Granted Patent B2

US 12,459,916 · App. 17/570,550 · Granted Nov 4, 2025

Inventors: Gerald Beddies (Leverkusen, DE); Adrian Foster (Sandwich, GB); Ulrich Bothe (Berlin, DE); Nicole Schmidt (Wuppertal, DE); Ulf Boemer (Glienicke, DE); Reinhard Nubbemeyer (Berlin, DE); Maria De Lourdes Mottier (Langenfeld, DE)

Assignee: Bayer Pharma Aktiengesellschaft

C07D401/12C07D405/14

Abstract

Claims (94)

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-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;

19) 5-Fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide;

20) N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide;

21) 6-(2-Hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]pyridine-2-carboxamide; and

22) N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide; or

a diastereomer, an enantiomer, a metabolite, a salt, a solvate, and a solvate of the salt thereof.

12 . The method of claim 1 , wherein the allergic disease is allergic dermatitis, atopic dermatitis, or Flea Allergy Dermatitis.

13 . A method for the treatment of allergic disease in a dog, the method comprising orally administering to the dog an effective amount of compound 12,

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

wherein the allergic disease is allergic dermatitis, atopic dermatitis, flea allergy dermatitis, or pruritus associated with allergic disease.

14 . The method of claim 1 , wherein the allergic disease is Canine Atopic Dermatitis.

15 . The method of claim 1 , wherein the allergic disease is Flea Allergy Dermatitis.

16 . A method for the treatment and/or prophylaxis of allergic diseases in a dog, wherein the method comprises administering to the dog, a pharmaceutical composition comprising the compound of claim 1 and an inert, non-toxic, pharmaceutically suitable excipient.

17 . The method of claim 16 , wherein the disease is allergic dermatitis, atopic dermatitis, or Flea Allergy Dermatitis.

18 . The method of claim 17 , wherein disease is Canine Atopic Dermatitis.

19 . The method of claim 17 , wherein the allergic disease is Flea Allergy Dermatitis.

20 . The method of claim 1 , wherein an effective amount of the compound is administered to a dog in need thereof.

21 . A method for the treatment, and/or prophylaxis of symptoms of allergic diseases in a dog comprising administering to the dog a compound of the general formula (III)

wherein

R 1 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, 2-(methylsulphonyl)ethyl, 3-(methylsulphonyl) propyl or 2-(1-hydroxycyclopropyl)ethyl;

R 4 is difluoromethyl, trifluoromethyl or methyl; and

R 5 is hydrogen or fluorine;

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

22 . The method of claim 21 , 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.

Assignments (2)

Priority Claims (1)

Continuity (2)

References Cited (347)