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

Patent metadata

Field	Value
Publication number	US-10793545-B2
Application number	US-201916377025-A
Country	US
Kind code	B2
Filing date	Apr 5, 2019
Priority date	Nov 26, 2014
Publication date	Oct 6, 2020
Grant date	Oct 6, 2020

Abstract

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.

First claim

The invention claimed is:

1. 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 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 compound 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 compound according to claim 1 , wherein R 4 is difluoromethyl, trifluoromethyl or methyl.

4. The compound according to claim 1 , wherein R 5 is hydrogen or fluorine.

5. The compound according to claim 1 , wherein R 2 and R 3 are both either hydrogen or methyl.

6. The compound 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 compound 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 compound according to claim 7 , wherein
R 1 is 2-(methylsulphonyl)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 compound according to claim 8 , wherein
R 1 is 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl;
R 2 and R 3 are both methyl;
R 4 is difluoromethyl or trifluoromethyl, and
R 5 is hydrogen.

10. The compound according to claim 8 , wherein
R 1 is 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl;
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 .

11. A method for treating arthritis in a human in need thereof, comprising administering to the human an effective amount of a compound of formula (I) according to claim 1 , or a diastereomer, an enantiomer, a salt, a solvate, or a solvate of the salt thereof.

12. The method of claim 11 , wherein the arthritis is osteoarthritis, rheumatoid arthritis, or spondyloarthritis.

13. The method according to claim 12 , wherein the arthritis is rheumatoid arthritis.

14. A medicament comprising a compound of formula (I) according to claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

15. A process for preparing a compound of formula (III) from a compound of formula (II)

wherein
R 1 is 2-(methylsulphonyl)ethyl or 3-(methylsulphonyl)propyl;
R 4 is difluoromethyl, trifluoromethyl or methyl; and
R 5 is hydrogen or fluorine;
comprising reacting the compound of formula (II) with an alkyl halide or alkyl 4-methylbenzenesulphonate, wherein the alkyl of the alkyl halide or the alkyl 4-methylbenzenesulphonate is R 1 , in the presence of potassium carbonate.

16. A compound of formula (III)

wherein
R 1 is 2-(methylsulphonyl)ethyl or 3-(methylsulphonyl)propyl;
R 4 is difluoromethyl, trifluoromethyl or methyl; and
R 5 is hydrogen or fluorine,
or a diastereomer, an enantiomer, a salt, a solvate, or a solvate of the salt thereof.

17. The compound according to claim 16 , wherein the compound is selected from the group consisting of:
methyl 2-(2-(methylsulfonyl)ethyl)-5-({[6-(trifluoromethyl) pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate,
a salt thereof,
a solvate thereof, and
a solvate of the salt thereof.

18. A compound selected from the group consisting of:
N-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;
N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide; and
6-(Difluoromethyl)-N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}pyridine-2-carboxamide, or a salt, a solvate, or a solvate of the salt thereof.

19. A method for treating arthritis in a human in need thereof, comprising administering to the human an effective amount of a compound according to claim 18 , or a salt, or a solvate, or a solvate of the salt thereof.

20. The method of claim 19 , wherein the arthritis is osteoart

Assignees

• Bayer Pharma AG

Inventors

• Bothe Ulrich
• Siebeneicher Holger
• Schmidt Nicole
• Nubbemeyer Reinhard
• Bömer Ulf
• Günther Judith
• Steuber Holger
• Lange Martin
• Stegmann Christian
• Sutter Andreas
• Rausch Alexandra
• Friedrich Christian
• Hauff Peter

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title