Substituted indazoles useful for treatment and prevention of allergic and/or inflammatory diseases in animals

Patent metadata

Field	Value
Publication number	US-12459916-B2
Application number	US-202217570550-A
Country	US
Kind code	B2
Filing date	Jan 7, 2022
Priority date	Jun 1, 2016
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

The present application relates to the use of substituted indazoles for treatment and/or prophylaxis of allergic and/or inflammatory diseases in animals, especially for treatment and/or prophylaxis of atopic dermatitis, Flea Allergy Dermatitis, inflammatory bowel disease, osteoarthritis and inflammatory pain, non-infectious recurrent airway disease, insect hypersensitivity, asthma, respiratory disease, mastitis and endometritis in animals.

First claim

The invention claimed is:

1 . A method for the treatment, and/or prophylaxis of allergic diseases in a dog, comprising administering to the dog a compound of the general 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 , R 7 SO 2 , R 7 SO or R 8 O group, or a group selected from:

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 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 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, wherein 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;

R 8 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;
or a diastereomer, an enantiomer, a metabolite, a salt, a solvate, a solvate of the salt thereof.

2 . The method of claim 1 , 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 , R 7 SO 2 , R 7 SO or R 8 O group; R 2 and R 3 always have the same definition and are 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 of claim 2 , 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 , R 7 SO 2 , or R 80 , 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 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; R 7 is 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.

4 . The method of claim 3 , 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 is a methyl-SO 2 -substituted C 2 -C 4 -alkyl group or is an oxetan-3-yl-substituted C 1 -C 2 -alkyl group; R 2 and R 3 always have the same definition and are hydrogen or methyl; R 4 is 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.

5 . The method of claim 4 , 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, 2-hydroxyethyl, 2-(methylsulphonyl)ethyl or 3-(methylsulphonyl) propyl; R 2 and R 3 are methyl or hydrogen; R 4 is difluoromethyl, trifluoromethyl or methyl; and R 5 is hydrogen or fluorine.

6 . The method of claim 5 , wherein
R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulphonyl) propyl or 2-(methylsulphonyl)ethyl; R 2 and R 3 are methyl; R 4 is difluoromethyl or trifluoromethyl; and R 5 is hydrogen.

7 . The method of claim 5 , wherein
R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulphonyl) propyl or 2-(methylsulphonyl)ethyl; R 2 and R 3 are methyl; R 4 is methyl; and R 5 is fluorine, wherein R 5 is in the ortho position to R 4 .

8 . The method of claim 1 , wherein R 4 is difluoromethyl, trifluoromethyl or methyl.

9 . The method of claim 1 , wherein R 5 is hydrogen or fluorine.

10 . The method of claim 1 , wherein R 2 and R 3 are either hydrogen or methyl.

11 . The method of claim 1 , wherein the compound is selected from the group consisting of:
1) N-[6-(2-Hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 2) N-[6-(Hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 3) N-[6-(2-Hydroxypropan-2-yl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 4) N-[6-(Hydroxymethyl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 5) N-[2-(2-Hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 6) N-[6-(2-Hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 7) N-[2-(2-Hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 8) N-[6-(2-Hydroxypropan-2-yl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 9) N-[6-(Hydroxymethyl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 10) N-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide; 11) N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 12) N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide; 13) 6-(Difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]pyridine-2-carboxamide; 14) 6-(Difluoromethyl)-N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}pyridine-2-carboxamide; 15) 6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]pyridine-2-carboxamide; 16) N-[6-(2-Hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide; 17) N-{6-(2-Hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide; 18) N-{6-(2-Hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]-2H-indazol-5

Assignees

• Bayer Pharma AG

Inventors

• Beddies Gerald
• Foster Adrian
• Bothe Ulrich
• Schmidt Nicole
• Boemer Ulf
• Nubbemeyer Reinhard
• Mottier Maria De Lourdes

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/12 Primary

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title