Substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said substituted indazoles, and use of said 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. A method for 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 monosubstituted with an R 7 SO 2 or R 7 SO 2 group, or
wherein the C 1 -C 6 -alkyl group is polysubstituted with at least one of an R 7 SO 2 group or R 7 SO group, and one or more additional substituents selected from the group consisting of halogen, hydroxyl, an unsubstituted or mono- or poly-halogen substituted C 3 -C 6 -cycloalkyl, an R 6 group, and an R 8 O group;
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 from the group of O, S, SO and SO 2 ;
R 7 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, hydroxyl or C 3 -C 6 -cycloalkyl;
or R 7 is C 3 -C 6 -cycloalkyl; 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.
2. The method according to claim 1 , wherein:
R 1 is C 1 -C 6 -alkyl, wherein the C 1 -C 6 -alkyl group is monosubstituted with an R 7 SO 2 group or an R 7 SO group, or
wherein the C 1 -C 6 -alkyl group is polysubstituted with at least one of an R 7 SO 2 group or an R 7 SO group, and one or more additional substituents selected from the group consisting of fluorine, hydroxyl, an R 6 group, and an 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;
R 7 is C 1 -C 4 -alkyl, wherein the C 1 -C 4 -alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms, and
R 8 is an unsubstituted C 1 -C 4 -alkyl group or a tri-fluorine-substituted C 1 -C 4 -alkyl group.
3. The method according to claim 1 , wherein R 4 is difluoromethyl, trifluoromethyl or methyl.
4. The method according to claim 1 , wherein R 5 is hydrogen or fluorine.
5. The method according to claim 1 , wherein R 2 and R 3 are both either hydrogen or methyl.
6. The method according to claim 2 , wherein
R 1 is C 2 -C 6 -alkyl, wherein the C 2 -C 6 -alkyl group is monosubstituted by an R 7 SO 2 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 7 is C 1 -C 3 -alkyl.
7. The method according to claim 6 , wherein
R 1 is a methyl-SO 2 -substituted C 2 -C 4 -alkyl group;
R 2 and R 3 always have the same definition and are both either 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.
8. The method according to claim 7 , wherein
R 1 is 2-(methyl sulphonyl)ethyl or 3-(methylsulphonyl)propyl;
R 2 and R 3 are both either methyl or hydrogen;
R 4 is difluoromethyl, trifluoromethyl or methyl; and
R 5 is hydrogen or fluorine.
9. The method according to claim 8 , wherein
R 1 is 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl;
R 2 and R 3 re both methyl;
R 4 is difluoromethyl or trifluoromethyl; and
R 5 is hydrogen.
10. The method according to claim 8 , wherein
R 1 is 3-(methylsulphonyl)propyl or 2-(methyl sulphonyl)ethyl;
R 2 and R 3 re both methyl;
R 4 is methyl; and
R 5 is fluorine, wherein R 5 is in the ortho position to R 4 .
11. The method according to claim 1 , wherein the compound is:
or a metabolite, a salt, a solvate, a solvate of the salt thereof.
12. The method according to claim 1 , wherein the compound is:
or a salt thereof.
13. The method according to claim 1 , wherein the dermatological disease or disorder is psoriasis, atopic dermatitis, Kindler's syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inversa or acne vulgaris.
14. The method according to claim 1 , wherein the dermatological disease or disorder is psoriasis, atopic dermatitis, allergic contact dermatitis, or acne inversa.
15. The method according to claim 1 , wherein the dermatological disease or disorder is atopic dermatitis.
16. The method according to claim 11 , wherein the dermatological disease or disorder is psoriasis, atopic dermatitis, Kindler's syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inversa or acne vulgaris.
17. The method according to claim 11 , wherein the dermatological disease or disorder is psoriasis, atopic dermatitis, allergic contact dermatitis, or acne inversa.
18. The method according to claim 11 , wherein the dermatological disease or disorder is atopic dermatitis.
19. The method according to claim 12 , wherein the dermatological disease or disorder is psoriasis, atopic dermatitis, Kindler's syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inversa or acne vulgaris.
20. The method according to claim 12 , wherein the dermatological disease or disorder is psoriasis, atopic dermatitis, allergic contact dermatitis, or acne inversa.
21. The method according to claim 12 , wherein the dermatological disease or disorder is atopic dermatitis.
22. The method according to claim 1 , wherein the compound is administered to the human in a dosage form comprising at least one pharmaceutically suitable excipient.
23. The method according to claim 11 , wherein the compound is administered to the human in a dosage form comprising at least one pharmaceutically suitable excipient.
24. The method according to claim 12 , wherein the compound is administered to the human in a dosage form comprising at least one pharmaceutically suitable excipient.