Novel compounds for modulation of orphan nuclear receptor RAR-related orphan receptor-gamma (RORgamma, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune disease

A compound represented by Formula (1)

• and the enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof,
• wherein:
• R1 is hydrogen;
• C1-12-alkyl;
• C1-12-alkenyl, C1-12-alkynyl;
• C3-10-cycloalkyl;
• COOC1-6-alkyl;
• CONR1OR11;
• CN;
• NR10R11;
• a saturated 3-10 membered heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S;
• a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S;
• or a 6-10 membered mono- or bicyclic aromatic ring system;
• wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocyclic groups are unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, oxo, halogen, cyano, halo-C1-6-alkyl, O—C1-6-alkyl, O-(halo-C1-6-alkyl), CONR10R11 and NR10R11;
• and wherein the heteroaromatic and the aromatic ring systems are independently from each other unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, oxo, halogen, cyano, halo-C1-12-alkyl, C3-6-cycloalkyl, O-(halo-C1-6-alkyl), COOH, CO2NR10R11, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, a 6-10 membered mono- or bicyclic aromatic ring system, and a saturated 3-8 membered heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S;
• wherein the ring systems, the alkyl and the cycloalkyl groups are independently from each other unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxy, oxo, halogen, cyano, halo-C1-6-alkyl, O—C1-6-alkyl, O-(halo-C1-6-alkyl) and COOH;
• or wherein the heteroaromatic and the aromatic ring systems are fused with a saturated 5-8 membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O and S;
• wherein the fused ring system is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, oxo, halogen, cyano, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, O-(halo-C1-6-alkyl), COOH, CO2NR10R11 and NR10R11;
• R2 is C1-12-alkyl;
• C3-10-cycloalkyl;
• a saturated 3-10 membered heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S;
• a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S;
• or a 6-10 membered mono- or bicyclic aromatic ring system;
• wherein the alkyl, the cycloalkyl and the heterocycle groups are unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, oxo, halogen, cyano, halo-C1-6-alkyl, O—C1-6-alkyl, O-(halo-C1-6-alkyl), COOH, CONR10R11 and NR10R11;
• and wherein the heteroaromatic and the aromatic ring systems are independently from each other unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, oxo, halogen, cyano, halo-C1-12-alkyl, C3-6-cycloalkyl, O-(halo-C1-6-alkyl), O—C1-6-alkyl substituted with a saturated 5 or 6 membered heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, COOH, CO2(C1-6-alkyl), CONR10R11, SO2(C1-6-alkyl), a saturated 3-10 membered heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, and a 6-10 membered mono- or bicyclic aromatic ring system;
• wherein the heteroaromatic and the aromatic ring systems are independently from each other unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, oxo, halogen, cyano, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, O—C1-6-alkyl, O-(halo-C1-6-alkyl), COOH, CO2NR10R11 and NR10R11;
• or wherein the heteroaromatic and the aromatic ring systems are fused with a saturated 5-8 membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O and S;
• wherein the fused ring system is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, oxo, halogen, cyano, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, O-(halo-C1-6-alkyl), COOH, CO2NR10R11 and NR10R11;
• L is —(CR62)x—, —NR7—(CR62)x—, —(CR62)x—NR7—, —(CR62)x—O—, or —(CR62)x—O—(CR62)x—;
• R6 is independently H, C1-6-alkyl, halo-C1-6-alkyl or halogen;
• R7 is H, C1-6-alkyl, halo-C1-6-alkyl and hydroxy-C1-6-alkyl;
• R10 and R11 in each occurrence are independently selected from hydrogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl;
• or R10 and R11 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S, SO, SO2 or NR7, wherein the ring is unsubstituted or substituted with one or more halogen, oxo or C1-6-alkyl;
• R12 is H, C1-6-alkyl or halo-C1-6-alkyl;
• x is independently 1, 2, 3 or 4;
• Ar is a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O and S;
• or a 6-10 membered mono- or bicyclic aromatic ring system;
• wherein the heteroaromatic and the aromatic ring system is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, halogen, cyano, halo-C1-6-alkyl, C1-6-alkyl, C3-6-cycloalkyl, O—C1-6-alkyl, O-(halo-C1-6-alkyl), COOH, CO2NR10R11, NR10R11, a saturated 3-10 membered heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, a 5-10 membered mono- or bicyclic heteroaromatic ring system containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S and a 6-10 membered mono- or bicyclic aromatic ring system;
• wherein the heteroaromatic and aromatic ring system is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, oxo, halogen, cyano, C3-6-cycloalkyl, O—C1-6-alkyl and COOH;
• X, and Y are independently from each other selected from the group consisting of O, CH2, C(CH3)2, NH, N(C1-6-alkyl), N(hydroxy-C1-6-alkyl), S, SO2, C═O and
• wherein C1-6-alkyl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of oxo, halogen and cyano;
• Z is CH2, C(CH3)2 or CO;
• wherein:
• (1) combinations of X, Y and Z where O is directly connected to O, NH, N(C1-6-alkyl), N(hydroxy-C1-6-alkyl), S, CO or SO2,
• (2) combinations of X, Y and Z where NH, N(C1-6-alkyl), N(hydroxy-C1-6-alkyl) is directly connected to S, NH, N(C1-6-alkyl), N(hydroxy-C1-6-alkyl), and
• (3) combinations of X, Y and Z where S is directly connected to S, CO or SO2,
• are excluded and
• with the proviso that
• (1) the compound wherein Ar is unsubstituted phenyl, X is O, Y is CH2, Z is CH2, R2 is phenyl para-substituted with CH3 and (L)a-R1 is CH2Ph, and
• (2) the compounds, where the carbon atom in ring Ar directly neighbouring the bridgehead atom marked with “*” is substituted with an aromatic, C3-6-cycloalkyl or heterocyclic group,
• are excluded.