# US 10,308,634 B2 · 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

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,308,634 B2
- Document ID: US10308634B2
- Status: Granted
- Kind: B2
- Application number: 15/529,996
- Filed: 2015-11-25
- Published: 2017-12-07
- Granted: 2019-06-04
- Earliest claimed: 2014-11-26
- Assignees: Bayer Pharma Aktiengesellschaft
- Applicants: Bayer Pharma Aktiengesellschaft
- Inventors: Ulrich Bothe; Holger Siebeneicher; Nicole Schmidt; Reinhard Nubbemeyer; Ulf Bömer; Judith Günther; Holger Steuber; Martin Lange; Christian Stegmann; Andreas Sutter; Alexandra Rausch; Christian Friedrich; Peter Hauff
- Web page: https://patentgrep.com/patent/US10308634B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07D 405/14: containing three or more hetero rings
- C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## 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.

## Claims

### Claim 1

A compound of formula (I)
wherein:
R1 is C1-C6-alkyl, wherein the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl, an unsubstituted or mono- or poly-halogen-substituted C3-C6-cycloalkyl, or an R6 or R8O group,
or a group selected from the group consisting of:
wherein * represents the bonding site of the group to the rest of the molecule;
R2 and R3 always have the same definition and are both either hydrogen or C1-C6-alkyl;
R4 is halogen, cyano, an unsubstituted or a singly or multiply, identically or differently substituted C1-C6-alkyl or an unsubstituted or a singly or multiply, identically or differently substituted C3-C6-cycloalkyl, and the substituents are selected from the group consisting of halogen and hydroxyl;
R5 is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6-alkyl;
R6 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 SO2; and
R8 is C1-C6-alkyl, where the C1-C6-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.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein
R1 is C1-C6-alkyl, wherein the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R6 or R8O group;
R2 and R3 always have the same definition and are both either hydrogen or C1-C3-alkyl;
R4 is halogen, cyano or C1-C3-alkyl, wherein the C1-C3-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl;
R5 is hydrogen, fluorine, chlorine or C1-C3-alkyl;
R6 is oxetanyl or tetrahydrofuranyl; and
R8 is an unsubstituted C1-C4-alkyl group or a mono-, di- or tri-fluorine-substituted C1-C4-alkyl group.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R4 is difluoromethyl, trifluoromethyl, or methyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R5 is hydrogen or fluorine.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R2 and R3 are both either hydrogen or methyl.

### Claim 6 (depends on 2)

The compound according to claim 2, wherein
R1 is C2-C6-alkyl, wherein the C2-C6-alkyl group is unsubstituted, or
the C2-C6-alkyl group is mono-, di- or tri-fluorine-substituted or
the C2-C6-alkyl group is monosubstituted by hydroxyl, R6 or R8O; or
R1 is an oxetanyl-substituted C1-C3-alkyl group;
R2 and R3 always have the same definition and are both either hydrogen or methyl;
R4 is an unsubstituted or mono- or poly-halogen-substituted C1-C3-alkyl group or a C1-C3-alkyl group substituted by one hydroxyl group or a C1-C3-alkyl group substituted by one hydroxyl group and three fluorine atoms;
R5 is hydrogen, fluorine or C1-C3-alkyl; and
R8 is C1-C4-alkyl, wherein the C1-C4-alkyl group is unsubstituted or mono-, di- or tri-fluorine-substituted.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein
R1 is a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl; or
R1 is an oxetan-3-yl-substituted C1-C2-alkyl group;
R2 and R3 always have the same definition and are both hydrogen or methyl;
R4 is selected from the group consisting of methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl, and
R5 is hydrogen, fluorine, or methyl.

### Claim 8 (depends on 7)

The compound according to claim 7, wherein
R1 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;
R2 and R3 are both methyl or hydrogen;
R4 is difluoromethyl, trifluoromethyl or methyl, and
R5 is hydrogen or fluorine.

### Claim 9 (depends on 8)

The compound according to claim 8, wherein
R1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, or 3-hydroxy-2,2-dimethylpropyl;
R2 and R3 are both methyl;
R4 is difluoromethyl or trifluoromethyl, and
R5 is hydrogen.

### Claim 10 (depends on 8)

The compound according to claim 8, wherein
R1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, or 3-hydroxy-2,2-dimethylpropyl;
R2 and R3 are both methyl;
R4 is methyl, and
R5 is fluorine, wherein R5 is in the ortho position to R4.

### Claim 11

A compound 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-m ethylbutyl)-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.

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 1)

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

### Claim 14

A process for preparing a compound of formula (III) from a compound of formula (II)
wherein
R1 is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, or 2-hydroxyethyl;
R4 is difluoromethyl, trifluoromethyl or methyl; and
R5 is hydrogen or fluorine;
comprising reacting the compound of formula (II) with an appropriately substituted alkyl halide or alkyl 4-methylbenzenesulphonate in the presence of potassium carbonate.

### Claim 15

A compound of formula (III)
wherein
R1 is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, or 2-(1-hydroxycyclopropyl)ethyl;
R4 is difluoromethyl, trifluoromethyl or methyl; and
R5 is hydrogen or fluorine,
or a diastereomer, an enantiomer a salt, a solvate, or a solvate of the salt thereof.

### Claim 16 (depends on 15)

The compound according to claim 15, wherein the compound is selected from the group consisting of:
methyl 5-{[(5-fluoro-6-methylpyridin-2-yl)carbonyl]amino}-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate; and
methyl 2-(3-hydroxy-3-methylbutyl)-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.

### Claim 17 (depends on 12)

The method according to claim 12, wherein the arthritis is osteoarthritis, rheumatoid arthritis, or spondyloarthritis.

### Claim 18

A compound, wherein the compound is N-[2-(3-Hydroxy-3-methylbutyl)-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.

### Claim 19 (depends on 11)

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 11, or a salt, a solvate, or a solvate of the salt thereof.

### Claim 20 (depends on 17)

The method according to claim 17, wherein the arthritis is rheumatoid arthritis.

### Claim 21 (depends on 19)

The method of claim 19, wherein the arthritis is osteoarthritis, rheumatoid arthritis, or spondyloarthritis.

### Claim 22 (depends on 21)

The method according to claim 21, wherein the arthritis is rheumatoid arthritis.

### Claim 23 (depends on 18)

A compound of claim 18, wherein the compound is N-[2-(3-Hydroxy-3 -methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide, or a salt thereof.

### Claim 24 (depends on 23)

A compound of claim 23, wherein the compound is N-[2-(3-Hydroxy-3 -methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide.

### Claim 25 (depends on 24)

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 24.

### Claim 26 (depends on 25)

The method of claim 25, wherein the arthritis is osteoarthritis, rheumatoid arthritis, or spondyloarthritis.

### Claim 27 (depends on 26)

The method according to claim 26, wherein the arthritis is rheumatoid arthritis.