SUBSTITUTED INDAZOLES, METHODS FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS THAT CONTAIN SAID NEW SUBSTITUTED INDAZOLES, AND USE OF SAID NEW SUBSTITUTED INDAZOLES TO PRODUCE DRUGS
The present application relates to novel substituted indazoles, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, dyspareunia, dysuria and dyschezia, of lymphoma, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondyloarthritis and Bekhterev's disease), lupus erythematosus, multiple sclerosis, macular degeneration, COPD, gout, fatty liver disorders, insulin resistance, neoplastic disorders and psoriasis.
1 - 23 . (canceled)
24 : A method of treating a dermatological disease or disorder in a human in need thereof, comprising administering to the human an effective amount of a compound of formula (I),
wherein:
R 1 is C 1 -C 6 -alkyl, wherein the C 1 -C 6 -alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl, an unsubstituted or mono- or poly-halogen-substituted C 3 -C 6 -cycloalkyl, or an R 6 or R 8 O group, or a group selected from the group consisting of:
wherein * represents the bonding site of the group to the rest of the molecule;
R 2 and R 3 always have the same definition and are both either hydrogen or C 1 -C 6 -alkyl;
R 4 is halogen, cyano, an unsubstituted or a singly or multiply, identically or differently substituted C 1 -C 6 -alkyl or an unsubstituted or a singly or multiply, identically or differently substituted C 3 -C 6 -cycloalkyl, and the substituents are selected from the group consisting of halogen and hydroxyl;
R 5 is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C 1 -C 6 -alkyl;
R 6 is an unsubstituted or mono- or di-methyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms, which contains a heteroatom or a heterogroup selected from the group consisting of O, S, SO and SO 2 ; and
R 8 is C 1 -C 6 -alkyl, where the C 1 -C 6 -alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen,
or a diastereomer, an enantiomer, a salt, a solvate, or a solvate of the salt thereof.
25 : The method of claim 24 , wherein the dermatological disease or disorder is dermatitis, psoriasis, or acne inversa.
26 : The method of claim 24 , wherein the dermatological disease or disorder is atopic dermatitis or allergic contact dermatitis.
27 : The method of claim 24 , wherein the dermatological disease or disorder is psoriasis.
28 : The method of claim 24 , wherein the dermatological disease or disorder is acne inversa.
29 : The method of claim 24 , wherein:
R 1 is C 1 -C 6 -alkyl, wherein the C 1 -C 6 -alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R 6 or R 8 O group;
R 2 and R 3 always have the same definition and are both either hydrogen or C 1 -C 3 -alkyl;
R 4 is halogen, cyano or C 1 -C 3 -alkyl, wherein the C 1 -C 3 -alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl;
R 5 is hydrogen, fluorine, chlorine or C 1 -C 3 -alkyl;
R 6 is oxetanyl or tetrahydrofuranyl; and
R 8 is an unsubstituted C 1 -C 4 -alkyl group or a mono-, di- or tri-fluorine-substituted C 1 -C 4 -alkyl group.
30 : The method of claim 24 , wherein R 4 is difluoromethyl, trifluoromethyl, or methyl.
31 : The method of claim 24 , wherein R 5 is hydrogen or fluorine.
32 : The method of claim 24 , wherein R 2 and R 3 are both either hydrogen or methyl.
33 : The method of claim 24 , wherein
R 1 is C 2 -C 6 -alkyl, wherein the C 2 -C 6 -alkyl group is unsubstituted, or the C 2 -C 6 -alkyl group is mono-, di- or tri-fluorine-substituted or the C 2 -C 6 -alkyl group is monosubstituted by hydroxyl, R 6 , or R 8 O; or
R 1 is an oxetanyl-substituted C 1 -C 3 -alkyl group;
R 2 and R 3 always have the same definition and are both either hydrogen or methyl;
R 4 is an unsubstituted or mono- or poly-halogen-substituted C 1 -C 3 -alkyl group or a C 1 -C 3 -alkyl group substituted by one hydroxyl group or a C 1 -C 3 -alkyl group substituted by one hydroxyl group and three fluorine atoms;
R 5 is hydrogen, fluorine or C 1 -C 3 -alkyl; and
R 8 is C 1 -C 4 -alkyl, wherein the C 1 -C 4 -alkyl group is unsubstituted or mono-, di- or tri-fluorine-substituted.
34 : The method of claim 33 , wherein
R 1 is a C 2 -C 5 -alkyl group substituted by hydroxyl or C 1 -C 3 -alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl; or
R 1 is an oxetan-3-yl-substituted C 1 -C 2 -alkyl group;
R 2 and R 3 always have the same definition and are both hydrogen or methyl;
R 4 is selected from the group consisting of methyl, ethyl, trifluoro-C 1 -C 3 -alkyl, difluoro-C 1 -C 3 -alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl, and
R 5 is hydrogen, fluorine, or methyl.
35 : The method of claim 34 , wherein
R 1 is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, or 2-hydroxyethyl;
R 2 and R 3 are both methyl or hydrogen;
R 4 is difluoromethyl, trifluoromethyl or methyl, and
R 5 is hydrogen or fluorine.
36 : The method of claim 35 , wherein
R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, or 3-hydroxy-2,2-dimethylpropyl;
R 2 and R 3 are both methyl;
R 4 is difluoromethyl or trifluoromethyl, and
R 5 is hydrogen.
37 : The method of claim 35 , wherein
R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, or 3-hydroxy-2,2-dimethylpropyl;
R 2 and R 3 are both methyl;
R 4 is methyl, and
R 5 is fluorine, wherein R 5 is in the ortho position to R 4 .
38 : A method of treating a dermatological disease or disorder in a human in need thereof, comprising administering to the human an effective amount of a compound of formula (I), wherein the compound of formula (I) is selected from the group consisting of:
N-[6-(2-Hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
N-[6-(Hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
N-[6-(2-Hydroxypropan-2-yl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
N-[6-(Hydroxymethyl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
N-[2-(2-Hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
N-[6-(2-Hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
N-[2-(2-Hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
N-[6-(2-Hydroxypropan-2-yl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
N-[6-(Hydroxymethyl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
6-(Difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]pyridine-2-carboxamide;
6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]pyridine-2-carboxamide;
N-[6-(2-Hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;
N-{6-(2-Hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;
N-{6-(2-Hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;
5-Fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide;
N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide;
6-(2-Hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]pyridine-2-carboxamide; and
N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide,
or a salt, a solvate, or a solvate of the salt thereof.
39 : A method of treating a dermatological disease or disorder in a human in need thereof, comprising administering to the human an effective amount of a compound
or a salt, a solvate, or a solvate of the salt thereof.
40 : The method of claim 39 , wherein the skin disease is dermatitis, psoriasis, or acne inversa.
41 : The method of claim 39 , wherein the skin disease is atopic dermatitis or allergic contact dermatitis.
42 : The method of claim 39 , wherein the skin disease is psoriasis.
43 : The method of claim 39 , wherein the skin disease is acne inversa.