.34 (m, 3H), 7.09-7.19 (m, 2H), 4.71-4.87 (m, 1H), 3.64-3.82 (m, 5H), 3.49-3.62 (m, 2H), 2.14-2.26 (m, 2H), 1.84-1.99 (m, 2H).

[2163] LC-MS (Method 1): R.sub.t=1.47 min; MS (ESIpos): m/z=524 [M+H].sup.+

Example 131

8-chloro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2164] ##STR00249##

[2165] A suspension of 120 mg 4,8-dichloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (446 μmol, intermediate 59), 144 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (535 μmol, CAS 287952-67-4) and 230 μL N,N-diisopropylethylamine (1.3 mmol) in 3 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with water, ethanol and hexane. The resulting solid was dried to give 212 mg of the title compound (99% yield, 99% purity).

[2166] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82 (ddd, 2H), 7.28-7.35 (m, 3H), 7.12-7.17 (m, 2H), 4.74-4.82 (m, 1H), 3.72-3.80 (m, 2H), 3.70 (s, 3H), 3.55 (ddd, 2H), 2.20 (ddd, 2H), 1.86-1.97 (m, 2H).

[2167] LC-MS (Method 1): R.sub.t=1.49 min; MS (ESIpos): m/z=478.4 [M+H].sup.+

Example 132

1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3,8-dicarbonitrile

[2168] ##STR00250##

[2169] To a solution of 120 mg 8-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (230 μmol, example 130) in 2.6 mL DMF was added 103 mg copper(I)cyanide (1.15 mmol, CAS 544-92-3) and the mixture was stirred for 12 h at 150° C. in the microwave. The mixture was cooled down to rt, a solution of 745 mg trichloroiron hexahydrate in 720 μL water and 120 μL hydrochloric acid (concentrated) was added and the mixture was stirred for 15 min. at 70° C. After cooled down to rt, water was added and the precipitate was collected by filtration and washed with ethanol. The resulting solid was dried to give 91 mg of the title compound (80% yield, 95% purity).

[2170] .sup.1H NMR (DMSO-d.sub.6) δ: 8.09-8.32 (m, 2H), 7.40-7.48 (m, 1H), 7.24-7.38 (m, 2H), 7.08-7.21 (m, 2H), 4.66-4.90 (m, 1H), 3.89 (s, 3H), 3.68-3.80 (m, 2H), 3.45-3.62 (m, 2H), 2.12-2.26 (m, 2H), 1.84-2.01 (m, 2H).

[2171] LC-MS (Method 1): R.sub.t=1.39 min; MS (ESIpos): m/z=469 [M+H].sup.+

Example 133

1-methyl-2-oxo-8-(2-oxopyrrolidin-1-yl)-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2172] ##STR00251##

[2173] A suspension of 100 mg 8-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (191 μmol, example 130), 32.6 mg pyrrolidin-2-one (383 μmol, CAS 616-45-5), 82 μL N,N′-dimethylethane-1,2-diamine (770 μmol), 7.3 mg copper(I)iodide (38 μmol) and 58 mg potassium carbonate (421 μmol) in 3.3 mL toluene was stirred overnight at 110° C. The mixture was cooled down to rt, water was added and the mixture was extracted with dichloromethane. The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-100%, dichloromethane/ethanol gradient 0-10%). The impure product was stirred in ethanol, the precipitate was collected by filtration and dried in vacuum. 30 mg of the title compound were obtained (28% yield, 95% purity).

[2174] .sup.1H NMR (DMSO-d.sub.6) δ: 7.78-7.89 (m, 1H), 7.63-7.71 (m, 1H), 7.24-7.41 (m, 3H), 7.10-7.19 (m, 2H), 4.71-4.91 (m, 1H), 3.84-3.93 (m, 1H), 3.68-3.82 (m, 3H), 3.48-3.63 (m, 2H), 3.35 (s, 3H), 2.43-2.47 (m, 2H), 2.12-2.28 (m, 4H), 1.85-2.00 (m, 2H).

[2175] LC-MS (Method 1): R.sub.t=1.30 min; MS (ESIpos): m/z=528 [M+H].sup.+

Example 134

8-{[dimethyl(oxo)-λ.SUP.6.-sulfanylidene]amino}-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2176] ##STR00252##

[2177] To a solution of 100 mg 8-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (191 μmol, example 130) in 2.0 mL 1,4-dioxane was added 21.4 mg sulfonimidoyldimethane (230 μmol, CAS 1520-31-6), 12 mg tris(dibenzylideneacetone)dipalladium (13 μmol, CAS 51364-51-3), 11 mg biphenyl-2-yl(di-tert-butyl)phosphine (38 μmol, CAS 224311-51-7) and 26 mg sodium 2-methylpropan-2-olate (268 μmol). The reaction was stirred for 1.5 h at 80° C. in the microwave. The mixture was cooled down to rt and was concentrated under reduced pressure. To the residue was added water and the mixture was extracted with dichloromethane. The combined organic phases were washed with brine, filtered (using a waterresistant filter) and concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient) to give 21 mg of the title compound (95% purity, 19% yield).

[2178] .sup.1H NMR (DMSO-d.sub.6) δ: 7.25-7.48 (m, 4H), 7.06-7.21 (m, 3H), 4.69-4.84 (m, 1H), 3.68-3.81 (m, 5H), 3.43-3.62 (m, 2H), 3.23 (s, 6H), 2.14-2.24 (m, 2H), 1.84-1.95 (m, 2H).

[2179] LC-MS (Method 1): R.sub.t=1.33 min; MS (ESIpos): m/z=535 [M+H].sup.+

Example 135

8-(dimethylphosphoryl)-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2180] ##STR00253##

[2181] To a mixture of 100 mg 8-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (191 μmol, example 130), 6.7 mg (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (11.5 μmol), 2.2 mg palladium(II)diacetate (9.6 μmol) and 45 mg tripotassium phosphate (211 μmol) in 1.6 mL degassed DMF was added 18 mg dimethylphosphine oxide (211 μmol, CAS 7211-39-4) and the reaction was stirred for 40 min. at 130° C. in the microwave. The mixture was filtered and residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient) to give 20 mg of the title compound (95% purity, 19% yield).

[2182] .sup.1H NMR (DMSO-d.sub.6) δ: 8.02-8.14 (m, 1H), 7.94-8.02 (m, 1H), 7.22-7.39 (m, 3H), 7.08-7.18 (m, 2H), 4.75-4.85 (m, 1H), 3.70-3.82 (m, 5H), 3.49-3.62 (m, 2H), 2.14-2.27 (m, 2H), 1.87-1.99 (m, 2H), 1.81 (d, 6H).

[2183] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=520 [M+H].sup.+

Example 136

8-(methanesulfonyl)-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2184] ##STR00254##

[2185] A solution of 940 mg 8-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (1.71 mmol, example 130) in 8 mL DMSO was degassed with argon. To the mixture was added 828 mg sodium methanesulfinate (7.68 mmol, CAS 20277-69-4), 252 μL (1S,2S)-cyclohexane-1,2-diamine (2.1 mmol, CAS 1121-22-8) and 258 mg copper(I)trifluoromethanesulfonate-benzene (2:2:1) (513 μmol). The reaction was stirred for 73 h at 110° C. The mixture was filtered and residue was purified by RP-HPLC (column: X-Bridge C18 5μ 100×30 mm; mobile phase: water (0.2 vol. % aq. ammonia 32%)/acetonitrile 45-85%) to give 100 mg of the title compound (98% purity, 11% yield).

[2186] .sup.1H NMR (DMSO-d.sub.6) δ: 8.35-8.46 (m, 1H), 8.04-8.16 (m, 1H), 7.37-7.47 (m, 1H), 7.27-7.36 (m, 2H), 7.11-7.20 (m, 2H), 4.74 (s, 1H), 3.69-3.82 (m, 2H), 3.51-3.65 (m, 8H), 2.16-2.27 (m, 2H), 1.86-2.02 (m, 2H).

[2187] LC-MS (Method 2): R.sub.t=1.29 min; MS (ESIpos): m/z=522.5 [M+H].sup.+

Example 137

6-bromo-4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2188] ##STR00255##

[2189] A suspension of 300 mg 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.01 mmol, intermediate 62), 236 mg 4-(4-fluorophenoxy)piperidine (1.21 mmol, CAS 3202-34-4) and 530 μL N,N-diisopropylethylamine (3.0 mmol) in 10 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried in vacuum at 100° C. to give 310 mg of the title compound (64% yield, 95% purity).

[2190] .sup.1H NMR (DMSO-d.sub.6) δ: 7.83-7.95 (m, 2H), 7.50-7.59 (m, 1H), 6.98-7.19 (m, 4H), 4.60-4.79 (m, 1H), 3.69-3.82 (m, 2H), 3.47-3.61 (m, 5H), 2.11-2.24 (m, 2H), 1.79-1.94 (m, 2H).

[2191] LC-MS (Method 1): R.sub.t=1.41 min; MS (ESIpos): m/z=458 [M+H].sup.+

Example 138

6-bromo-4-[4-(3-methoxyphenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2192] ##STR00256##

[2193] A suspension of 359 mg 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.21 mmol, intermediate 62), 250 mg 4-(3-methoxyphenoxy)piperidine (1.21 mmol, CAS 162402-37-1) and 340 μL N,N-diisopropylethylamine (2.4 mmol) in 8 mL 2-propanol was stirred for 3 h at 90° C. After this time, ethyl acetate was added and the reaction was refluxed for 15 min. The mixture was stirred for 48 h at rt. Water was added and the residue was collected by filtration. The impure product was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 220 mg of the title compound were obtained (38% yield, 95% purity).

[2194] .sup.1H NMR (DMSO-d.sub.6) δ: 7.85-7.95 (m, 2H), 7.49-7.58 (m, 1H), 7.15-7.24 (m, 1H), 6.58-6.65 (m, 2H), 6.48-6.55 (m, 1H), 4.69-4.82 (m, 1H), 3.68-3.83 (m, 5H), 3.51-3.62 (m, 5H), 2.20 (ddd, 2H), 1.82-1.97 (m, 2H).

[2195] LC-MS (Method 2): R.sub.t=1.34 min; MS (ESIpos): m/z=469.3 [M+H].sup.+

Example 139

6-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2196] ##STR00257##

[2197] A suspension of 260 mg 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (874 μmol, intermediate 62), 274 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (1.05 mmol, CAS 287952-67-4) and 460 μL N,N-diisopropylethylamine (2.6 mmol) in 10 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried to give 320 mg of the title compound (67% yield, 95% purity).

[2198] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.96 (m, 2H), 7.51-7.60 (m, 1H), 7.27-7.36 (m, 2H), 7.10-7.20 (m, 2H), 4.74-4.87 (m, 1H), 3.70-3.84 (m, 2H), 3.50-3.65 (m, 5H), 2.21 (ddd, 2H), 1.82-1.98 (m, 2H).

[2199] LC-MS (Method 1): R.sub.t=1.53 min; MS (ESIpos): m/z=524 [M+H].sup.+

Example 140

6-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile

[2200] ##STR00258##

[2201] A suspension of 300 mg 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.01 mmol, intermediate 62), 278 mg 4-(phenylsulfanyl)piperidine hydrogen chloride salt (1.21 mmol, CAS 101798-66-7) and 530 μL N,N-diisopropylethylamine (3.0 mmol) in 10 mL 2-propanol was stirred for 2 h at 90° C. After this ti me, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with ethanol. The resulting solid was dried to give 330 mg of the title compound (68% yield, 95% purity).

[2202] .sup.1H NMR (DMSO-d.sub.6) δ: 7.82-7.92 (m, 2H), 7.44-7.60 (m, 3H), 7.33-7.41 (m, 2H), 7.24-7.32 (m, 1H), 3.60-3.83 (m, 3H), 3.45-3.59 (m, 5H), 2.04-2.22 (m, 2H), 1.65-1.82 (m, 2H).

[2203] LC-MS (Method 1): R.sub.t=1.47 min; MS (ESIpos): m/z=456 [M+H].sup.+

Example 141

4-[4-(4-fluorophenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2204] ##STR00259##

[2205] A suspension of 142 mg 6-bromo-4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (311 μmol, example 137), 177 mg 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (1.24 mmol, CAS 94242-85-0), 1.1 mL tripotassium phosphate (0.50 M, 560 μmol) and 73.4 mg chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (93 μmol, CAS 1310584-14-5) in 4.9 mL THF was stirred overnight at 70° C. Water was added and the reaction was extracted with dichloromethane (2×). The organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-100%). The impure product was stirred in DMSO for some time. The precipitate was collected by filtration and dried in vacuum. 32 mg of the title compound were obtained (22% yield, 85% purity).

[2206] .sup.1H NMR (DMSO-d.sub.6) δ: 7.61-7.66 (m, 1H), 7.55-7.59 (m, 1H), 7.44-7.51 (m, 1H), 6.99-7.22 (m, 4H), 4.61-4.79 (m, 1H), 3.71-3.80 (m, 2H), 3.50-3.62 (m, 5H), 2.37-2.43 (m, 3H), 2.11-2.28 (m, 2H), 1.83-1.98 (m, 2H).

[2207] LC-MS (Method 1): R.sub.t=1.32 min; MS (ESIpos): m/z=392 [M+H].sup.+

Example 142

1,6-dimethyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile

[2208] ##STR00260##

[2209] A suspension of 138 mg 6-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile (304 μmol, example 140), 173 mg 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (1.21 mmol, CAS 94242-85-0), 1.1 mL tripotassium phosphate (0.50 M, 550 μmol) and 72 mg chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (91 μmol, CAS 1310584-14-5) in 4.8 mL THF was stirred overnight at 70° C. Water was added and the reaction was extracted with dichloromethane (2×). The organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-100%). The impure product was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient). 7 mg of the title compound were obtained (6% yield, 95% purity).

[2210] .sup.1H NMR (DMSO-d.sub.6) δ: 7.52-7.61 (m, 2H), 7.43-7.51 (m, 3H), 7.33-7.42 (m, 2H), 7.22-7.32 (m, 1H), 3.60-3.84 (m, 3H), 3.41-3.57 (m, 5H), 2.37-2.43 (m, 3H), 2.06-2.21 (m, 2H), 1.71-1.91 (m, 2H).

[2211] LC-MS (Method 1): R.sub.t=1.42 min; MS (ESIpos): m/z=390 [M+H].sup.+

Example 143

1,6-dimethyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2212] ##STR00261##

[2213] A suspension of 142 mg 6-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (272 μmol, example 139), 77 mg 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (544 μmol, CAS 94242-85-0), 1 mL tripotassium phosphate (0.50 M, 490 μmol) and 32 mg chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (41 μmol, CAS 1310584-14-5) in 4.3 mL THF was stirred overnight at 70° C. Water was added and the reaction was extracted with dichloromethane (2×). The organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-90%). The impure product was stirred in DMSO for some time. The precipitate was collected by filtration and dried in vacuum. 20 mg of the title compound were obtained (15% yield, 95% purity). The filtrate was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient). 34 mg of the title compound were obtained (26% yield, 95% purity).

[2214] .sup.1H NMR (DMSO-d.sub.6) δ: 7.62-7.66 (m, 1H), 7.54-7.60 (m, 1H), 7.45-7.52 (m, 1H), 7.26-7.37 (m, 2H), 7.09-7.19 (m, 2H), 4.68-4.89 (m, 1H), 3.69-3.88 (m, 2H), 3.48-3.63 (m, 5H), 2.39-2.44 (m, 3H), 2.16-2.28 (m, 2H), 1.84-2.01 (m, 2H).

[2215] LC-MS (Method 1): R.sub.t=1.48 min; MS (ESIpos): m/z=458 [M+H].sup.+

Example 144

1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3,6-dicarbonitrile

[2216] ##STR00262##

[2217] To a solution of 138 mg 6-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile (304 μmol, example 140) in 3.4 mL DMF was added 136 mg copper(I)cyanide (1.52 mmol, CAS 544-92-3) and the mixture was stirred for 12 h at 150° C. in the microwave. The mixture was cooled down to rt, a solution of 985 mg trichloroiron hexahydrate in 950 μL water and 160 μL concentrated hydrochloric acid was added and the mixture was stirred for 15 min. at 70° C. After cooled down to rt, water was added and the precipitate was collected by filtration and washed with ethanol. The resulting solid was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient). 13 mg of the title compound were obtained (10% yield, 95% purity).

[2218] .sup.1H NMR (DMSO-d.sub.6) δ: 8.15-8.22 (m, 1H), 8.06-8.13 (m, 1H), 7.65-7.76 (m, 1H), 7.43-7.50 (m, 2H), 7.33-7.41 (m, 2H), 7.24-7.31 (m, 1H), 3.73-3.85 (m, 2H), 3.60-3.73 (m, 1H), 3.48-3.59 (m, 5H), 2.07-2.17 (m, 2H), 1.76-1.91 (m, 2H).

[2219] LC-MS (Method 1): R.sub.t=1.29 min; MS (ESIpos): m/z=401 [M+H].sup.+

Example 145

1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3,6-dicarbonitrile

[2220] ##STR00263##

[2221] To a solution of 126 mg 6-bromo-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile (241 μmol, example 139) in 2.7 mL DMF was added 108 mg copper(I)cyanide (1.21 mmol, CAS 544-92-3) and the mixture was stirred for 12 h at 150° C. in the microwave. The mixture was cooled down to rt, a solution of 782 mg trichloroiron hexahydrate in 760 μL water and 130 μL concentrated hydrochloric acid was added and the mixture was stirred for 15 min. at 70° C. After cooled down to rt, water was added and the precipitate was collected by filtration and washed with ethanol. The resulting solid was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient). 6 mg of the title compound were obtained (5% yield, 95% purity).

[2222] .sup.1H NMR (DMSO-d.sub.6) δ: 8.19-8.30 (m, 1H), 8.07-8.15 (m, 1H), 7.67-7.78 (m, 1H), 7.27-7.36 (m, 2H), 7.13-7.19 (m, 2H), 4.70-4.97 (m, 1H), 3.74-3.87 (m, 2H), 3.68 (br d, 5H), 2.16-2.29 (m, 2H), 1.87-2.03 (m, 2H).

[2223] LC-MS (Method 1): R.sub.t=1.37 min; MS (ESIpos): m/z=469 [M+H].sup.+

Example 146

4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3,6-dicarbonitrile

[2224] ##STR00264##

[2225] To a solution of 115 mg 6-bromo-4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (252 μmol, example 137 in 2.9 mL DMF was added 113 mg copper(I)cyanide (1.26 mmol, CAS 544-92-3) and the mixture was stirred for 12 h at 150° C. in the microwave. The mixture was cooled down to rt, a solution of 817 mg trichloroiron hexahydrate in 790 μL water and 130 μL concentrated hydrochloric acid was added and the mixture was stirred for 15 min. at 70° C. After cooled down to rt, water was added and the precipitate was collected by filtration and washed with ethanol. The resulting solid was purified by RP-HPLC (column: Chromatorex 125×30 mm, 10 μm mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient). 16 mg of the title compound were obtained (15% yield, 95% purity).

[2226] .sup.1H NMR (DMSO-d.sub.6) δ: 8.20-8.28 (m, 1H), 8.06-8.14 (m, 1H), 7.67-7.75 (m, 1H), 7.05-7.21 (m, 4H), 4.63-4.80 (m, 1H), 3.75-3.85 (m, 2H), 3.66 (s, 5H), 2.11-2.27 (m, 2H), 1.83-2.09 (m, 2H).

[2227] LC-MS (Method 1): R.sub.t=1.24 min; MS (ESIpos): m/z=403 [M+H].sup.+

Example 147

6-cyclopropyl-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile

[2228] ##STR00265##

mg 6-bromo-1-methyl-2-oxo-4-[4-(phenylsulfanyl)piperidin-1-yl]-1,2-dihydroquinoline-3-carbonitrile (66.0 μmol, example 140 and 5.8 mg di-μ-iodobis(tri-tert-butylphosphino)dipalladium(I) (6.6 μmol, CAS 166445-62-1) were sealed in a vessel and degassed with argon. 1.0 mL toluene was added and the mixture was stirred at rt. 400 μL bromo(cyclopropyl)zinc (0.50 M, 200 μmol, CAS 126403-68-7) was added dropwise. The mixture was stirred at rt for 1 h. The mixture was filtered via a silica column. The column was washed with dichloromethane and dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient) to give 24.4 mg of the title compound (100% purity, 89% yield).

[2229] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.30-7.35 (m, 2H), 7.27-7.30 (m, 1H), 7.17-7.26 (m, 4H), 7.09-7.15 (m, 1H), 3.55-3.64 (m, 2H), 3.38-3.41 (m, 3H), 3.26-3.38 (m, 3H), 1.98-2.05 (m, 2H), 1.80-1.89 (m, 1H), 1.62-1.73 (m, 2H), 0.81-0.88 (m, 2H), 0.48-0.54 (m, 2H).

[2230] LC-MS (Method 1): R.sub.t=1.47 min; MS (ESIpos): m/z=416.4 [M+H].sup.+

Example 148

6-cyclopropyl-4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2231] ##STR00266##

[2232] 30 mg 6-bromo-4-[4-(4-fluorophenoxy)piperidin-1-yl]-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (65.7 μmol, example 137 and 5.7 mg di-μ-iodobis(tri-t-butylphosphino)dipalladium(I) (6.6 μmol, CAS 166445-62-1) were sealed in a vessel and degassed with argon. 1.0 mL toluene was added and the mixture was stirred at rt. 390 μL bromo(cyclopropyl)zinc (0.50 M, 200 μmol, CAS 126403-68-7) was added dropwise. The mixture was stirred at rt for 1 h. The mixture was filtered via a silica column. The column was washed with dichloromethane and dichloromethane/methanol (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.1 vol. % formic acid)-gradient) to give 13.1 mg of the title compound (99% purity, 47% yield).

[2233] .sup.1H NMR (ACETONITRILE-d.sub.3) δ: 7.28-7.35 (m, 1H), 7.10-7.26 (m, 2H), 6.75-6.90 (m, 4H), 4.36-4.48 (m, 1H), 3.51-3.64 (m, 2H), 3.28-3.40 (m, 5H), 1.97-2.06 (m, 2H), 1.74-1.84 (m, 3H), 0.73-0.87 (m, 2H), 0.44-0.53 (m, 2H).

[2234] LC-MS (Method 1): R.sub.t=1.42 min; MS (ESIpos): m/z=418.4 [M+H].sup.+

Example 149

1,6-dimethyl-4-[4-(3-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2235] ##STR00267##

[2236] A solution of 150 mg 4-chloro-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (612 μmol, synthesis described in WO2004074218), 148 mg 4-(3-methylphenoxy)piperidine (735 μmol, CAS 63843-46-9) and 0.17 mL triethylamine (1.2 mmol) in 6.2 mL 2-propanol was stirred for 4 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 110 mg of the title compound were obtained (95% purity, 44% yield).

[2237] .sup.1H NMR (DMSO-d.sub.6) δ: 7.52-7.66 (m, 2H), 7.42-7.49 (m, 1H), 7.11-7.22 (m, 1H), 6.79-6.90 (m, 2H), 6.71-6.77 (m, 1H), 4.67-4.81 (m, 1H), 3.70-3.82 (m, 2H), 3.50-3.64 (m, 5H), 2.39-2.42 (m, 3H), 2.27-2.30 (m, 3H), 2.15-2.24 (m, 2H), 1.86-1.96 (m, 2H).

[2238] LC-MS (Method 2): R.sub.t=1.40 min; MS (ESIpos): m/z=388.5 [M+H].sup.+

Example 150

1,6-dimethyl-4-[4-(2-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2239] ##STR00268##

[2240] A solution of 150 mg 4-chloro-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (612 μmol, synthesis described in WO2004074218), 148 mg 4-(2-methylphenoxy)piperidine (735 μmol, CAS 63843-42-5) and 0.17 mL triethylamine (1.2 mmol) in 6.2 mL 2-propanol was stirred for 4.5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 40 mg of the title compound were obtained (95% purity, 16% yield).

[2241] .sup.1H NMR (DMSO-d.sub.6) δ: 7.61-7.66 (m, 1H), 7.53-7.60 (m, 1H), 7.40-7.49 (m, 1H), 7.11-7.22 (m, 2H), 7.04-7.09 (m, 1H), 6.80-6.89 (m, 1H), 4.69-4.86 (m, 1H), 3.70-3.81 (m, 2H), 3.48-3.61 (m, 5H), 2.37-2.44 (m, 3H), 2.14-2.26 (m, 5H), 1.86-1.99 (m, 2H).

[2242] LC-MS (Method 2): R.sub.t=1.43 min; MS (ESIpos): m/z=388.5 [M+H].sup.+

TABLE-US-00008 TABLE 8 synthesis in analogy to example 150. Starting Example Structure IUPAC-Name Materials Analytics 151 [00269] 4-[4-(2- chlorophenoxy) piperidin-1-yl]-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile 4-chloro-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile (WO2004074218) and 4-(2- chlorophenoxy) piperidine (CAS 245057-65-2) .sup.1H NMR (DMSO-d.sub.6) δ: 7.54-7.67 (m, 2H), 7.40- 7.53 (m, 2H), 7.27-7.36 (m, 2H), 6.93-7.03 (m, 1H), 4.81-4.98 (m, 1H), 3.74-3.85 (m, 2H), 3.50- 3.66 (m, 5H), 2.37-2.44 (m, 3H), 2.16-2.28 (m, 2H), 1.91-2.03 (m, 2H). LC-MS (Method 2): R.sub.t = 1.40 min; MS (ESIpos): m/z = 408.5 [M + H].sup.+ 152 [00270] 4-[4-(3- methoxyphenoxy) piperidin-1-yl]- 1,6-dimethyl-2- oxo-1 2- dihydroquinoline- 3-carbonitrile 4-chloro-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile (WO2004074218) and 4-(3- methoxyphenoxy) piperidine (CAS 162402- 37-1) .sup.1H NMR (DMSO-d.sub.6) δ: 7.52-7.70 (m, 2H), 7.44- 7.50 (m, 1H), 7.14-7.24 (m, 1H), 6.48-6.67 (m, 3H), 4.67-4.85 (m, 1H), 3.67-3.86 (m, 5H), 3.46- 3.61 (m, 5H), 2.37-2.45 (m, 3H), 2.13-2.28 (m, 2H), 1.84-1.98 (m, 2H). LC-MS (Method 2): R.sub.t = 1.31 min; MS (ESIpos): m/z = 404.5 [M + H].sup.+ 153 [00271] 4-[4-(2-methoxy- 4- methylphenoxy) piperidin-1-yl]-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile 4-chloro-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile (WO2004074218) and 4-(2- methoxy-4- methylphenoxy) piperidine (CAS 883543-21-3) .sup.1H NMR (DMSO-d.sub.6) δ: 7.53-7.67 (m, 2H), 7.43- 7.51 (m, 1H), 6.95-7.05 (m, 1H), 6.77-6.87 (m, 1H), 6.64-6.70 (m, 1H), 4.49-4.60 (m, 1H), 3.71- 3.83 (m, 5H), 3.44-3.59 (m, 5H), 2.37-2.45 (m, 3H), 2.23-2.29 (m, 3H), 2.08-2.22 (m, 2H), 1.81- 1.97 (m, 2H). LC-MS (Method 2): R.sub.t = 1.36 min; MS (ESIpos): m/z = 418.5 [M + H].sup.+ 154 [00272] 4-[4-(2- methoxyphenoxy) piperidin-1-yl]- 1,6-dimethyl-2- oxo-1,2- dihydroquinoline- 3-carbonitrile 4-chloro-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile (WO2004074218) and 4-(2- methoxyphenoxy) piperidine (CAS 28033-32- 1) .sup.1H NMR (DMSO-d.sub.6) δ: 7.52-7.68 (m, 2H), 7.44- 7.49 (m, 1H), 7.07-7.16 (m, 1H), 6.85-7.04 (m, 3H), 4.58-4.69 (m, 1H), 3.72-3.84 (m, 5H), 3.49- 3.59 (m, 5H), 2.41 (s, 3H), 2.17 (ddd, 2H), 1.85-2.01 (m, 2H). LC-MS (Method 2): R.sub.t = 1.29 min; MS (ESIpos): m/z = 404.5 [M + H].sup.+ 155 [00273] 4-[4-(2- cyanophenoxy) piperidin-1-yl]-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile 4-chloro-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile (WO2004074218) and 2- (piperidin-4- yloxy)benzonitrile (CAS 900572- 37-4) .sup.1H NMR (DMSO-d.sub.6) δ: 7.76 (dd, J = 7.6, 1.5 Hz, 1H), 7.61-7.72 (m, 2H), 7.54-7.60 (m, 1H), 7.41- 7.52 (m, 2H), 7.07-7.16 (m, 1H), 4.92-5.04 (m, 1H), 3.71-3.85 (m, 2H), 3.54-3.65 (m, 5H), 2.41 (s, 3H), 2.21-2.31 (m, 2H), 1.92-2.05 (m, 2H). LC-MS (Method 2): R.sub.t = 1.23 min; MS (ESIpos): m/z = 399.5 [M + H].sup.+

Example 156

6-methoxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2243] ##STR00274##

[2244] A solution of 100 mg 4-chloro-6-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (402 μmol, intermediate 48), 126 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (483 μmol, CAS 287952-67-4) and 0.11 mL triethylamine (0.8 mmol) in 5.7 mL 2-propanol was stirred for 4.5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 35 mg of the title compound were obtained (95% purity, 17% yield).

[2245] .sup.1H NMR (DMSO-d.sub.6) δ: 7.48-7.56 (m, 1H), 7.36-7.43 (m, 1H), 7.27-7.34 (m, 2H), 7.20-7.25 (m, 1H), 7.12-7.19 (m, 2H), 4.72-4.84 (m, 1H), 3.87 (s, 3H), 3.70-3.82 (m, 2H), 3.50-3.62 (m, 5H), 2.23 (ddd, 2H), 1.83-2.01 (m, 2H).

[2246] LC-MS (Method 2): R.sub.t=1.41 min; MS (ESIpos): m/z=474.5 [M+H].sup.+

Example 157

6-chloro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2247] ##STR00275##

[2248] A solution of 90 mg 4,6-dichloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (356 μmol, intermediate 70), 111 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (427 μmol, CAS 287952-67-4) and 0.1 mL triethylamine (710 μmol) in 5 mL 2-propanol was stirred for 5 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100×30 mm, mobile phase: acetonitrile/water (0.2 vol. % ammonia 32%)-gradient). 82 mg of the title compound were obtained (95% purity, 46% yield).

[2249] .sup.1H NMR (DMSO-d.sub.6) δ: 7.84 (d, J=9.1 Hz, 1H), 7.51-7.59 (m, 1H), 7.26-7.37 (m, 3H), 7.10-7.22 (m, 2H), 4.73-4.90 (m, 1H), 3.95 (s, 3H), 3.82-3.92 (m, 2H), 3.55-3.73 (m, 2H), 2.17-2.30 (m, 2H), 1.83-2.04 (m, 2H).

[2250] LC-MS (Method 2): R.sub.t=1.59 min; MS (ESIpos): m/z=478.5 [M+H].sup.+

Example 158

1,6-dimethyl-4-[4-(3-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide

[2251] ##STR00276##

[2252] A mixture of 71 mg 1,6-dimethyl-4-[4-(3-methylphenoxy)piperidin-1-yl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile (174 μmol, example 149), 9.8 mg palladium(II)diacetate (44 μmol) and 103 mg N-[(1E)-ethylidene]hydroxylamine (1.74 mmol, CAS 107-29-9) in 10 mL ethanol was stirred for 4 h at 80° C. Water was added and the reaction was extracted with ethyl acetate (2×). The organic phase was washed with brine and dried over sodium sulfate. After evaporation the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 58 mg of the title compound (95% purity, 78% yield).

[2253] .sup.1H NMR (DMSO-d.sub.6) δ: 7.60-7.71 (m, 2H), 7.39-7.51 (m, 3H), 7.13-7.21 (m, 1H), 6.71-6.88 (m, 3H), 4.50-4.65 (m, 1H), 3.58 (s, 3H), 3.36 (br d, 2H), 3.04-3.19 (m, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 2.08-2.17 (m, 2H), 1.78-1.93 (m, 2H).

[2254] LC-MS (Method 2): R.sub.t=1.25 min; MS (ESIpos): m/z=406.6 [M+H].sup.+

Example 159

4-[4-(3-methoxyphenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carboxamide

[2255] ##STR00277##

[2256] A mixture of 71 mg 4-[4-(3-methoxyphenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (167 μmol, example 152), 9.4 mg palladium(II)diacetate (42 μmol) and 99 mg N-[(1E)-ethylidene]hydroxylamine (1.67 mmol, CAS 107-29-9) in 10 mL ethanol was stirred for 4 h at 80° C. Water was added and the reaction was extracted with ethyl acetate (2×). The organic phase was washed with brine and dried over sodium sulfate. After evaporation the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-3%) to give 60 mg of the title compound (95% purity, 81% yield).

[2257] .sup.1H NMR (DMSO-d.sub.6) δ: 7.61-7.72 (m, 2H), 7.38-7.49 (m, 3H), 7.13-7.23 (m, 1H), 6.46-6.64 (m, 3H), 4.49-4.68 (m, 1H), 3.73 (s, 3H), 3.58 (s, 3H), 3.34-3.41 (m, 2H), 3.09-3.20 (m, 2H), 2.41 (s, 3H), 2.09-2.17 (m, 2H), 1.79-1.92 (m, 2H).

[2258] LC-MS (Method 2): R.sub.t=1.18 min; MS (ESIpos): m/z=422.6 [M+H].sup.+

TABLE-US-00009 TABLE 9 synthesis in analogy to example 159. Starting Example Structure IUPAC-Name Materials Analytics 160 [00278] 1,6-dimethyl-2- oxo-4-{4-[4- (trifluoromethoxy) phenoxy] piperidin-1-yl}-1,2- dihydroquinoline-3- carboxamide 1,6-dimethyl-2- oxo-4-{4-[4- (trifluoromethoxy) phenoxy]piperidin- 1-yl}-1,2- dihydroquinoline- 3-carbonitrile (example 143) .sup.1H NMR (DMSO-d.sub.6) δ: 7.67 (s, 2H), 7.39-7.50 (m, 3H), 7.27-7.33 (m, 2H), 7.07-7.19 (m, 2H), 4.56-4.69 (m, 1H), 3.57 (s, 3H), 3.38 (br s, 2H), 3.08-3.22 (m, 2H), 2.41 (s, 3H), 2.07-2.21 (m, 2H), 1.74-1.99 (m, 2H). LC-MS (Method 2): R.sub.t = 1.34 min; MS (ESIpos): m/z = 476.5 [M + H].sup.+ 161 [00279] 4-[4-(2- methoxy-4- methylphenoxy) piperidin-1-yl]- 1,6-dimethyl-2- oxo-1,2- dihydroquinoline-3- carboxamide 4-[4-(2-methoxy- 4- methylphenoxy) piperidin-1-yl]-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile (example 153) .sup.1H NMR (DMSO-d.sub.6) δ: 7.60-7.73 (m, 2H), 7.37-7.52 (m, 3H), 6.88-7.00 (m, 1H), 6.78-6.86 (m, 1H), 6.66 (dt, 1H), 4.31-4.42 (m, 1H), 3.76 (s, 3H), 3.57 (s, 3H), 3.34-3.40 (m, 2H), 2.99-3.14 (m, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.04-2.10 (m, 2H), 1.75-1.89 (m, 2H). LC-MS (Method 2): R.sub.t = 1.20 min; MS (ESIpos): m/z = 436.6 [M + H].sup.+ 162 [00280] 4-[4-(2- methoxyphenoxy) piperidin-1- yl-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carboxamide 4-[4-(2- methoxyphenoxy) piperidin-1-yl]- 1,6-dimethyl-2- oxo-1,2- dihydroquinoline- 3-carbonitrile (example 154) .sup.1H NMR (DMSO-d.sub.6) δ: 7.61-7.73 (m, 2H), 7.40-7.47 (m, 3H), 7.04-7.12 (m, 1H), 6.97-7.02 (m, 1H), 6.83-6.96 (m, 2H), 4.37-4.56 (m, 1H), 3.78 (s, 3H), 3.56 (s, 3H), 3.34-3.43 (m, 2H), 3.06-3.18 (m, 2H), 2.42 (s, 3H), 2.03-2.15 (m, 2H), 1.76-1.96 (m, 2H). LC-MS (Method 2): R.sub.t = 1.12 min; MS (ESIpos): m/z = 422.5 [M + H].sup.+ 163 [00281] 4-[4-(2- chlorophenoxy) piperidin-1-yl]- 1,6-dimethyl-2- oxo-1,2- dihydroquinoline- 3-carboxamide 4-[4-(2- chlorophenoxy) piperidin-1-yl]-1,6- dimethyl-2-oxo- 1,2- dihydroquinoline- 3-carbonitrile (example 151) .sup.1H NMR (DMSO-d.sub.6) δ: 7.59-7.77 (m, 2H), 7.40-7.51 (m, 4H), 7.24-7.34 (m, 2H), 6.90-7.05 (m, 1H), 4.63-4.76 (m, 1H), 3.56 (s, 3H), 3.36-3.46 (m, 2H), 3.09-3.24 (m, 2H), 2.42 (s, 3H), 2.09-2.19 (m, 2H), 1.82-1.98 (m, 2H). LC-MS (Method 2): R.sub.t = 1.24 min; MS (ESIpos): m/z = 426.4 [M + H].sup.+ 164 [00282] 8-chloro-1- methyl-2-oxo- 4-{4-[4- (trifluoromethoxy) phenoxy] piperidin-1-yl}-1,2- dihydroquinoline- 3-carboxamide 8-chloro-1- methyl-2-oxo-4- (4-4- (trifluoromethoxy) phenoxy]piperidin- 1-yl}-1,2- dihydroquinoline- 3-carbonitrile (example 131) .sup.1H NMR (DMSO-d.sub.6) δ: 7.90 (dd, 1H), 7.65- 7.77 (m, 2H), 7.48-7.58 (m, 1H), 7.25-7.33 (m, 3H), 7.08-7.14 (m, 2H), 4.63 (dt, 1H), 3.73 (s, 3H), 3.08-3.19 (m, 2H), 2.07-2.17 (m, 2H), 1.79-1.91 (m, 2H). LC-MS (Method 2): R.sub.t = 1.36 min; MS (ESIpos): m/z = 496.5 [M + H].sup.+ 165 [00283] 6-fluoro-1- methyl-2-oxo- 4-{4-[4- (trifluoromethoxy) phenoxy] piperidin-1-yl}-1,2- dihydroquinoline- 3-carboxamide 6-fluoro-1- methyl-2-oxo-4- (4-4- (trifluoromethoxy) phenoxy]piperidin- 1-yl}-1,2- dihydroquinoline- 3-carbonitrile (example 166) .sup.1H NMR (DMSO-d.sub.6) δ: 7.47-7.60 (m, 3H), 7.28 (d, 2H), 7.06-7.12 (m, 2H), 4.56-4.65 (m, 1H), 3.57 (s, 3H),3.36 (br d, 2H), 3.06-3.17 (m, 2H), 2.12 (br dd, 2H), 1.78- 1.89 (m, 2H). LC-MS (Method 2): R.sub.t = 1.29 min; MS (ESIpos): m/z = 480.5 [M + H].sup.+

Example 166

6-fluoro-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2259] ##STR00284##

[2260] A suspension of 120 mg 4-chloro-6-fluoro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (507 μmol, CAS 749865-80-3, synthesis described in WO2004074218), 164 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (535 μmol, CAS 287952-67-4) and 260 μL N,N-diisopropylethylamine (1.3 mmol) in 3 mL 2-propanol was stirred for 2 h at 90° C. After this time, water was added and the reaction was stirred for some time. The residue was collected by filtration and washed with water and ethanol. The resulting solid was dried to give 209 mg of the title compound (88% yield, 98% purity).

[2261] .sup.1H NMR (DMSO-d.sub.6) δ: 7.61-7.71 (m, 2H), 7.57 (dd, 1H), 7.31 (d, 2H), 7.12-7.18 (m, 2H), 4.77 (tt, 1H), 3.71-3.80 (m, 2H), 3.51-3.60 (m, 5H), 2.21 (ddd, 2H), 1.87-1.97 (m, 2H).

[2262] LC-MS (Method 2): R.sub.t=1.43 min; MS (ESIpos): m/z=462.4 [M+H].sup.+

Example 167

6-hydroxy-1-methyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2263] ##STR00285##

[2264] A solution of 100 mg 4-chloro-6-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (426 μmol, intermediate 63), 111 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (426 μmol, CAS 287952-67-4) and 0.12 mL triethylamine (850 μmol) in 5 mL 2-propanol was stirred for 2 h at 90° C. After this time, water and ethyl acetate were added and the reaction was stirred for some time. The solid that precipitated from this procedure was collected by filtration, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-6%). 45 mg of the title compound were obtained (95% purity, 22% yield).

[2265] .sup.1H NMR (DMSO-d.sub.6) δ: 9.85 (br s, 1H), 7.40-7.50 (m, 1H), 7.28-7.37 (m, 2H), 7.10-7.26 (m, 4H), 4.72-4.91 (m, 1H), 3.65-3.79 (m, 2H), 3.42-3.59 (m, 5H), 2.14-2.29 (m, 2H), 1.84-1.99 (m, 2H).

[2266] LC-MS (Method 2): R.sub.t=1.08 min; MS (ESIpos): m/z=460.4 [M+H].sup.+

Example 168

8-bromo-1,6-dimethyl-2-oxo-4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}-1,2-dihydroquinoline-3-carbonitrile

[2267] ##STR00286##

[2268] A solution of 300 mg 8-bromo-4-chloro-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (963 μmol, intermediate 66), 291 mg 4-[4-(trifluoromethoxy)phenoxy]piperidine (1.06 mmol, CAS 287952-67-4) and 0.27 mL triethylamine (1.9 mmol) in 13 mL 2-propanol was stirred for 3 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-2%). 520 mg of the title compound were obtained (95% purity, 96% yield).

[2269] .sup.1H NMR (DMSO-d.sub.6) δ: 7.81-7.95 (m, 1H), 7.56-7.68 (m, 1H), 7.24-7.36 (m, 2H), 7.08-7.19 (m, 2H), 4.69-4.83 (m, 1H), 3.71-3.82 (m, 2H), 3.68 (s, 3H), 3.50-3.61 (m, 2H), 2.38 (s, 3H), 2.14-2.25 (m, 2H), 1.83-2.02 (m, 2H).

[2270] LC-MS (Method 2): R.sub.t=1.52 min; MS (ESIpos): m/z=538.4 [M+H].sup.+

Example 169

8-bromo-4-[4-(3-chlorophenoxy)piperidin-1-yl]-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile

[2271] ##STR00287##

[2272] A solution of 300 mg 8-bromo-4-chloro-1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (963 μmol, intermediate 66), 224 mg 4-(3-chlorophenoxy)piperidine (1.06 mmol, CAS 97840-40-9) and 0.27 mL triethylamine (1.9 mmol) in 13 mL 2-propanol was stirred for 3 h at 90° C. After this time, water was added and the reaction was extracted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography (silica, dichloromethane/methanol gradient 0-2%). 315 mg of the title compound were obtained (95% purity, 64% yield).

[2273] .sup.1H NMR (DMSO-d.sub.6) δ: 7.83-7.93 (m, 1H), 7.59-7.66 (m, 1H), 7.30-7.39 (m, 1H), 7.12-7.18 (m, 1H), 6.97-7.07 (m, 2H), 4.76-4.88 (m, 1H), 3.71-3.80 (m, 2H), 3.67 (s, 3H), 3.52-3.61 (m, 2H), 2.39 (s, 3H), 2.15-2.24 (m, 2H), 1.84-1.96 (m, 2H).

[2274] LC-MS (Method 2): R.sub.t=1.52 min; MS (ESIpos): m/z=488.5 [M+H].sup.+

EXPERIMENTAL SECTION—BIOLOGICAL ASSAYS

Human DGKα Kinase Activity Inhibition Assay

[2275] Human DGKα inhibitory activity of compounds of the present invention was quantified employing the human DGKα kinase activity assay as described in the following paragraphs. In essence, the enzyme activity was measured by quantification of the adenosine-di-phosphate (ADP) generated as a co-product of the enzyme reaction via the “ADP-Glo™ Kinase Assay” kit from the company Promega. This detection system works as follows: In a first step the ATP not consumed in the kinase reaction is quantitatively converted to cAMP employing an adenylate cyclase (“ADP-Glo-reagent”), then the adenylate cyclase is stopped and the ADP generated in the kinase reaction converted to ATP, which subsequently generates in a luciferase-based reaction a glow-luminescence signal (“Kinase Detection Reagent”).

[2276] C-terminally FLAG-tagged, recombinant full-length human DGKα (expressed in baculovirus infected insect cells, purified using anti-Flag pulldown and size exclusion chromatography as described below, DGKα_hu_1) was used as enzyme. As substrate for the kinase 1,2-dioleoyl-sn-glycerol, reconstituted in octyl-β-D-glucopyranoside micelles, was used. For the preparation of the micelles, 1 volume of a 16.1 mM solution of 1,2-dioleoyl-sn-glycerol (Avanti, Cat. #O8001-25G) in chloroform was slowly evaporated using a nitrogen stream. Subsequently, 22.55 volumes of a 510 mM solution of octyl-β-D-glucopyranoside (Sigma-Aldrich, Cat. #O8001-10G) in 50 mM MOPS buffer (pH 7.4) were added, and the mixture was sonicated in an ultrasonic bath for 20 s. Then 35 volumes of 50 mM MOPS buffer (pH 7.4) were added to yield a solution of 0.28 mM 1,2 dioleoyl-sn-glycerol and 200 mM octyl-β-D-glucopyranoside, which was aliquoted, flash-frozen in liquid nitrogen, and stored at −20° C. until use. For each experiment, a fresh aliquot was quickly thawed and diluted 24-fold with aqueous assay buffer (described below) containing 95.7 μM adenosine triphosphate (Promega) to yield a 1.67-fold concentrated substrate solution.

[2277] For the assay 50 nl of a 100-fold concentrated solution of the test compound in dimethyl sulfoxide (DMSO, Sigma) was pipetted into either a white 1536-well or a white low-volume 384-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany). Subsequently, 2 μl of a solution of human DGKα in aqueous assay buffer [50 mM (3-(N-morpholino)propanesulfonic acid (MOPS, pH 7.4, Sigma-Aldrich), 1 mM dithiothreitol (DTT, Sigma-Aldrich), 100 mM NaCl (Sigma-Aldrich), 10 mM MgCl.sub.2 (Sigma-Aldrich), 0.1% (w/v) bovine gamma globulin (BGG, Sigma-Aldrich), 1 μM CaCl.sub.2 (Sigma-Aldrich)] were added to the wells, and the mixture was incubated for 15 min at 22° C. to allow pre-binding of the test compounds to the enzyme. The reaction was initiated by the addition of 3 μl of substrate solution [preparation described above; 11.7 μM 1,2-dioleoyl-sn-glycerol (=>final conc. in the 5 μl assay volume is 7 μM), 8.33 mM octyl-β-D-glucopyranoside (=>final conc. in 5 μl assay volume is 5 mM), and 91.67 μM adenosine triphosphate (=>final conc. in 5 μl assay volume is 55 μM) in assay buffer] and the resulting mixture was incubated for a reaction time of 20 min at 22° C. The concentration of DGK a was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, a typical concentration is about 0.1 nM. The reaction was stopped by the addition of 2.5 μl of “ADP-Glo-reagent” (1 to 1.5 diluted with water) and the resulting mixture was incubated at 22° C. for 1 h to convert the ATP not consumed in the kinase reaction completely to cAMP. Subsequently 2.5 μl of the “kinase detection reagent” (1.2-fold more concentrated than recommended by the producer) were added, the resulting mixture was incubated at 22° C. for 1 h and then the luminescence measured with a suitable measurement instrument (e.g. Viewlux™ from Perkin-Elmer). The amount of emitted light was taken as a measure for the amount of ADP generated and thereby for the activity of the DGKα.

[2278] The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition). Usually the test compounds were tested on the same microtiterplate in 11 different concentrations in the range of 20 μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series prepared separately before the assay on the level of the 100-fold concentrated solutions in DMSO by serial dilutions, exact concentrations may vary depending pipettors used) in duplicate values for each concentration and IC.sub.50 values were calculated using Genedata Screener™ software.

TABLE-US-00010 TABLE 10 IC.sub.50 values of examples in in vitro human DGKα kinase activity inhibition assays. Example IC.sub.50 [nM] 1 4.2 2 3.9 3 6.2 4 6.3 5 7.7 6 8.4 7 8.6 8 13 9 9.1 10 10 11 11 12 12 13 14 14 14 15 14 16 33 17 45 18 55 19 64 20 81 21 119 22 129 23 181 24 266 25 283 26 415 27 318 28 521 29 654 30 1530 31 6.8 32 31 33 13 34 9 35 646 36 164 37 10 38 18 39 4 40 11 41 173 42 27 43 339 44 45 45 31 46 32 47 8.6 48 0.9 49 1.7 50 3.1 51 6.1 52 3.8 53 1.1 54 5.8 55 4.4 56 9.9 57 17 58 19 59 18 60 27 61 22 62 2.3 63 12 64 16 65 7.3 66 14 67 6.4 68 29 69 507 70 17 71 5.7 72 16 73 13 74 3.5 75 3.7 76 6.8 77 17 78 1130 79 416 80 534 81 3 82 12 83 14 84 25 85 28 86 32 87 40 88 5.8 89 4.7 90 1.7 91 4.5 92 6.2 93 39 94 28 95 15 96 12 97 122 98 1.9 99 1.2 100 8.3 101 7.4 102 18 103 18 104 40 105 33 106 8.3 107 7.2 108 10 109 16 110 5.3 111 4.8 112 10 113 12 114 16 115 29 116 6.4 117 6. 118 123 119 34 120 51 121 16 122 7.1 123 14 124 30 125 43 126 14 127 14 128 29 129 29 130 202 131 18 132 536 133 55 134 37 135 1370 136 2.5 137 1.9 138 1.5 139 2.5 140 1.4 141 7.7 142 2 143 4.7 144 3 145 4.4 146 17 147 32 148 73 149 7.7 150 50 151 60 152 3.8 153 10 154 13 155 9.3 156 7 157 1240 158 12 159 12 160 3.1 161 21 162 57 163 59 164 37 165 0.17 166 0.97 167 0.94 168 556 169 2530

Transactivation Assay in Jurkat I1L2-Reporter Cell Line

[2279] Transactivation assays were carried out in Jurkat cells purchased from Promega (Promega, #CS187001) stably transfected with a firefly luciferase reporter gene construct under the control of the IL2-promoter. Cells were cultured as specified by the manufacturer. Bulk cells were harvested at a culture density of approx. 1E+06 cells/ml, suspended in cryo-storage medium (70% RPMI/20% FCS/10% DMSO), frozen at controlled rate of −1°/min in 1.8 ml cryo-vials with cell densities of 1E+07 to 1E+08 cells per vial, and stored at −150° C. or below until further use. Frozen cells were thawed and cultured in medium at a starting density of 3.5E+05 cells/ml for 6 days. On day 6 cells were centrifuged for 5 min at 300×g, medium was decanted and cell concentration was adjusted to 5.0E+06 cells/ml with fresh assay medium (500 ml RPMI (Gibco, #22400)+5 ml L-Glutamin (Sigma, #G7513)+5 ml Penicillin/Streptomycin (Sigma #P0781)+5 ml Non-essential amino acids (Invitrogen, #11140)+5 ml sodium-pyruvate (Gibco #1136088), 5 ml FBS (Biochrom, #S0615)). Cell working stock was split in two parts: neutral control and compounds with EC30 stimulation, high control with EC100 stimulation.

[2280] An antibody premix was prepared by diluting anti-CD3 (BD Pharmingen, #555329), anti-CD28 (BD Pharmingen, #555725) and goat anti mouse anti-IgG (ThermoFisher, #31160) antibodies at 1/1/4 ratio in assay medium at 2-fold of final concentration (final concentrations depend on cell batch, typically for neutral control 0.055/0.055/0.22 μg/ml, for high control 0.5/0.5/2 mg/ml). The premix solutions were added to the cells in 1+1 volume prior use.

[2281] Fifty nl of a 100-fold concentrated solution of the test compounds in DMSO were transferred into a white microtiter test plate (384, Greiner Bio-One, Germany). For this, either a Hummingbird liquid handler (Digilab, USA) or an Echo acoustic system (Labcyte, USA) was used. Five μl of the freshly prepared cell suspension was added to the wells of a test plate and incubated at 37° C. in a 5% CO.sub.2 atmosphere. After completion of the incubation for 4 hours, 3 μl of Bio-Glo Luciferase assay reagent (Promega, #G7941, prepared as recommended by the supplier) were added to all wells. The test plate was incubated at 20° C. for 10 min before measurement of the luminescence in a microplate reader (typically Pherastar by BMG, Germany, or ViewLux by Perkin-Elmer, USA). Data were normalized (neutral control=0% effect, high control=100% effect). Compounds were tested in duplicates at up to 11 concentrations (typically 20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 nM and 0.073 nM). Dilution series were made prior to the assay in a 100-fold concentrated form by serial dilution. EC.sub.50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Analyzer, Switzerland).

Polyclonal Activation of Human PBMCs

[2282] To test the effect of DGKα compounds on IL-2 and IFN-γ secretion of human Peripheral Blood Mononuclear Cells (PBMCs) a 24 h human PBMC assay is performed as screening assay. For this, a 96 well flat bottom plate is coated with a suboptimal stimulation condition (EC 10-30) of human aCD3 (Invitrogen, clone OKT3) antibody in 50 μl PBS/well at 4° C. overnight. PBMCs isolated and frozen at liquid N.sub.2 from leucapherese samples is thawed and resuspended in culture medium (X-Vivo-20). 4×10.sup.5 cells/well are plated. Wells are treated with the respective compound concentrations (5-fold dilution steps from 10 μM to 3 nM) and the final DMSO concentration per well is 0.1%. Medium+DMSO (0.1%) is used as baseline value. As positive controls 1000 ng/ml aCD3+aCD28 (1 μg/ml) and a DGKα reference compound is used. After 24 h the medium is collected and hIL-2 or hIFN-γ ELISA are performed. The following parameters are calculated: EC.sub.50 value, concentration at 50% increase; max increase in % and respective concentration and maximum effect normalized to max concentration (10 μM) of a selected DGKα reference compound.

In Vitro Activation of Mouse OT-I Antigen-Specific T-Cells

[2283] To test the effect of DGKα compounds in murine antigen-specific T-cells, spleens and lymph nodes of OT-I mice are collected and mashed through a 40 μm cell strainer and incubated for 1 min in 1 ml ACK lysing buffer (Gibco)/spleen. 4×106 cells/ml are incubated in medium containing 0.05 ng/ml SIINFEKL in a 50 ml falcon at 37° C. for 30 min. Afterwards cells are centrifuged and 4×106 cells/ml are resuspended in fresh medium (DMEM; 10% FCS, 1% Pen/Strep, 0.1% β-mercaptoethanol, 1% HEPES). 4×105 cells are plated per well in a 96-well round bottom plate. Wells are treated with respective compound concentrations (5-fold dilution steps from 10 μM to 3 nM) in a final DMSO concentration of 0.1%. Medium+DMSO (0.1%) is used as baseline value. As positive controls cells incubated with the 4× SIINFEKL concentration (0.2 ng/ml) and a DGKα reference compound are used. The plates are centrifuged to reduce the distance between T-cells and APCs before incubation. After 24 h the medium is collected and mIL-2 or mIFN-γ ELISAs are performed. The following parameters are calculated: EC.sub.50 value, concentration at 50% increase; max increase in % and respective concentration and maximum effect normalized to max concentration (10 μM) of a selected DGKα reference compound.

DGKα Surface Plasmon Resonance Interaction Assay

[2284] The ability of the compounds described in this invention to bind to DGKα may be determined using surface plasmon resonance (SPR). This allows for the quantification of binding in terms of the equilibrium dissociation constant (K.sub.D [M]), as well as association and dissociation rate constants (k.sub.on[1/Ms] and k.sub.off [1/s], respectively). The measurements may be performed using Biacore® T200, Biacore® S200 or Biacore® 8K (GE Healthcare).

[2285] All buffers described in this section were prepared with 10×HBS-P+Buffer (GE Healthcare, #BR100671) supplemented with additional buffer components as indicated below, dithiothreitol (DTT from Sigma, #D0632-25G), Adenosine 5′-triphosphate (ATP from Sigma, #A26209-10G), MgCl.sub.2 (Sigma, #M1028-100ML), dimethyl sulfoxide (DMSO from Biomol, #54686.500).

[2286] For SPR measurements, recombinant and biotinylated human DGKα (DGKα_hu_1 Avi) was immobilized via the streptavidin-biotin interaction onto a Series S Sensor Chip SA (GE Healthcare, #BR-1005-31). Briefly, DGKα was diluted to a concentration of 19 μg/ml in Immobilization Buffer (10 mM HEPES, 150 mM NaCl, 0.05% v/v Surfactant P20, 2 mM MgCl.sub.2, 1 mM DTT, pH 7.4) and captured on the SA Chip surface using a flow rate of 10 μl/min for 500 seconds at a temperature of 10° C. Immobilization levels of approximately 8000-10000 RU were typically achieved. The reference surface consisted of a streptavidin surface without immobilized protein. Compounds were diluted from 10 mM DMSO stock solution into Running Buffer (10 mM HEPES, 150 mM NaCl, 0.05% v/v Surfactant P20, 2 mM MgCl.sub.2, 1 mM DTT, 0.2 mM ATP and 1% v/v DMSO, pH 7.4). For SPR-binding measurements serial dilutions (typically 1:3 dilutions resulting in 8 concentrations up to 2 μM or 20 μM) were injected over immobilized protein. Binding affinity and kinetics were measured at 18° C. and at a flow rate of 100 μl/min.

[2287] For regeneration of slowly dissociating compounds an additional regeneration step was included by injection of Regeneration Buffer without ATP (10 mM HEPES, 150 mM NaCl, 0.05% v/v Surfactant P20, 1 mM DTT and 1% v/v DMSO, pH 7.4) for 200 s at a flow rate of 30 μl/min

[2288] The double-referenced sensorgrams were fit to a simple reversible Langmuir 1:1 reaction mechanism as implemented in the Biacore® T200, S200 and 8K evaluation software (Biacore T200 Evaluation Software version 2.0, Biacore S200 Evaluation Software version 1.0, Biacore 8K Evaluation Software v 1.1.1.7442, GE Healthcare).

Expression of DGKα in Insect Cells Using the Baculovirus System

[2289] Expression Constructs:

[2290] The cDNA encoding the full length sequence of human DGKα (Uniprot P23743) was optimized for expression in eukaryotic cells and synthesized by the GeneArt Technology at Life Technologies.

[2291] The DNA sequence encoded the following sequence:

[2292] Construct DGKα_hu amino acid M1 to S735

[2293] Additionally the expression construct encoded: a Kozak DNA sequence for translation initiation (GCCACC), at the C-terminus a Flag (DYKDDDDK) sequence followed by two stop codons and additionally 5′ and 3′ att-DNA sequences for Gateway Cloning.

[2294] The DGKα construct was subcloned using the Gateway Technology into the Destination vector pD-INS. The vector pD-INS is a Baculovirus transfer vector (based on vector pVL1393, Pharmingen) which enables the expression of the DGK-Flag protein. The respective protein was named DNA_hu_1.

[2295] Additionally the DNA construct DGKα_hu with C-terminal Flag tag was also subcloned in to the Destination vector pD-INSA. This Baculovirus transfer vector is designed to fuse a His6 tag +Avi tag protein sequence to N-terminus of the DGKα_hu-Flag protein. The complete encoded protein was designated DGKα_hu_1Avi. The Avi-tag sequence enables a site-specific in-vitro biotinylation of the DGKα protein.

[2296] Generation of Recombinant Baculovirus

[2297] In separate approaches each of the two DGK transfer vectors was co-transfected in Sf9 cells with Baculovirus DNA (Flashbac Gold DNA, Oxford Expression Technologies) using Fugene HD (Roche). After 5 days the supernatant of the transfected cells containing the recombinant Baculovirus encoding the various DGK proteins was used for further infection of Sf9 cells for virus amplification whereby the virus titer was monitored using qPCR.

[2298] DGK Expression in Sf9 Cells Using Bioreactor

[2299] Sf9 cells cultured (Insect-xpress medium, Lonza, 27° C.) in a Wave-bioreactor with a disposable culture bag were infected at a cell density of 10.sup.6 cells/mL with one of the recombinant baculovirus stocks at a multiplicity of infection of 1 and incubated for 72. Subsequently the cells were harvested by centrifugation (800×g) and cell pellet frozen at −80° C.

[2300] To produce biotinylated DGKα_hu_1Avi the Sf9 cells in the bioreactor were co-infected with the Baculovirus encoding DGKα_hu_1Avi as well as with a Baculovirus encoding the biotinylation enzyme BirA.

[2301] Purification of the DGK-Flag Proteins:

[2302] Purification of the DGK-Flag proteins was achieved by a two-step chromatography procedure as follows.

[2303] The pelleted cells (from 8 L cell culture) were resuspended in Lysis-Buffer (50 mM Tris HCl 7.4; 150 mM NaCl; 10 mM MgCl.sub.2; 1 μM CaCl.sub.2; 1 mM DTT; 0.1% NP-40; 0.1% NP-40; Complete Protease Inhibitor Cocktail-(Roche)) and lysed by a freeze-thaw cycle followed by an incubation on ice for 60 min. The lysate was centrifuged at 63.000×g for 30 min. at 4° C. The soluble supernatant was than incubated with 25 mL anti-Flag M2 Agarose (Sigma) in a plastic flask rotating for 16 h at 4° C. for binding of the DGK-Flag proteins, subsequently rinsed with 10×25 mL Wash-Buffer (50 mM Tris HCl 7.4; 150 mM NaCl; 10 mM MgCl.sub.2; 1 μM CaCl.sub.2; 1 mM DTT) and finally the bound protein was eluted using Elusion-Buffer (Wash-Buffer with 300 μg/mL FLAG-Peptide, incubated 30 min. at 4° C. with 3×15 mL).

[2304] The elution fractions from the affinity chromatography were concentrated (using Amicon Ultra 15, Centrifugal Filters, 30 kDa MW cut-off; Millipore #UFC903024) to 10 mL and applied to a size exclusion chromatography column (S200 prep grade 26/60, GE Healthcare) and the resulting monomeric peak fraction was collected, pooled and again concentrated. Wash-buffer was used for size exclusion chromatography and the final concentrated sample. The final protein sample concentration was 5-10 mg/mL and the yield was 1-2 mg final protein per L cell culture.

[2305] For DGKα_hu_1Avi a biotinylation level of 100% was demonstrated by mass spectromentry.

[2306] In Vivo Activation of Murine Antigen Specific OT1 T Cells

[2307] Oral Administration of compounds enhances antigen-specific T cell activation in vivo.

[2308] Direct detection of antigen-specific T cell proliferation in vivo is technically challenging, since it requires the presence of T cells specific for a cognate antigen and also a specific measurement procedure for cell proliferation. Both these requirements are fulfilled in the OT-1 transfer model, which utilizes the direct transfer of CD8 T cells transgenic for a T cell receptor recognizing an Ovalbumin-derived peptide as antigen. Before transfer, these cells are labeled with the fluorescent dye CFSE, which is diluted by every cell division and therefore allows detection of cell proliferation. After transfer of the CFSE-labeled T cells, mice are vaccinated with the Ovalbumin antigen OVA-30. Only transferred OT-1 cells are able to recognize the OVA-antigen presented by APC and only these transferred T cells then get activated. Flow cytometric analysis of CFSE-levels in the OT-1 cells can be combined with measurement of multiple activation markers like CD69, CD25 and PD1.

[2309] In particular, mice receive 2×10×6 CFSE-labeled OT-1 T cells and are vaccinated one day later by intravenous application of 2.5 μg OVA-30. Mice are then divided into groups which receive vehicle only, compound alone or in combination with other immune modulating agents. Mice are treated for 2 to 20 days and T cell composition (incl. transferred OT-1 cells) of spleen, blood and lymphodes are analysed by FACS.

[2310] In Vivo Syngeneic Tumor Models

[2311] Animals are assigned to a study at the age of 6-8 weeks. Animal husbandry, feeding and health conditions are according to animal welfare guidelines. Syngeinic tumor cell lines are cultivated with appropriate medium and splitted at least 3 times before inoculation. Female mice are inoculated with appropriate amount of tumor cells in medium or a medium/matrigel mixture s.c, i.v. or i.p depending on the model. After 4-10 days the animals are randomized and therapeutic treatment starts when tumors reach a size of approx. 40-70 mm2.

[2312] Tumor size is measured using calipers determining length (a) and width (b). Tumor volume is calculated according to:

v=(a×b{circumflex over ( )}2)/2

[2313] Significance of monotherapies and combination treatment is calculated versus control group as determined by 2-Way ANOVA analysis.