Methods and compositions for control of pain and inflammation

Abstract

Compositions comprising an IRAK4 inhibitor and methods of use to treat pain and inflammation associated with pain in mammals are provided.

Description

International Patent Application Attorney Docket No.2920951-439977 METHODS AND COMPOSITIONS FOR CONTROL OF PAIN AND INFLAMMATION CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This International Patent Application claims benefit of priority of U.S. Provisional Patent Application No.63 / 418,192, filed 21 October 2022, the entire contents of which is incorporated herein by reference. BACKGROUND

[0002] Osteoarthritis (OA) is the most common form of arthritis in dogs, affecting about a quarter of the population. Osteoarthritis is a chronic joint disease characterized by loss of joint cartilage, thickening of the joint capsule, and new bone formation around the joint (osteophytosis). Osteoarthritis includes pain and limb dysfunction. The majority of osteoarthritis in dogs occur secondarily to developmental orthopedic disease, such as cranial cruciate ligament disease, hip dysplasia, elbow dysplasia, osteochondritis dissecans (OCD), and patella dislocation. Osteoarthritis can occur with no clear primary causes and can be related to genetics and age. Other contributing factors to osteoarthritis include bodyweight, obesity, gender, exercise, and diet. American College of Veterinary Surgeons website “Osteoarthritis in Dogs” (2022).

[0003] Accordingly, there is a need for improved methods and compositions for the control and treatment of pain and inflammation in mammals (e.g., dogs).

[0004] SUMMARY

[0005] In an aspect, the IRAK4 inhibitors described herein can be used in methods of treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0006] In an aspect, the IRAK4 inhibitors described herein can be used in methods for the treatment and / or prevention of degenerative joint disease (DJD).

[0007] In an aspect, the IRAK4 inhibitors described herein can be formulated into medicaments for use in the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0008] In an aspect, the IRAK4 inhibitors described herein can be formulated into medicaments for use in the treatment and / or prevention of degenerative joint disease (DJD).International Patent Application Attorney Docket No.2920951-439977

[0009] In an aspect, the IRAK4 inhibitors described herein can be formulated into compositions for the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0010] In an aspect, the IRAK4 inhibitors described herein can be formulated into compositions for the treatment and / or prevention of degenerative joint disease (DJD).

[0011] In an aspect, method of treating or preventing pain in a mammal can comprise administering a composition comprising an effective amount of an IRAK4 inhibitor, wherein the IRAK4 inhibitor is a compound of the general formula (I) R5in which:R1is C1-C6-alkyl, where 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, R7SO2, R7SO or R8O group, or a group selected from:rest of the molecule; R2and R3always have the same definition and are both either hydrogen or C1-C6-alkyl; R4is 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 of halogen and hydroxyl; R5is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6- alkyl; R6is 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 SO2; R7is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- orInternational Patent Application Attorney Docket No.2920951-439977 polysubstituted identically or differently by halogen, hydroxyl or C3-C6-cycloalkyl; or R7is C3-C6-cycloalkyl; R8is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof.

[0012] In an aspect, method of treating or preventing osteoarthritis in a mammal can comprise administering a composition comprising an effective amount of an IRAK4 inhibitor, wherein the IRAK4 inhibitor is a compound of the general formula (I) R5(I) in which:R1is C1-C6-alkyl, where 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, R7SO2, R7SO or R8O group, or a group selected from: where *R2and R3always have the same definition and are both either hydrogen or C1-C6-alkyl; R4is 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 of halogen and hydroxyl; R5is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6- alkyl; R6is 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 SO2; R7is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- orInternational Patent Application Attorney Docket No.2920951-439977 polysubstituted identically or differently by halogen, hydroxyl or C3-C6-cycloalkyl; or R7is C3-C6-cycloalkyl; R8is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof.

[0013] In an aspect, R1is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R6, R7SO2, R7SO or R8O group; R2and R3always have the same definition and are both either hydrogen or C1-C3-alkyl; R4is halogen, cyano or C1-C3-alkyl, where the C1-C3-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl; R5is hydrogen, fluorine, chlorine or C1-C3-alkyl; R6is oxetanyl or tetrahydrofuranyl; R7is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms; R8is an unsubstituted C1-C4-alkyl group or a tri-fluorine-substituted C1-C4-alkyl group.

[0014] In an aspect, R4is difluoromethyl, trifluoromethyl or methyl.

[0015] In an aspect, R5is hydrogen or fluorine.

[0016] In an aspect, R2and R3are both either hydrogen or methyl.

[0017] In an aspect, R1is C2-C6-alkyl, where 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, R7SO2, or R8O, or R1is an oxetanyl-substituted C1-C3-alkyl group; R2and R3always have the same definition and are both either hydrogen or methyl; R4is 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; R5is hydrogen, fluorine or C1-C3-alkyl; R7is C1-C3-alkyl; R8is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or mono-, di- or tri- fluorine-substituted.International Patent Application Attorney Docket No.2920951-439977

[0018] In an aspect, R1is a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or is a methyl-SO2 -substituted C2-C4-alkyl group or is an oxetan-3-yl-substituted C1-C2-alkyl group; R2and R3always have the same definition and are both hydrogen or methyl; R4is methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl; R5is hydrogen, fluorine or methyl.

[0019] In an aspect, R1is 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; R2and R3are both methyl or hydrogen; R4is difluoromethyl, trifluoromethyl or methyl; R5is hydrogen or fluorine.

[0020] In an aspect, R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is difluoromethyl or trifluoromethyl; R5is hydrogen.

[0021] In an aspect, R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is methyl; R5is fluorine, where R5is in the ortho position to R4.

[0022] In an aspect, the IRAK4 inhibitor is: 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-International Patent Application Attorney Docket No.2920951-439977 (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-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-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; N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-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-[2-(methylsulphonyl)ethyl]-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-methylbutyl)-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-International Patent Application Attorney Docket No.2920951-439977 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; or N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}- 6-(trifluoromethyl)pyridine-2-carboxamide.

[0023] In an aspect, the IRAK4 inhibitor is Compound 1: .treats pain associated with osteoarthritis.

[0025] In an aspect, the composition comprising an effective amount of an IRAK4 inhibitor treats inflammation associated with osteoarthritis.

[0026] In an aspect, a method for treating pain in mammal can comprise administering a composition comprising an effective amount of an IRAK4 inhibitor, wherein the IRAK4 inhibitor is a compound of the general formula (I) R5(I) in which:R1is C1-C6-alkyl, where 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, R7SO2, R7SO or R8O group, or a group selected from:International Patent Application Attorney Docket No.2920951-439977 where *R2and R3same are or C1-C6-alkyl; R4is 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 of halogen and hydroxyl; R5is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6- alkyl; R6is 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 SO2; R7is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C3-C6-cycloalkyl; or R7is C3-C6-cycloalkyl; R8is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof.

[0027] In an aspect, R1is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R6, R7SO2, R7SO or R8O group; R2and R3always have the same definition and are both either hydrogen or C1-C3-alkyl; R4is halogen, cyano or C1-C3-alkyl, where the C1-C3-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl; R5is hydrogen, fluorine, chlorine or C1-C3-alkyl; R6is oxetanyl or tetrahydrofuranyl; R7is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms; R8is an unsubstituted C1-C4-alkyl group or a tri-fluorine-substituted C1-C4-alkyl group.International Patent Application Attorney Docket No.2920951-439977

[0028] In an aspect, R4is difluoromethyl, trifluoromethyl or methyl.

[0029] In an aspect, R5is hydrogen or fluorine.

[0030] In an aspect, R2and R3are both either hydrogen or methyl.

[0031] In an aspect, R1is C2-C6-alkyl, where 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, R7SO2, or R8O, or R1is an oxetanyl-substituted C1-C3-alkyl group; R2and R3always have the same definition and are both either hydrogen or methyl; R4is 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; R5is hydrogen, fluorine or C1-C3-alkyl; R7is C1-C3-alkyl; R8is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or mono-, di- or tri- fluorine-substituted.

[0032] In an aspect, R1is a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or is a methyl-SO2 -substituted C2-C4-alkyl group or is an oxetan-3-yl-substituted C1-C2-alkyl group; R2and R3always have the same definition and are both hydrogen or methyl; R4is methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl; R5is hydrogen, fluorine or methyl.

[0033] In an aspect, R1is 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; R2and R3are both methyl or hydrogen; R4is difluoromethyl, trifluoromethyl or methyl; R5is hydrogen or fluorine.

[0034] In an aspect, R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl;International Patent Application Attorney Docket No.2920951-439977 R2and R3are both methyl; R4is difluoromethyl or trifluoromethyl; R5is hydrogen.

[0035] In an aspect, R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is methyl; R5is fluorine, where R5is in the ortho position to R4.

[0036] In an aspect, the IRAK4 inhibitor can be: 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-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-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; N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6- (trifluoromethyl)pyridine-2-carboxamide;International Patent Application Attorney Docket No.2920951-439977 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-[2-(methylsulphonyl)ethyl]-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-methylbutyl)-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; or N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}- 6-(trifluoromethyl)pyridine-2-carboxamide.

[0037] In an aspect, the IRAK4 inhibitor is Compound 1 .

[0038]

[0039] In an aspect, the pain is perioperative.

[0040] In an aspect, method for treating inflammation in a mammal can comprise aInternational Patent Application Attorney Docket No.2920951-439977 composition comprising administering an effective amount of wherein the IRAK4 inhibitor is a compound of the general formula (I) R5(I) in which:R1is C1-C6-alkyl, where the group or mono- or polysubstituted identically or differently by halogen, hydroxyl, an unsubstituted or mono- or poly-halogen-substituted C3-C6-cycloalkyl, or an R6, R7SO2, R7SO or R8O group, or a group selected from: where *R2and R3always have the same definition and are both either hydrogen or C1-C6-alkyl; R4is 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 of halogen and hydroxyl; R5is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6- alkyl; R6is 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 SO2; R7is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C3-C6-cycloalkyl; or R7is C3-C6-cycloalkyl; R8is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the saltsInternational Patent Application Attorney Docket No.2920951-439977 thereof.

[0041] In an aspect, R1is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R6, R7SO2, R7SO or R8O group; R2and R3always have the same definition and are both either hydrogen or C1-C3-alkyl; R4is halogen, cyano or C1-C3-alkyl, where the C1-C3-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl; R5is hydrogen, fluorine, chlorine or C1-C3-alkyl; R6is oxetanyl or tetrahydrofuranyl; R7is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms; R8is an unsubstituted C1-C4-alkyl group or a tri-fluorine-substituted C1-C4-alkyl group.

[0042] In an aspect, R4is difluoromethyl, trifluoromethyl or methyl.

[0043] In an aspect, R5is hydrogen or fluorine.

[0044] In an aspect, R2and R3are both either hydrogen or methyl.

[0045] In an aspect, R1is C2-C6-alkyl, where 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, R7SO2, or R8O, or R1is an oxetanyl-substituted C1-C3-alkyl group; R2and R3always have the same definition and are both either hydrogen or methyl; R4is 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; R5is hydrogen, fluorine or C1-C3-alkyl; R7is C1-C3-alkyl; R8is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or mono-, di- or tri- fluorine-substituted.

[0046] In an aspect, R1is a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or is a methyl-SO2 -substituted C2-C4-alkyl group or is an oxetan-3-yl-substituted C1-C2-alkyl group; R2and R3always have the same definition and are both hydrogen or methyl; R4is methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1-International Patent Application Attorney Docket No.2920951-439977 hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl; R5is hydrogen, fluorine or methyl.

[0047] In an aspect, R1is 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; R2and R3are both methyl or hydrogen; R4is difluoromethyl, trifluoromethyl or methyl; R5is hydrogen or fluorine.

[0048] In an aspect, R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is difluoromethyl or trifluoromethyl; R5is hydrogen.

[0049] In an aspect, R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is methyl; R5is fluorine, where R5is in the ortho position to R4.

[0050] In an aspect, IRAK4 inhibitor can be: 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-International Patent Application Attorney Docket No.2920951-439977 (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-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-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; N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-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-[2-(methylsulphonyl)ethyl]-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-methylbutyl)-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; or N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}- 6-(trifluoromethyl)pyridine-2-carboxamide.

[0051] In an aspect, the IRAK4 inhibitor can be Compound 1International Patent Application Attorney Docket No.2920951-439977 .

[0052]

[0053] In an aspect, the inflammation is associated with degenerative joint disease (DJD).

[0054] In an aspect, the inflammation is associated with inflammatory bowel disease (IBD), diabetes mellitus, kidney disease, intervertebral disc disease, and allergic inflammation.

[0055] In an aspect, a method for treating or preventing degenerative joint disease (DJD) in a mammal can comprise a composition comprising administering an effective amount of wherein the IRAK4 inhibitor is a compound of the general formula (I) R5(I) in which:R1is C1-C6-alkyl, where 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, R7SO2, R7SO or R8O group, or a group selected from: where *R2and R3always have the same definition and are both either hydrogen or C1-C6-alkyl; R4is 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 orInternational Patent Application Attorney Docket No.2920951-439977 differently substituted C3-C6-cycloalkyl, and the substituents are selected from the group of halogen and hydroxyl; R5is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6- alkyl; R6is 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 SO2; R7is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C3-C6-cycloalkyl; or R7is C3-C6-cycloalkyl; R8is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof.

[0056] In an aspect, R1is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R6, R7SO2, R7SO or R8O group; R2and R3always have the same definition and are both either hydrogen or C1-C3-alkyl; R4is halogen, cyano or C1-C3-alkyl, where the C1-C3-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl; R5is hydrogen, fluorine, chlorine or C1-C3-alkyl; R6is oxetanyl or tetrahydrofuranyl; R7is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms; R8is an unsubstituted C1-C4-alkyl group or a tri-fluorine-substituted C1-C4-alkyl group.

[0057] In an aspect, R4is difluoromethyl, trifluoromethyl or methyl.

[0058] In an aspect, R5is hydrogen or fluorine.

[0059] In an aspect, R2and R3are both either hydrogen or methyl.

[0060] In an aspect, R1is C2-C6-alkyl, where 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, R7SO2, or R8O, or R1is an oxetanyl-substituted C1-C3-alkyl group; R2and R3always have the same definition and are both either hydrogen or methyl;International Patent Application Attorney Docket No.2920951-439977 R4is 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; R5is hydrogen, fluorine or C1-C3-alkyl; R7is C1-C3-alkyl; R8is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or mono-, di- or tri- fluorine-substituted.

[0061] In an aspect, R1is a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or is a methyl-SO2-substituted C2-C4-alkyl group or is an oxetan-3-yl-substituted C1-C2-alkyl group; R2and R3always have the same definition and are both hydrogen or methyl; R4is methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl; R5is hydrogen, fluorine or methyl.

[0062] In an aspect, R1is 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; R2and R3are both methyl or hydrogen; R4is difluoromethyl, trifluoromethyl or methyl; R5is hydrogen or fluorine.

[0063] In an aspect, R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is difluoromethyl or trifluoromethyl; R5is hydrogen.

[0064] In an aspect, R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is methyl;International Patent Application Attorney Docket No.2920951-439977 R5is fluorine, where R5is in the ortho position to R4.

[0065] In an aspect, the IRAK4 inhibitor can be: 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-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-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; N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-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-[2-(methylsulphonyl)ethyl]-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;International Patent Application Attorney Docket No.2920951-439977 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-methylbutyl)-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; or N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}- 6-(trifluoromethyl)pyridine-2-carboxamide.

[0066] In an aspect, the IRAK4 inhibitor can be Compound 1 .

[0067] In an aspect, the mammal is a dog, cat, horse, pig, cow, sheep, or goat. The mammal can be a dog.

[0068] In an aspect, the effective amount is between about 1 and 25 mg / kg of Compound 1. The effective amount can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg / kg of Compound 1. The effective amount can be about 5 mg / kg of Compound 1. The effective amount can be about 15 mg / kg of Compound 1.

[0069] In an aspect, the effective amount is between about 1 and 25 mg / kg of a compound described herein. The effective amount can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg / kg of a compound described herein. TheInternational Patent Application Attorney Docket No.2920951-439977 effective amount can be about 5 mg / kg of a compound described herein. The effective amount can be about 15 mg / kg of a compound described herein.

[0070] In an aspect, composition is administered 1, 2, 3, 4, or 5 times a day.

[0071] In an aspect, the composition is administered every other day.

[0072] In an aspect, the composition is administered once a day.

[0073] In an aspect, the composition is a pharmaceutical composition comprising an effective amount of the IRAK4 inhibitor and a carrier. The carrier can be an excipient, lubricant, antioxidant, emulsifier, stabilizer, solvent, diluent, buffer, vehicle, or a combination thereof.

[0074] In an aspect, the composition is in the form of a tablet, optionally a chewable tablet.

[0075] In an aspect, the composition is administered intravenously, intramuscularly, orally, buccally, or a combination thereof. The composition can be administered orally. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 depicts an exemplary IRAK4 inhibitor (Compound 1) used Compound 1in a urate synovitis model in dogs comparing two exemplary doses, 15 mg / kg and 5 mg / kg to a placebo. DETAILED DESCRIPTION

[0077] Various exemplary aspects are described in detail and may be further illustrated by the provided examples. Additional viable variations can easily be envisioned. Definitions

[0078] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which this description belongs.

[0079] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise.

[0080] “Effective amount,” as used herein, refers broadly to the amount of a compound, antibody, antigen, or cells that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The effective amount may be an amount effective for prophylaxis, and / or an amount effective for prevention. The effective amount may be an amount effective to reduce, an amount effective to prevent the incidence of signs / symptoms, to reduce the severity of the incidence of signs / symptoms, to eliminate the incidence of signs / symptoms, to slow the development of the incidence of signs / symptoms, to prevent the development of the incidence of signs / symptoms, and / or effect prophylaxis of the incidence of signs / symptoms. The “effective amount” may vary depending on the disease andInternational Patent Application Attorney Docket No.2920951-439977 its severity and the age, weight, medical history, susceptibility, and pre-existing conditions, of the patient to be treated. The term “effective amount” is synonymous with “therapeutically effective amount” for purposes of this description.

[0081] “Mammal,” as used herein, refers broadly to any and all warm-blooded vertebrate animals of the class Mammalia, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young. Mammals include, but are not limited to, humans, domestic and farm animals, and zoo, sports, or pet animals. Examples of mammals include but are not limited to alpacas, armadillos, capybaras, cats, camels, chimpanzees, chinchillas, cattle, dogs, gerbils, goats, gorillas, guinea pigs, hamsters, horses, humans, lemurs, llamas, mice, non-human primates, pigs, rats, sheep, shrews, squirrels, and tapirs. Mammals include but are not limited to bovine, canine, equine, feline, murine, ovine, porcine, primate, and rodent species. Similarly, the term “subject” or “patient” includes both human and veterinary subjects and / or patients.

[0082] “Treatment” refers broadly to both therapeutic treatment and prophylactic or preventative measures. “Treatment” also refers to prescription of medication, drug, or treatment to a patient by a healthcare professional (e.g., doctor, physician’s assistant, nurse practitioner, pharmacist etc.) Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. As used herein, the term “treating,” refers broadly to treating a disease, arresting, or reducing the development of the disease or its clinical symptoms, and / or relieving the disease, causing regression of the disease or its clinical symptoms. Therapy encompasses prophylaxis, treatment, remedy, reduction, alleviation, and / or providing relief from a disease, signs, and / or symptoms of a disease. Therapy encompasses an alleviation of signs and / or symptoms in patients with ongoing disease signs and / or symptoms. Therapy also encompasses “prophylaxis”. The term “reduced”, for purpose of therapy, refers broadly to the clinically significant reduction in signs and / or symptoms. Therapy includes treating relapses or recurrent signs and / or symptoms. Therapy encompasses but is not limited to precluding the appearance of signs and / or symptoms anytime as well as reducing existing signs and / or symptoms and eliminating existing signs and / or symptoms. Therapy includes treating chronic disease (“maintenance”) and acute disease. For example, treatment includes treating or preventing relapses or the recurrence of signs and / or symptoms. IRAK-4 inhibitor CompoundsInternational Patent Application Attorney Docket No.2920951-439977

[0083] Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are the standard of care for management of clinical signs associated with osteoarthritis in dogs, but are associated with significant gastrointestinal, hepatic, and renal side effects.

[0084] Human IRAK4 (interleukin-1 receptor-associated kinase 4) plays a key role in the activation of the immune system. Therefore, this kinase is an important therapeutic target molecule for the development of inflammation-inhibiting substances. IRAK4 is expressed by a multitude of cells and mediates the signal transduction of Toll-like receptors (TLRs), except TLR3, and receptors of the interleukin (IL)-1β family consisting of the IL-1R (receptor), IL- 18R, IL-33R and IL-36R. Janeway and Medzhitov (2002) Annu. Rev. Immunol.20: 197– 216; Dinarello (2009) Annu. Rev. Immunol.27: 519–50; Flannery and Bowie (2010) Biochemical Pharmacology 80(12): 1981–91.

[0085] IRAK4 inhibitors, as described herein, include inhibitors of IRAK4. [ANY FURTHER COMMENTS OR STRUCTURES?]

[0086] IRAK4 inhibitors, as described herein, include, but are not limited to IRAK4 inhibitors described in U.S. Patent No.10,793,545 and U.S. Patent Application Number 17 / 570,550. IRAK4 inhibitors, as described herein, can be used on their own and / or combined with other active ingredients to treat pain and / or inflammation, including, but not limited to compounds of the general formula (I) R5in which:R1is C1-C6-alkyl, where 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, R7SO2, R7SO or R8O group, or a group selected from:rest of the molecule;International Patent Application Attorney Docket No.2920951-439977 R2and R3always have the same definition and are both either hydrogen or C1-C6-alkyl; R4is 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 of halogen and hydroxyl; R5is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6- alkyl, optionally wherein the halogen is fluorine; R6is 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 SO2; R7is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C3-C6-cycloalkyl, or R7is C3-C6-cycloalkyl; R8is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof.

[0087] An exemplary IRAK4 inhibitor described herein includes, but is not limited to, the IRAK4 inhibitors described in U.S. Patent No.10,793,545 and U.S. Patent Application Number 17 / 570,550. IRAK4 inhibitors, as described herein. A preferred IRAK4 inhibitor is Compound 1:International Patent Application Attorney Docket No.2920951-439977

[0088] An exemplary study in an acute canine urate synovitis pain model inducing severe lameness was performed. Surprisingly, Compound 1 strongly relieved acute pain and improved lameness significantly better than placebo and reveals equal or better effectiveness in this model than expected. Dogs treated with Compound 1 showed minimal to no pain and lameness following synovitis induction which is a magnitude of effect that we have not documented with any other class of drugs outside of NSAIDs.

[0089] In the case of the mentioned use of the synthesis intermediates and working examples of the invention described hereinafter, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and / or purification process. Unless specified in more detail, additions to names and structural formulae, such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCl”, “x CF3COOH”, “x Na+” should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein.

[0090] This applies correspondingly if synthesis intermediates or working examples or salts thereof were obtained in the form of solvates, for example hydrates, of unknown stoichiometric composition (if they are of a defined type) by the preparation and / or purification processes described.

[0091] Present compounds are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds that are encompassed by formula (I) and are of the formulae mentioned below and the salts, solvates and solvates of the salts thereof and the compounds that are encompassed by the formula (I) and are mentioned below as embodiments and the salts, solvates and solvates of the salts thereof if the compounds that are encompassed by the formula (I) and are mentioned below are not already salts, solvates and solvates of the salts.

[0092] Preferred salts in the context of the compositions described herein are physiologically acceptable salts of the present compounds. However, the compositions described herein also encompasses salts which themselves are unsuitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the present compounds.

[0093] Physiologically acceptable salts of the present compounds include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,International Patent Application Attorney Docket No.2920951-439977 trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

[0094] Physiologically acceptable salts of the present compounds also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

[0095] Solvates in the context of the compounds are described as those forms of the present compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water.

[0096] The compounds described herein may, depending on their structure, exist in different stereoisomeric forms, i.e., in the form of configurational isomers or else, if appropriate, of conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers). The present compounds encompass the use of enantiomers and diastereomers, and the respective mixtures thereof. The stereoisomerically homogeneous constituents can be isolated from such mixtures of enantiomers and / or diastereomers in a known manner; chromatography processes are preferably used for this purpose, especially HPLC chromatography on an achiral or chiral phase.

[0097] If the present compounds can occur in tautomeric forms, the methods and compositions described herein encompass the use of all the tautomeric forms.

[0098] The methods and compositions described herein also encompass the use of all suitable isotopic variants of the present compounds. An isotopic variant of a present compound is understood here as meaning a compound in which at least one atom within the present compound has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into an present compound are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as2H (deuterium),3H (tritium),13C,14C,15N,17O,18O,32P,33P,33S,34S,35S,36S,18F,36Cl,82Br,123I,124I,129I and131I. Particular isotopic variants of an present compound,International Patent Application Attorney Docket No.2920951-439977 such as, in particular, those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active ingredient distribution in the body; because of the comparative ease of preparability and detectability, particularly compounds labelled with3H or14C isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, may lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. Isotopic variants of the present compounds can be prepared by the processes known to those skilled in the art, for example by the methods described further below and the procedures described in the working examples, by using corresponding isotopic modifications of the respective reagents and / or starting compounds.

[0099] The methods and compositions described herein provides the use of all the possible crystalline and polymorphous forms of the present compounds, where the polymorphs may be present either as single polymorphs or as a mixture of a plurality of polymorphs in all concentration ranges.

[0100] The methods and compositions described herein additionally also encompass the use of prodrugs of the compounds described herein. The term “prodrugs” in this context refers to compounds which may themselves be biologically active or inactive but are converted (for example metabolically or hydrolytically) to present compounds during their residence time in the body.

[0101] In the context of the methods and compositions described herein, unless specified otherwise, the substituents have the following meanings:

[0102] Alkyl represents a straight-chain or branched alkyl group having the particular number of carbon atoms specified. Examples include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, 1- methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 2-ethylbutyl. Preference is given to methyl, ethyl, n-propyl, n-butyl, 2-methylbutyl, 3-methylbutyl and 2,2- dimethylpropyl.

[0103] Cycloalkyl is a monocyclic saturated alkyl group having the number of carbon atoms specified in each case. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.International Patent Application Attorney Docket No.2920951-439977

[0104] Alkoxy represents a straight-chain or branched alkoxy group having the particular number of carbon atoms specified.1 to 6 carbon atoms are preferred. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy and n-hexoxy. Particular preference is given to a linear or branched alkoxy group having 1 to 4 carbon atoms. Examples which may be mentioned as being preferred are methoxy, ethoxy, n-propoxy, 1-methylpropoxy, n-butoxy and isobutoxy.

[0105] Halogen is fluorine, chlorine and bromine. Preference is given to fluorine.

[0106] Hydroxyl is OH.

[0107] A monocyclic saturated heterocycle is a monocyclic saturated heterocycle which has 4 to 6 ring atoms and contains a heteroatom or a heterogroup from the group of O, S, SO and SO2. A heterocycle having a heteroatom or a heterogroup from the group of O, SO and SO2 is preferred. Examples include: oxetane, tetrahydrofuran, tetrahydro-2H-pyran-4-yl, 1,1- dioxidotetrahydro-2H-thiopyran-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-2-yl, 1,1- dioxidotetrahydro-2H-thiopyran-4-yl, 1,1-dioxidotetrahydrothiophen-3-yl, 1,1- dioxidotetrahydrothiophen-2-yl, 1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl. Particular preference is given here to oxetane and tetrahydrofuran. Very particular preference is given to oxetan-3-yl.

[0108] A symbol * at a bond denotes the bonding site in the molecule.

[0109] When groups in the compounds described herein are substituted, the groups may be mono- or polysubstituted, unless specified otherwise. All groups which occur more than once are defined independently of one another. Substitution by one, two or three identical or different substituents is preferred.

[0110] A preferred embodiment of R1is a C2-C6-alkyl group substituted by 1, 2 or 3 fluorine atoms. Particular preference is given to 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 4,4,4- trifluorobutyl. Very particular preference is given to a 4,4,4-trifluorobutyl group.

[0111] A further preferred embodiment of R1is a C2-C6-alkyl group substituted by one or two hydroxyl group(s) or one C1-C3-alkoxy or a tri-fluorine-substituted C1-C3-alkoxy. Particular preference is given to a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy. Very particular preference is given to 3- hydroxy-3-methylbutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-trifluoromethoxypropyl, 2- methoxyethyl or 2-hydroxyethyl. Especially preferred is the 3-hydroxy-3-methylbutyl group.International Patent Application Attorney Docket No.2920951-439977

[0112] Further preferably, R1is a C2-C6-alkyl group substituted by a C1-C6-alkyl-SO2group. A methyl-SO2-substituted C2-C4-alkyl group is particularly preferred. Especially preferred for R1are 2-(methylsulphonyl)ethyl or 3-(methylsulphonyl)propyl. From the latter group, 2- (methylsulphonyl)ethyl is particularly preferred.

[0113] Additionally preferably, R1is a C1-C3-alkyl group substituted by oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyran-4-yl, 1,1-dioxidotetrahydro-2H-thiopyran-3-yl, 1,1- dioxidotetrahydro-2H-thiopyran-2-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, 1,1- dioxidotetrahydrothiophen-3-yl, 1,1-dioxidotetrahydrothiophen-2-yl, 1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl. Particular preference is given to a C1-C3-alkyl group substituted by an oxetane group. Especially preferred for R1is an oxetan-3-ylmethyl group.

[0114] For R2and R3, which always have the same definition, hydrogen or methyl are preferred. Methyl is particularly preferred.

[0115] In the case of R4, preference is given to 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.

[0116] For R4, particular preference is given to the following groups: methyl, ethyl, trifluoro- C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl. For R4, particular preference is given to the methyl, trifluoromethyl and difluoromethyl groups. Particular preference is given here to a trifluoromethyl group.

[0117] A preferred embodiment of R5is hydrogen, fluorine, chlorine or C1-C3-alkyl. More preferably, R5is hydrogen, fluorine or methyl. Most preferably, R5is hydrogen or fluorine.

[0118] Particular preference is also given to compounds in which R4is methyl or trifluoromethyl and R5is fluorine. Very particular preference is given to compounds in which R4is methyl and R5is fluorine, where R5is in the ortho position to R4.

[0119] For R6, preferred embodiments include oxetanyl, tetrahydrofuranyl, tetrahydro-2H- pyran-4-yl, 1,1-dioxidotetrahydro-2H-thiopyran-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-2- yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, 1,1-dioxidotetrahydrothiophen-3-yl, 1,1- dioxidotetrahydrothiophen-2-yl, 1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl. Particular preference is given here to oxetanyl. Very particular preference is given to oxetan-3-yl.

[0120] R7is exclusively connected to the functional groups –SO2- and –SO-, i.e. is an R7- substituted -SO2- or SO group. In this connection, R7is preferably C1-C4-alkyl, where the C1- C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms. Additionally preferred for R7is a cyclopropyl group.International Patent Application Attorney Docket No.2920951-439977 Particularly preferred for R7are methyl, ethyl or hydroxyethyl. Very particular preference is given to methyl for R7.

[0121] This means that, in the case of a C1-C6-alkyl group substituted by R7SO2- or R7SO-, in the context of R1, preference is given to a C1-C6-alkyl substituted by a C1-C6-alkyl-SO2or a C1-C6-alkyl-SO. For R1, preference is given here especially to methylsulphonylethyl and methylsulphonylpropyl. Very particular preference is given here to methylsulphonylethyl.

[0122] For R8, preference is given to an unsubstituted C1-C4-alkyl group or a tri-fluorine- substituted C1-C4-alkyl group. Particular preference is given to methyl, ethyl, trifluoromethyl or 2,2,2-trifluoroethyl. Very particular preference is given to methyl, trifluoromethyl or 2,2,2- trifluoroethyl.

[0123] Preference is given to compounds of the formula (I) in which R1is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R6, R7SO2, R7SO or R8O group; R2and R3always have the same definition and are both either hydrogen or C1-C3-alkyl; R4is halogen, cyano or C1-C3-alkyl, where the C1-C3-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl; R5is hydrogen, fluorine, chlorine or C1-C3-alkyl; R6is oxetanyl or tetrahydrofuranyl; R7is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms; R8is unsubstituted C1-C4-alkyl or tri-fluorine-substituted C1-C4-alkyl; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof, for use in the treatment and / or prophylaxis of osteoarthritis, including pain and / or inflammation associated with osteoarthritis, in animals.

[0124] Preference is additionally given to compounds of the formula (I) in which R1is C2-C6-alkyl, where C2-C6-alkyl is unsubstituted, or C2-C6-alkyl is mono-, di- or tri- fluorine-substituted or C2-C6-alkyl is monosubstituted by hydroxyl, R6, R7SO2, or R8O, or in which R1is an oxetanyl-substituted C1-C3-alkyl; R2and R3always have the same definition and are both either hydrogen or methyl; R4is 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; R5is hydrogen, fluorine or C1-C3-alkyl; R7is C1-C3-alkyl;International Patent Application Attorney Docket No.2920951-439977 R8is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or mono-, di- or tri-fluorine- substituted; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof, for use in the treatment and / or prophylaxis of osteoarthritis, including pain and / or inflammation associated with osteoarthritis, in animals. Further the IRAK4 inhibitors described herein can be used in methods of treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0125] Particular preference is also given to compounds of the general formula (I) in which R1is a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or is a methyl-SO2 -substituted C2-C4-alkyl group or is an oxetan-3-yl-substituted C1-C2-alkyl group; R2and R3always have the same definition and are both hydrogen or methyl; R4is 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 R5is hydrogen, fluorine or methyl; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof, for use in the treatment and / or prophylaxis of osteoarthritis, including pain and / or inflammation associated with osteoarthritis, in animals. Further the IRAK4 inhibitors described herein can be used in methods of treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0126] Very particular preference is given to compounds in which R1is 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; R2and R3are both methyl or hydrogen and R4is difluoromethyl, trifluoromethyl or methyl and R5is hydrogen or fluorine; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the saltsInternational Patent Application Attorney Docket No.2920951-439977 thereof, for use in the treatment and / or prophylaxis of osteoarthritis, including pain and / or inflammation associated with osteoarthritis, in animals. Further the IRAK4 inhibitors described herein can be used in methods of treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0127] Very particular preference is also given to compounds in which R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is difluoromethyl or trifluoromethyl; and R5is hydrogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof, for use in the treatment and / or prophylaxis of osteoarthritis, including pain and / or inflammation associated with osteoarthritis, in animals. Further the IRAK4 inhibitors described herein can be used in methods of treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0128] Particular preference is additionally also given to compounds in which R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is methyl and R5is fluorine, where R5is in the ortho position to R4; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof, for use in the treatment and / or prophylaxis of osteoarthritis, including pain and / or inflammation associated with osteoarthritis, in animals. Further the IRAK4 inhibitors described herein can be used in methods of treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0129] The disclosure especially provides the following compounds: (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-carboxamideInternational Patent Application Attorney Docket No.2920951-439977 (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-carboxamideInternational Patent Application Attorney Docket No.2920951-439977 (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 (22) N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}- 6-(trifluoromethyl)pyridine-2-carboxamide, for use in the treatment and / or prophylaxis of osteoarthritis, including pain and / or inflammation in animals. Further the IRAK4 inhibitors described herein can be used in methods of treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0130] The disclosure further provides compounds of the general formula (III) R5R1is 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; R4is difluoromethyl, trifluoromethyl or methyl; and R5is hydrogen or fluorine; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof, for use in the treatment and / or prophylaxis of osteoarthritis, including pain and / or inflammation associated with osteoarthritis, in animals. Further the IRAK4 inhibitors described herein can be used in methods of treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0131] Preference is especially given to the following compounds of the general formula (III):International Patent Application Attorney Docket No.2920951-439977 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, for use in the treatment and / or prophylaxis of osteoarthritis, including pain and / or inflammation associated with osteoarthritis, in animals. Further the IRAK4 inhibitors described herein can be used in methods of treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof. The IRAK4 inhibitors described herein can be used in methods for the treatment and / or prevention of degenerative joint disease (DJD).

[0132] The IRAK4 inhibitors described herein can be formulated into medicaments for use in the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0133] The IRAK4 inhibitors described herein can be formulated into medicaments for use in the treatment and / or prevention of degenerative joint disease (DJD).

[0134] The IRAK4 inhibitors described herein can be formulated into compositions for the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0135] The IRAK4 inhibitors described herein can be formulated into compositions for the treatment and / or prevention of degenerative joint disease (DJD).

[0136] The compounds of the general formula (III) are suitable for preparation of a portion of the compounds of the general formula (I). Furthermore, the compounds of the general formula (III) are inhibitors of interleukin-1 receptor associated kinase-4 (IRAK4).

[0137] Compounds of the general formula (III) can be prepared from compounds of the general formula (II)International Patent Application Attorney Docket No.2920951-439977 R5R5R13-hydroxypropyl, 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; R4is difluoromethyl, trifluoromethyl or methyl; and R5is hydrogen or fluorine; by the reaction of (II) with appropriately substituted alkyl halides or alkyl 4- methylbenzenesulphonates in the presence of potassium carbonate.

[0138] Further, compounds of the general formula (I) can be prepared from compounds of the formula (III) 55R R R1R1is 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, 3-(methylsulphonyl)propyl 2-(1- hydroxycyclopropyl)ethyl; R2and R3are methyl; R4is difluoromethyl, trifluoromethyl or methyl; and R5is hydrogen or fluorine; by a Grignard reaction with methylmagnesium bromide.International Patent Application Attorney Docket No.2920951-439977

[0139] As described below, Compound 1 provides efficacy similar to NSAIDs in dogs with osteoarthritis, but with a much improved safety profile, enabling more dogs to be treated proactively and appropriately for the pain and disability associated, for example, with their osteoarthritis.

[0140] Preparation of the compounds

[0141] The preparation of the present compounds is illustrated by the synthesis schemes which follow.

[0142] Starting materials used for synthesis of the present compounds are carboxylic acids (Intermediate V3), which are commercially available or can be prepared by routes known from the literature or analogously to routes known from the literature (see, for example, European Journal of Organic Chemistry 2003, 8, 1559 – 1568, Chemical and Pharmaceutical Bulletin, 1990, 38, 9, 2446 – 2458, Synthetic Communications 2012, 42, 658 – 666, Tetrahedron, 2004, 60, 51, 11869 - 11874) (see, for example, Synthesis Scheme 1). Some carboxylic acids V3 can be prepared proceeding from carboxylic esters (Intermediate V2) by hydrolysis (cf., for example, the reaction of ethyl 6-(hydroxymethyl)pyridine-2-carboxylate with aqueous sodium hydroxide solution in methanol, WO2004113281) or – in the case of a tert-butyl ester – by reaction with an acid, for example hydrogen chloride or trifluoroacetic acid (cf., for example, Dalton Transactions, 2014, 43, 19, 7176 – 7190). The carboxylic acids V3 can also be used in the form of their alkali metal salts. The Intermediates V2 can optionally also be prepared from the Intermediates V1 which bear a chlorine, bromine or iodine as substituent X1by reaction in a carbon monoxide atmosphere, optionally under elevated pressure, in the presence of a phosphine ligand, for example 1,3- bis(diphenylphosphino)propane, a palladium compound, for example palladium(II) acetate, and a base, for example triethylamine, with addition of ethanol or methanol in a solvent, for example dimethyl sulphoxide (for preparation methods see, for example, WO2012112743, WO 2005082866, Chemical Communications (Cambridge, England), 2003, 15, 1948 – 1949, WO200661715). The Intermediates V1 are either commercially available or can be prepared by routes known from the literature. Illustrative preparation methods are detailed in WO 2012061926, European Journal of Organic Chemistry, 2002, 2, 327 – 330, Synthesis, 2004, 10, 1619 – 1624, Journal of the American Chemical Society, 2013, 135, 32, 12122 – 12134, Bioorganic and Medicinal Chemistry Letters, 2014, 24, 16, 4039 – 4043, US2007185058, WO2009117421.

[0143] Synthesis Scheme 1International Patent Application Attorney Docket No.2920951-439977 X1isRdis methyl, ethyl, benzyl or tert-butyl. R4, R5are each as defined in the general formula (I).

[0144] Methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 2) can be obtained proceeding from methyl 1H-indazole-6-carboxylate (Intermediate 0) according to Synthesis Scheme 2 by nitration and reduction of the nitro group of Intermediate 1 with hydrogen in the presence of palladium on charcoal analogously to WO 2008 / 001883. For preparation of the Intermediates 3 proceeding from Intermediate 2, it is possible to use various coupling reagents known from the literature (Amino Acids, Peptides and Proteins in Organic Chemistry, Vol.3 – Building Blocks, Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiley, Chapter 12 - Peptide-Coupling Reagents, 407-442; Chem. Soc. Rev., 2009, 38, 606). For example, it is possible to use 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in combination with 1-hydroxy-1H-benzotriazole hydrate (HOBt, WO2012107475; Bioorg. Med. Chem. Lett., 2008 , 18, 2093), (1H-benzotriazol-1- yloxy)(dimethylamino)-N,N-dimethylmethaniminium tetrafluoroborate (TBTU, CAS 125700-67-6), (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3- yloxy)methanaminium hexafluorophosphate (HATU, CAS 148893-10-1), propanephosphonic anhydride (as solution in ethyl acetate or DMF, CAS68957-94-8) or di- 1H-imidazol-1-ylmethanone (CDI) as coupling reagents, with addition of a base such as triethylamine or N-ethyl-N-isopropylpropan-2-amine in each case to the reaction mixture. Preference is given to the use of TBTU and N-ethyl-N-isopropylpropan-2-amine in THF.

[0145] Synthesis Scheme 2International Patent Application Attorney Docket No.2920951-439977The substituents R4, R5are each as defined in the general formula (I).

[0146] Proceeding from the Intermediates 3, it is possible to prepare 2-substituted indazole derivatives (Intermediate 4) (see synthesis scheme 3). Useful reactions for this purpose include those with optionally substituted alkyl chlorides, alkyl bromides, alkyl iodides or alkyl 4-methylbenzenesulphonates. The alkyl halides or alkyl 4-methylbenzenesulphonates used are commercially available or can be prepared analogously to routes known from literature (for the preparation of alkyl 4-methylbenzenesulphonates, one example is the reaction of an appropriate alcohol with 4-methylbenzenesulphonyl chloride in the presence of triethylamine or pyridine; see, for example, Bioorganic and Medicinal Chemistry, 2006, 14, 12 4277 – 4294). Optionally, in the case of use of alkyl chlorides or alkyl bromides, it is also possible to add an alkali metal iodide such as potassium iodide or sodium iodide. Bases used may, for example, be potassium carbonate, cesium carbonate or sodium hydride. In the case of reactive alkyl halides, it is also possible in some cases to use N-cyclohexyl-N- methylcyclohexanamine. Useful solvents include, for example, 1-methylpyrrolidin-2-one, DMF, DMSO or THF. Optionally, the alkyl halides or alkyl 4-methylbenzenesulphonates used may have functional groups which have optionally been protected with a protecting group beforehand (see also P. G. M. Wuts, T. W. Greene, Greene’s Protective Groups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541). If, for example, alkyl halides or alkyl 4-methylbenzenesulphonates having one or more hydroxyl groups are used, these hydroxyl groups may optionally be protected by a tert-butyl(dimethyl)silyl group or a similar silicon-containing protecting group familiar to those skilled in the art. Alternatively, the hydroxyl groups may also be protected by the tetrahydro-2H-pyran (THP) group or by the acetyl or benzoyl group. The protecting groups used can then be detached subsequently to the synthesis of Intermediate 4, or else after the synthesis of (I). If, for example, a tert-International Patent Application Attorney Docket No.2920951-439977 butyl(dimethylsilyl) group is used as protecting group, it can be detached using tetrabutylammonium fluoride in a solvent such as THF, for example. A THP protecting group can be detached, for example, using 4-methylbenzenesulphonic acid (optionally in monohydrate form). Acetyl groups or benzoyl groups can be detached by treatment with aqueous sodium hydroxide solution.

[0147] Optionally, the alkyl halides or alkyl 4-methylbenzenesulphonates used may contain functional groups which can be converted by oxidation or reduction reactions known to those skilled in the art (see, for example, Science of Synthesis, Georg Thieme Verlag). If, for example, the functional group is a sulphide group, this can be oxidized by methods known in the literature to a sulphoxide or sulphone group. In the case of a sulphoxide group, this can likewise be oxidized to a sulphone group. For these oxidation steps, it is possible to use, for example, 3-chloroperbenzoic acid (CAS 937-14-4) (in this regard, see also, for example, US201094000 for the oxidation of a 2-(methylsulphanyl)ethyl-1H-pyrazole derivative to a 2- (methylsulphinyl)ethyl-1H-pyrazole derivative and the oxidation of a further 2- (methylsulphanyl)ethyl-1H-pyrazole derivative to a 2-(methylsulphonyl)ethyl-1H-pyrazole derivative). If the alkyl halides or tosylates used contain a keto group, this can be reduced by reduction methods known to those skilled in the art to an alcohol group (see, for example, Chemische Berichte, 1980, 113, 1907 – 1920 for the use of sodium borohydride). These oxidation or reduction steps can be effected subsequently to the synthesis of Intermediate 4, or else after the synthesis of the present compounds of the general formula (I). Alternatively, Intermediate 4 can be prepared via Mitsunobu reaction (see, for example, K. C. K. Swamy et. al. Chem. Rev.2009, 109, 2551 – 2651) of Intermediate 3 with optionally substituted alkyl alcohols. It is possible to utilize various phosphines such as triphenylphosphine, tributylphosphine or 1,2-diphenylphosphinoethane in combination with diisopropyl azodicarboxylate (CAS 2446-83-5) or further diazene derivatives mentioned in the literature (K. C. K. Swamy et. al. Chem. Rev.2009, 109, 2551 – 2651). Preference is given to the use of triphenylphosphine and diisopropyl azodicarboxylate. If the alkyl alcohol bears a functional group it is possible – as in the case of the abovementioned reactions with alkyl halides – for known protecting group strategies (further pointers can be found in P. G. M. Wuts, T. W. Greene, Greene’s Protective Groups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541) and – as in the case of the abovementioned reactions with alkyl halides – for oxidation or reduction steps to be effected correspondingly to the synthesis of Intermediate 4, or else after the synthesis of the present compounds of the general formula (I). Proceeding from Intermediate 4, present compounds of the general formula (I) where R2International Patent Application Attorney Docket No.2920951-439977 and R3are defined as C1-C6-alkyl (where R2and R3have the same definition) may be obtained by a Grignard reaction (cf., for example, the reaction of a methyl 1H-indazole-6- carboxylate derivative with methylmagnesium bromide in EP 2489663). For the Grignard reaction, it is possible to use alkylmagnesium halides. Particular preference is given to methylmagnesium chloride or methylmagnesium bromide in THF or diethyl ether, or else in mixtures of THF and diethyl ether. Alternatively, proceeding from Intermediate 4, present compounds of the general formula (I) where R2and R3are defined as C1-C6-alkyl (where R2and R3have the same definition) may be obtained by a reaction with an alkyllithium reagent (cf., for example, the reaction of a methyl 2-amino-4-chloro-1-methyl-1H-benzimidazole-7- carboxylate derivative with isopropyllithium or tert-butyllithium in WO2006116412). Proceeding from Intermediate 4, it is possible to prepare present compounds of the general formula (I) where R2and R3are defined as H by reduction with lithium aluminum hydride in THF, lithium borohydride in THF or sodium borohydride in THF, optionally with addition of methanol, or mixtures of lithium borohydride and sodium borohydride.

[0148] Synthesis Scheme 3 The

[0149] Proceeding from Intermediate 3, Intermediate 5 where R2and R3are defined as C1- C6-alkyl (where R2and R3have the same definition) may be obtained by a Grignard reaction (cf., for example, Synthesis Scheme 4). For this purpose, it is possible to use suitable alkylmagnesium halides, for example methylmagnesium chloride or methylmagnesium bromide in THF or in diethyl ether or else in mixtures of THF and diethyl ether.

[0150] Proceeding from Intermediate 5, it is then possible to prepare a portion (I-a) of the present compounds (I) where R2and R3are defined as C1-C6-alkyl (where R2and R3have the same definition). For this purpose, analogously to Synthesis Scheme 3 (preparation of Intermediate 3), useful reactions are those of Intermediate 5 with optionally substituted alkyl chlorides, alkyl bromides, alkyl iodides or alkyl 4-methylbenzenesulphonates. It is possible to use protecting group strategies analogously to those described in Synthesis Scheme 3.International Patent Application Attorney Docket No.2920951-439977

[0151] Alternatively, for preparation of a portion (I-a) of the present compounds (I) where R2and R3are defined as C1-C6-alkyl (where R2and R3have the same definition), it is possible to use the Mitsunobu reaction of Intermediate 5 with optionally substituted alkyl alcohols (analogously to Synthesis Scheme 3).

[0152] If R1in the compounds of the formula (I-a) includes a suitable functional group, it is optionally possible subsequently, in analogy to Synthesis Scheme 3, to use oxidation or reduction reactions for preparation of further present compounds.

[0153] Synthesis Scheme 4

[0154] The substituents R1, R4, R5are each as defined in the general formula (I). R2and R3always have the same definition and are both C1-C6-alkyl.

[0155] Proceeding from Intermediate 1, it is possible to prepare Intermediate 4 in an alternative manner (see Synthesis Scheme 5). First of all, Intermediate 1 is converted to Intermediate 6 by methods as in Synthesis Scheme 3 (preparation of Intermediate 4 from Intermediate 3).

[0156] Intermediate 6 can then be converted to Intermediate 7 by reduction of the nitro group. For example, the nitro group can be reduced with palladium on carbon under a hydrogen atmosphere (cf., for example, WO2013174744 for the reduction of 6-isopropoxy-5- nitro-1H-indazole to 6-isopropoxy-1H-indazol-5-amine) or by the use of iron and ammonium chloride in water and ethanol (see, for example, also Journal of the Chemical Society, 1955, 2412-2419), or by the use of tin(II) chloride (CAS 7772-99-8). The use of iron andInternational Patent Application Attorney Docket No.2920951-439977 ammonium chloride in water and ethanol is preferred. The preparation of Intermediate 4 from Intermediate 7 can be effected analogously to Synthesis Scheme 2 (preparation of Intermediate 3 from Intermediate 2).

[0157] As described for Synthesis Scheme 3, it is optionally possible to use protecting group strategies in the case of Synthesis Scheme 5 as well. Optionally, it is additionally possible, proceeding from Intermediate 6 or Intermediate 7, as described for Synthesis Scheme 3, to conduct oxidation or reduction reactions known to those skilled in the art (cf., for example Science of Synthesis, Georg Thieme Verlag).

[0158] Synthesis Scheme 5. Synthesis of the example compounds Abbreviations and elucidations DMF N,N-dimethylformamide DMSO dim th l l h xideInternational Patent Application Attorney Docket No.2920951-439977 solution. The chemical names of the intermediates and examples were generated using the ACD / LABS (Batch Version 12.01.) software. Methods

[0160] In some cases, the present compounds and precursors and / or intermediates thereof were analysed by LC-MS.

[0161] Method A1: UPLC (MeCN-HCOOH): Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C181.750 x 2.1 mm; eluent A: water + 0.1% by vol. of formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml / min; temperature: 60°C; injection: 2 µl; DAD scan: 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m / z; ELSD.

[0162] Method A2: UPLC (MeCN-NH3): Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C181.750 x 2.1 mm; eluent A: water + 0.2% by vol. of ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml / min; temperature: 60°C; injection: 2 µl; DAD scan: 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m / z; ELSD.

[0163] Method A3: (LC-MS) Instrument: Agilent 1290 Infinity LC; column: Acquity UPLC BEH C181.750 x 2.1 mm; eluent A: water + 0.05% by vol. of formic acid, eluent B: acetonitrile + 0.05% by vol. of formic acid; gradient: 0-1.7 min 2-90% B, 1.7-2.0 min 90% B; flow rate 1.2 ml / min; temperature: 60°C; injection: 2 µl; DAD scan: 190-390 nm; MS: Agilent TOF 6230.

[0164] Method A4: (LC-MS) Instrument: Waters Acquity; column: Kinetex (Phenomenex), 50 x 2 mm; eluent A: water + 0.05% by vol. of formic acid, eluent B: acetonitrile + 0.05% by vol. of formic acid; gradient: 0-1.9 min 1-99% B, 1.9-2.1 min 99% B; flow rate 1.5 ml / min; temperature: 60°C; injection: 0.5 µl; DAD scan: 200-400 nm. In some cases, the present compounds and the precursors and / or intermediates thereof were purified by the following illustrative preparative HPLC methods:

[0165] Method P1: system: Waters Autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; column: XBridge C185 µm 100 x 30 mm; eluent A: water + 0.1% by vol. of formic acid, eluent B: acetonitrile; gradient: 0-8 min 10-100% B, 8-10 min 100% B; flow: 50 ml / min; temperature: room temperature; solution: max.250 mg / max.2.5 ml DMSO or DMF; injection: 1 x 2.5 ml; detection: DAD scan range 210–400 nm; MS ESI+, ESI-, scan range 160-1000 m / z.

[0166] Method P2: system: Waters Autopurification system: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100; column: XBridge C185 µm 10 x 30 mm;International Patent Application Attorney Docket No.2920951-439977 eluent A: water + 0.2% by vol. of ammonia (32%), eluent B: methanol; gradient: 0-8 min 30- 70% B; flow: 50 ml / min; temperature: room temperature; detection: DAD scan range 210– 400 nm; MS ESI+, ESI-, scan range 160-1000 m / z; ELSD.

[0167] Method P3: system: Labomatic, pump: HD-5000, fraction collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2.1S; column: XBridge C185 µm 100x30 mm; eluent A: water + 0.2% by vol. of ammonia (25%), eluent B: acetonitrile; gradient: 0-1 min 15% B, 1-6.3 min 15-55% B, 6.3-6.4 min 55-100% B, 6.4-7.4 min 100% B; flow: 60 ml / min; temperature: room temperature; solution: max.250 mg / 2 ml DMSO; injection: 2 x 2 ml; detection: UV 218 nm; Software: SCPA PrepCon5.

[0168] Method P4: systemLabomatic, pump: HD-5000, fraction collector: LABOCOL Vario- 4000, UV detector: Knauer UVD 2.1S; column: Chromatorex RP C1810 µm 125 x 30 mm; eluent A: water + 0.1% by vol. of formic acid, eluent B: acetonitrile; gradient: 0-15 min 65 – 100% B; flow: 60 ml / min; temperature: room temperature; solution: max.250 mg / 2 ml DMSO; injection: 2 x 2 ml; detection: UV 254 nm; Software: SCPA PrepCon5.

[0169] Method P5: system: Sepiatec: Prep SFC100, column: Chiralpak IA 5 µm 250x20 mm; eluent A: carbon dioxide, eluent B: ethanol; gradient: isocratic 20% B; flow: 80 ml / min; temperature: 40°C; solution: max.250 mg / 2 ml DMSO; injection: 5 x 0.4 mL; detection: UV 254 nm.

[0170] Method P6: system: Agilent: Prep 1200, 2 x prep pump, DLA, MWD, Gilson: Liquid Handler 215; column: Chiralcel OJ-H 5 µm 250 x 20 mm; eluent A: hexane, eluent B: ethanol; gradient: isocratic 30% B; flow: 25 ml / min; temperature: 25°C; solution: 187 mg / 8 ml ethanol / methanol; injection: 8 x 1.0 ml; detection: UV 280 nm.

[0171] Method P7: system: Labomatic, pump: HD-5000, fraction collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2.1S; column: XBridge C185 µm 100 x 30 mm; eluent A: water + 0.1% by vol. of formic acid, eluent B: acetonitrile; gradient: 0-3 min: 65% B isocratic, 3-13 min: 65-100% B; flow: 60 ml / min; temperature: room temperature; solution: max.250 mg / 2 ml DMSO; injection: 2 x 2 ml; detection: UV 254 nm.

[0172] Method P8: system: Agilent: Prep 1200, 2 x prep pump, DLA, MWD, Gilson: Liquid Handler 215; column: Chiralpak IF 5 µm 250 x 20 mm; eluent A: ethanol, eluent B: methanol; gradient: isocratic 50% B; flow: 25 ml / min; temperature: 25°C; solution: 600 mg / 7 ml N,N-dimethylformamide; injection: 10 x 0.7 ml; detection: UV 254 nm.

[0173] In some cases, substance mixtures were purified by column chromatography on silica gel.International Patent Application Attorney Docket No.2920951-439977

[0174] For preparation of some of the compounds and the precursors and / or intermediates thereof, described herein a column chromatography purification (“flash chromatography”) can be conducted on silica gel using Isolera®devices from Biotage. This can be done using cartridges from Biotage, for example the “SNAP Cartridge, KP_SIL” cartridge of different size and “Interchim Puriflash Silica HP 15UM flash column” cartridges from Interchim of different size.

[0175] Starting materials Intermediate V2-1 Methyl 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate H3C H C O

[0176] 2.00 g (9.26 mmol) of 2-2-ol (CAS 638218-78-7) were dissolved in 20 ml of methanol and 20 ml of DMSO. Subsequently, 250 mg of 1,3- bis(diphenylphosphino)propane, 130 mg of palladium(II) acetate and 3 ml of triethylamine were added. The reaction mixture was purged three times with carbon monoxide at room temperature and stirred under a 13 bar carbon monoxide atmosphere for 30 min. The carbon monoxide atmosphere was removed by applying a vacuum and the mixture was stirred under a 14 bar carbon monoxide atmosphere at 100°C for 24 h. The autoclave was decompressed, water was added to the reaction mixture, and the reaction mixture was extracted three times with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and sodium chloride solution, filtered through a hydrophobic filter and concentrated. This gave 1.60 g of a crude product. UPLC-MS (Method A1): Rt = 0.76 min (UV detector: TIC), mass found 195.00. Intermediate V3-1 Potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate H C K

[0177] 1.60 g of the crude productwere initially charged in 15 ml of methanol, 0.74 g of potassium hydroxide was added and the mixture was stirred at 50°C for 16.5 h. After concentration, this gave 2.1 g of a residue which was used without further purification.International Patent Application Attorney Docket No.2920951-439977

[0178] UPLC-MS (Method A1): Rt= 0.47 min (UV detector: TIC), mass found 181.00. Intermediate 1-1 Methyl 5-nitro-1H-indazole-6-carboxylate O + N O N

[0179] 4.60 g (26.1 mmol) of methyl 1H-indazole-6-carboxylate (CAS No: 170487-40-8) were dissolved in 120 ml of sulphuric acid (96%) and cooled to -15°C in a three-neck flask having a CPG stirrer, dropping funnel and internal thermometer. Over a period of 15 min, the nitrating acid (10 ml of 96% sulphuric acid in 5 ml of 65% nitric acid), which had been prepared and cooled beforehand, was added dropwise to this solution. After the dropwise addition had ended, the mixture was stirred for a further 1 h (internal temperature at -13°C). The reaction mixture was added to ice, and the precipitate was filtered off with suction, washed with water and dried in a drying cabinet at 50°C under reduced pressure.5.49 g of the title compound were obtained. UPLC-MS (Method A2): Rt= 0.75 min MS (ESIpos): m / z = 222(M+H)+1H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.87 (s, 3 H), 7.96 (s, 1 H), 8.44 (s, 1 H), 8.70 (s, 1 H), 13.98 (br. s., 1 H). Intermediate 2-1 Methyl 5-amino-1H-indazole-6-carboxylate H2N N

[0180] 4.40 g (19.8 mmol) of methyl 5-nitro-1H-indazole-6-carboxylate (Intermediate 1-1) were dissolved in 236 ml of methanol and hydrogenated with 1.06 g (0.99 mmol) of palladium on activated carbon under standard hydrogen pressure at 25°C for 3 h. The reaction mixture was filtered through Celite, the filter was washed with methanol, and the filtrate was concentrated.3.53 g of the title compound were obtained.International Patent Application Attorney Docket No.2920951-4399771H NMR (300 MHz, DMSO-d6): δ [ppm] = 3.85 (s, 3 H) 6.01 (s, 2 H) 6.98 (s, 1 H) 7.79 - 7.91 (m, 1 H) 7.99 (s, 1 H) 12.84 (br. s., 1 H). Intermediate 3-1 Methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate F O N N

[0181] 4.95 g (25.9 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid were initially charged in 45 ml of THF.9.07 g (28.2 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium tetrafluoroborate and 4.92 ml (28.2 mmol) of N-ethyl-N- isopropylpropan-2-amine were added and the mixture was stirred at 25°C for 30 min. Subsequently, 4.50 g (23.5 mmol) of methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 2-1) were added and the mixture was stirred at 25°C for 24 h. The reaction mixture was filtered with suction through a membrane filter and the solids were washed with THF and with water, and dried in a drying cabinet overnight.7.60 g of the title compound were obtained. UPLC-MS (Method A2): Rt = 1.16 min MS (ESIpos): m / z = 365 (M+H)+1H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.97 (s, 3 H), 8.13 - 8.27 (m, 2 H), 8.30 (s, 1 H), - 8.45 (m, 1 H), 8.45 - 8.51 (m, 1 H), 9.15 (s, 1 H), 12.57 (s, 1 H), 13.44 (s, 1 H). Intermediate 3-2 Methyl 5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate NInternational Patent Application Attorney Docket No.2920951-439977

[0182] 2.85 g (23.5 mmol) of 6-(difluoromethyl)pyridine-2-carboxylic acid were initially charged in 30 ml of THF.6.05 g (18.8 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium tetrafluoroborate and 3.3 ml of N-ethyl-N-isopropylpropan-2-amine were added and the mixture was stirred at room temperature for 10 minutes. Subsequently, 3.00 g (15.7 mmol) of methyl 5-amino-1H-indazole-6-carboxylate were added and the mixture was stirred at room temperature overnight. The reaction mixture was admixed with water, and the precipitate was filtered off with suction and washed repeatedly with water and dichloromethane. This gave 1.53 g (27% of theory) of the title compound. The phases of the filtrate were separated, the organic phase was concentrated, admixed with a little dichloromethane and suspended in an ultrasound bath, and the precipitate was filtered off with suction. This gave a further 1.03 g of the title compound. 1H-NMR (first product fraction, 300MHz, DMSO-d6): δ [ppm]= 3.99 (s, 3H), 7.09 (t, 1H), 8.00 (d, 1H), 8.21 - 8.40 (m, 4H), 9.14 (s, 1H), 12.53 (s, 1H), 13.44 (s, 1H). Intermediate 3-3 Methyl 5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6- carboxylate H C N

[0183] 2.10 g of potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate (Intermediate V3-1) were initially charged in 15 ml of THF.3.69 g (11.5 mmol) of O-(benzotriazol-1-yl)- N,N,N′,N′-tetramethyluronium tetrafluoroborate and 2.00 ml of N-ethyl-N-isopropylpropan- 2-amine were added and the mixture was stirred at room temperature for 15 min. Subsequently, 1.83 g (9.58 mmol) of methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 2-1) were added and the mixture was stirred at room temperature for 19 h. The mixture was admixed with water and ethyl acetate, the undissolved solids were filtered off, the phases of the filtrate were separated, and the aqueous phase was extracted twice with ethyl acetate, washed with sodium chloride solution, filtered through a hydrophobic filter, concentrated and purified by column chromatography on silica gel (hexane / ethyl acetate).International Patent Application Attorney Docket No.2920951-439977 After the solvents had been removed, 1.56 g of the title compound were obtained as a yellow foam. UPLC-MS (Method A1): Rt= 1.00 min (UV detector: TIC Smooth), mass found 354.00. 1H-NMR (500MHz,DMSO-d6): δ [ppm] = 1.63 (s, 6H), 3.97 (s, 3H), 5.37(s ,1H), 7.90 - 7.95 (m, 1H), 8.03-8.07 (m, 2H), 8.23(s, 1H),8.29 (s, 1H), 9.19 (s, 1H), 12.79 (s, 1H), 13.41 (br.s., 1H). Intermediate 4-1 Methyl 2-(oxetan-3-ylmethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H- indazole-6-carboxylate F O O

[0184] 1.00 g (2.66 mmol) of methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)- 1H-indazole-6-carboxylate (Intermediate 3-1) was dissolved in 10 ml of DMF and, after addition of 1.10 g (7.99 mmol) of potassium carbonate and 221 mg (1.33 mmol) of potassium iodide, the mixture was stirred at 25°C for 30 min.603 mg (3.99 mmol) of 3- bromomethyloxetane were added, and the mixture was stirred at 25°C for 24 h. The reaction mixture was partitioned between water and ethyl acetate. The mixture was extracted twice with ethyl acetate, and the combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate).260 mg of the title compound were obtained. UPLC-MS (Method A2): Rt= 1.24 min MS (ESIpos): m / z = 435(M+H)+1H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.49 - 3.64 (m, 1 H), 3.95 (s, 3 H), 4.49 (t, 2 H), (dd, 2 H), 4.81 (d, 2 H), 8.20 (dd, 1 H), 8.35 - 8.41 (m, 1 H), 8.43 - 8.49 (m, 2 H), 8.55 - 8.58 (m, 1 H), 9.06 (s, 1 H), 12.53 (s, 1 H). Intermediate 4-2 Methyl 2-(2-methoxyethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H- indazole-6-carboxylateInternational Patent Application Attorney Docket No.2920951-439977 F O N F

[0185] 1.00 g (2.75 mmol) pyridin-2-yl]carbonyl}amino)- 1H-indazole-6-carboxylate (Intermediate 3-1) was dissolved in 5 ml of DMF, and 387 µl (4.12 mmol) of 2-bromoethyl methyl ether, 1.14 g (8.23 mmol) of potassium carbonate and 228 mg (1.37 mmol) of potassium iodide were added while stirring. The reaction mixture was stirred at 25°C for 24 h, diluted with water and extracted twice with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate).12 mg of the title compound were obtained. UPLC-MS (Method A1): Rt = 1.24 min MS (ESIpos): m / z = 423 (M+H)+1H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.24 (s, 3 H), 3.86 (t, 2 H), 3.96 (s, 3 H), 4.65 (t, 2 H), 8.21 (dd, 1 H), 8.35 - 8.42 (m, 1 H), 8.43 - 8.51 (m, 2 H), 8.52 (d, 1 H), 9.06 (s, 1 H), 12.53 (s, 1 H). Intermediate 4-3 Methyl 2-(3-methoxypropyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H- indazole-6-carboxylate F

[0186] 1.00 g (2.75 mmol) of methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)- 1H-indazole-6-carboxylate (Intermediate 3-1) was dissolved in 5 ml of DMF, and 460 µl (4.12 mmol) of 1-bromo-3-methoxypropane, 1.14 g (8.23 mmol) of potassium carbonate and 228 mg (1.37 mmol) of potassium iodide were added while stirring. The reaction mixture was stirred at 25°C for 72 h, diluted with water and extracted twice with ethyl acetate. TheInternational Patent Application Attorney Docket No.2920951-439977 combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate).28 mg of the title compound were obtained. UPLC-MS (Method A1): Rt = 1.29 min MS (ESIpos): m / z = 437 (M+H)+1H NMR (400 MHz, DMSO-d6): δ [ppm] = 2.17 (quin, 2 H), 3.24 (s, 3 H), 3.33 - 3.36 (m, 2 H), 3.96 (s, 3 H), 4.53 (t, 2 H), 8.21 (dd, 1 H), 8.35 - 8.42 (m, 1 H), 8.45 - 8.49 (m, 2 H), 8.54 (d, 1 H), 9.06 (s, 1 H), 12.54 (s, 1 H). Intermediate 4-4 Methyl 2-(3-hydroxy-3-methylbutyl)-5-({[6-(trifluoromethyl)pyridin-2- yl]carbonyl}amino)-2H-indazole-6-carboxylate Preparation Method 1 F 3

[0187] 930 mg (2.55 mmol) of methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)- 1H-indazole-6-carboxylate (Intermediate 3-1), 1.06 g of potassium carbonate and 212 mg of potassium iodide were initially charged in 9 ml of DMF and the mixture was stirred for 15 min. Then 0.62 ml of 4-bromo-2-methylbutan-2-ol was added and the mixture was stirred at 60°C for 16 h. The mixture was admixed with water and extracted twice with ethyl acetate, and the extract was washed three times with saturated sodium chloride solution, filtered and concentrated. Column chromatography purification on silica gel (hexane / ethyl acetate) gave 424 mg of the title compound. UPLC-MS (Method A2): Rt = 1.21 min (UV detector: TIC), mass found 450.00.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.16 (s, 6 H) 2.02 - 2.11 (m, 2 H) 3.96 (s, 3 H) 4.51 - 4.60 (m, 3 H) 8.20 (dd, J=7.83, 1.01 Hz, 1 H) 8.39 (s, 1 H) 8.45 (s, 2 H) 8.55 (d, J=0.76 Hz, 1 H) 9.05 (s, 1 H) 12.52 (s, 1 H)International Patent Application Attorney Docket No.2920951-439977 Preparation Method 2

[0188] 1.95 g (7.03 mmol) of methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6- carboxylate (Intermediate 7-1) were initially charged in 30 ml of THF.1.48 g (7.73 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid, 2.71 g (8.44 mmol) of O-(benzotriazol-1-yl)- N,N,N′,N′-tetramethyluronium tetrafluoroborate and 1.47 ml (8.44 mmol) of N-ethyl-N- isopropylpropan-2-amine were added and the mixture was stirred at 25°C for 20.5 h. Water was added, the mixture was extracted three times with ethyl acetate and the extracts were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was separated by column chromatography on silica gel (hexane / ethyl acetate gradient).2.79 g of the title compound were obtained. UPLC-MS (Method A1): Rt = 1.23 min (UV detector: TIC), mass found 450.00. Intermediate 4-5 Methyl 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-({[6-(trifluoromethyl)pyridin-2- yl]carbonyl}amino)-2H-indazole-6-carboxylate F O

[0189] 1.00 g (2.66 mmol, 97%) of methyl 5-({[6-(trifluoromethyl)pyridin-2- yl]carbonyl}amino)-1H-indazole-6-carboxylate (Intermediate 3-1) was initially charged in 50 ml of DMF, 1.10 g (7.99 mmol) of potassium carbonate and 221 mg (1.33 mmol) of potassium iodide were added while stirring, and the mixture was stirred at 25°C for 30 min. Subsequently, 857 µl (3.99 mmol) of (2-bromoethoxy)(tert-butyl)dimethylsilane were added and the mixture was stirred at 25°C for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate).400 mg of the title compound were obtained. UPLC-MS (Method A1): Rt = 1.58 min MS (ESIpos): m / z = 523(M+H)+1H NMR (300 MHz, DMSO-d6): δ [ppm] = -0.18 - -0.13 (m, 6 H), 0.74 (s, 9 H), 3.96 (s, 3 H), 4.08 (t, 2 H), 4.57 (t, 2 H), 8.15 - 8.25 (m, 1 H), 8.32 - 8.43 (m, 1 H), 8.43 - 8.52 (m, 3International Patent Application Attorney Docket No.2920951-439977 H), 9.07 (s, 1 H), 12.53 (s, 1 H). Intermediate 4-6 Methyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-({[6-(trifluoromethyl)pyridin-2- yl]carbonyl}amino)-2H-indazole-6-carboxylate F O N

[0190] Analogously to 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (Intermediate 3-1) was dissolved in 10 ml of DMF, 1.14 g (8.24 mmol) of potassium carbonate and 228 mg (1.37 mmol) of potassium iodide were added while stirring, and the mixture was stirred at 25°C for 30 min. Subsequently, 1.04 g (4.12 mmol) of (3-bromopropoxy)(tert- butyl)dimethylsilane were added and the mixture was stirred at 25°C for 24 h. The reaction mixture was filtered and the filtercake was washed with ethyl acetate. The reaction mixture was partitioned between water and ethyl acetate and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. Purification of the residue by preparative HPLC gave 428 mg of the title compound. UPLC-MS (Method A1): Rt = 1.63 min MS (ESIpos): m / z = 537(M+H)+1H NMR (400 MHz, DMSO-d6): δ [ppm] = -0.02 - 0.06 (m, 6 H), 0.87 (s, 9 H), 2.14 (quin, 2 , 3.62 (t, 2 H), 3.96 (s, 3 H), 4.54 (t, 2 H), 8.20 (d, 1 H), 8.35 - 8.42 (m, 1 H), 8.43 - 8.48 3 H), 8.49 - 8.53 (m, 1 H), 9.06 (s, 1 H). Intermediate 4-7 Methyl 5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-2-(4,4,4- trifluorobutyl)-2H-indazole-6-carboxylateInternational Patent Application Attorney Docket No.2920951-439977 H H3C 3 C O F N F F

[0191] 300 mg (0.80 yl)pyridin-2-yl]carbonyl}amino)-1H- were initially charged in 4.5 ml of DMF.287 mg (1.21 mmol) of 1,1,1-trifluoro-4-iodobutane and 333 mg of potassium carbonate were added and the mixture was stirred at 100°C for 23 h. Water was added, and the mixture was extracted three times with ethyl acetate. The mixture was concentrated and the product was purified by preparative HPLC. This gave 72 mg of the title compound. UPLC-MS (Method A1): Rt = 1.26 min (UV detector: TIC), mass found 464.17. Intermediate 4-8 Methyl 5-{[(5-fluoro-6-methylpyridin-2-yl)carbonyl]amino}-2-(3-hydroxy-3- methylbutyl)-2H-indazole-6-carboxylate F 3

[0192] 195 mg (0.46methylbutyl)-2H-indazole-6- carboxylate (Intermediate 7-1) were reacted with 78 mg (0.50 mmol) of 5-fluoro-6- methylpyridine-2-carboxylic acid analogous to Intermediate 4-4 (Preparation Method 2) within 19.5 h.228 mg of a crude product were obtained after analogous aqueous workup. UPLC-MS (Method A1): Rt= 1.20 min (UV detector: TIC), mass found 414.00. Intermediate 4-9 Methyl 2-(3-hydroxy-3-methylbutyl)-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H- indazole-6-carboxylateInternational Patent Application Attorney Docket No.2920951-439977 O 3

[0193] 195 mg (0.45 -2H-indazole-6-carboxylate (Intermediate 7-1) were reacted with 70 mg (0.50 mmol) of 6-methylpyridine-2- carboxylic acid analogously to preparation of Intermediate 4-4 (Preparation Method 2) within 19.5 h.278 mg of the title compound as crude product were obtained after analogous aqueous workup. UPLC-MS (Method A1): Rt= 1.14 min (UV detector: TIC), mass found 396.00. Intermediate 4-10 Methyl 2-[3-(2,2,2-trifluoroethoxy)propyl]-5-({[6-(trifluoromethyl)pyridin-2- yl]carbonyl}amino)-2H-indazole-6-carboxylate F F F F

[0194] A mixture of 250 mg (0.58 mmol) of methyl 5-({[6-(trifluoromethyl)pyridin-2- yl]carbonyl}amino)-1H-indazole-6-carboxylate (Intermediate 3-1), 193 mg (0.88 mmol) of 3- bromopropyl 2,2,2-trifluoroethyl ether, 242 mg of potassium carbonate and 145 mg of potassium iodide in 3 ml of DMF was stirred at 100°C for 20 h. Water was added, the mixture was extracted with ethyl acetate and the extract was washed with sodium chloride solution and concentrated. Purification by preparative HPLC gave 52 mg of the title compound. UPLC-MS (Method A1): Rt= 1.39 min (UV detector: TIC), mass found 504.12. Intermediate 4-11 Methyl 5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-2-(3-hydroxy-3- methylbutyl)-2H-indazole-6-carboxylateInternational Patent Application Attorney Docket No.2920951-439977

[0195] 2.00 g of methyl 5- -2H-indazole-6-carboxylate(Intermediate 7-1) were initially charged in 40 ml of THF.1.50 g of 6- (difluoromethyl)pyridine-2-carboxylic acid, 2.78 g of O-(benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU, CAS Number 125700-67-6) and 1.5 ml of N- ethyl-N-isopropylpropan-2-amine were added and the mixture was stirred at RT for 24 h. Water was added, the mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with sodium chloride solution and filtered through a hydrophobic filter. The mixture was concentrated and the residue was purified by column chromatography on silica gel (hexane / ethyl acetate). This gave 3.05 g of the title compound as a yellow solid. UPLC-MS (Method A1): Rt = 1.15 min (UV detector TIC), mass found 432.00.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.17 (s, 6H), 2.04 - 2.11 (m, 2H), 3.99 (s, 3H), 4.52 - 4.60 (m, 3H), 7.10 (t, 1H), 8.00 (dd, 1H), 8.28 - 8.38 (m, 2H), 8.44 – 8.47 (m, 1H), 8.56 (d, 1H), 9.05 (s, 1H), 12.49 (s, 1H). Intermediate 5-1 N-[6-(2-Hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2- carboxamide F N

[0196] To a solution, cooled in1.50 g (4.12 mmol) of methyl 5- ({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (Intermediate 3-1) in 20 ml of THF were cautiously added 6.9 ml (5 equivalents) of a 3M methylmagnesium bromide solution in diethyl ether. The mixture was stirred while cooling with an ice bath for 1 h and at room temperature for 19.5 h. Another 2 equivalents of methylmagnesium bromide solution were added and the mixture was stirred at roomInternational Patent Application Attorney Docket No.2920951-439977 temperature for a further 24 h. Saturated aqueous ammonium chloride solution was added and the mixture was stirred and extracted three times with ethyl acetate. The combined organic phases were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate).763 mg of the title compound were obtained.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.63 (s, 6H), 5.99 (s, 1H), 7.49 (s, 1H), 8.06 (s, 1H), 8.14 - 8.19 (m, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.32 (s, 1H), 12.97 (s, 1H). Intermediate 5-2 6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]pyridine-2- carboxamide F O N

[0197] Analogously to the2.40 g (6.93 mmol) of methyl 5- ({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (Intermediate 3-2) in 10 ml of THF were reacted with three portions of 3M methylmagnesium bromide solution in diethyl ether (6.9 ml, then stirring at room temperature for 45 min; 11.6 ml, then stirring at room temperature for 2 h; 6.9 ml, then stirring at room temperature for 2 h). After the workup as for Intermediate 5-1, 2.39 g of a crude product were obtained, which were used further without further purification. Intermediate 6-1 Methyl 2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-carboxylate O2N

[0198] 5.00 g (22.6 mmol) of methyl 5-nitro-1H-indazole-6-carboxylate (Intermediate 1-1) were initially charged in 40 ml of DMF.5.65 g (33.9 mmol) of 4-bromo-2-methylbutan-2-ol, 9.37 g (67.8 mmol) of potassium carbonate and 5.63 g (33.9 mmol) of potassium iodide were added and the mixture was stirred at 100°C for 20 h. Water was added, the mixture wasInternational Patent Application Attorney Docket No.2920951-439977 extracted three times with ethyl acetate and the extracts were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate). The solids obtained were stirred with diethyl ether, filtered off with suction, washed with diethyl ether and dried.2.49 g of the title compound were obtained. UPLC-MS (Method A1): Rt= 0.93 min (UV detector: TIC), mass found 307.00.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.15 (s, 6H), 2.02 - 2.11 (m, 2H), 3.84 (s, 3H), 4.54 (s, 1H), 4.58 - 4.65 (m, 2H), 8.05 (s, 1H), 8.69 (s, 1H), 8.86 (s, 1H). Intermediate 7-1 Methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate H2N N OHof ammonium chloride were added to 2.49 g (8.10 mmol) of methyl 2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-carboxylate (Intermediate 6-1) in 30 ml of ethanol and 10 ml of water, and the mixture was stirred at 90°C for 21.5 h. The mixture was filtered through Celite and washed through with ethanol three times, and the filtrate was concentrated and the residue was admixed with water. Extraction was effected three times with ethyl acetate (to improve the phase separation, sodium chloride solution was added). The combined organic phases were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. This gave 1.95 g (85% of theory) of the title compound. UPLC-MS (Method A1): Rt= 0.67 min (UV detector: TIC), mass found 277.00.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.14 (s, 6H), 1.96 - 2.08 (m, 2H), 3.85 (s, 3H), 4.39 - 4.51 (m, 3H), 5.81 (s, 2H), 6.80 (s, 1H), 8.05 (s, 1H), 8.18 (s, 1H).

[0200] Treating Osteoarthritis

[0201] The IRAK4 inhibitors described herein, including but not limited to Compound 1, can be used in methods of treating and preventing osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof. The compositions described herein comprising the IRAK4 inhibitors described herein, including but not limited to Compound 1, can be used to treat osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof. The compositionsInternational Patent Application Attorney Docket No.2920951-439977 described herein comprising the IRAK4 inhibitors described herein, including but not limited to Compound 1, can be used to treat osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof. The compositions described herein comprising the IRAK4 inhibitors described herein, including but not limited to Compound 1, can be used to treat osteoarthritis.

[0202] Compound 1 can be used in methods of treating and preventing pain and inflammation, for example, associated with osteoarthritis. The compositions described herein comprising Compound 1 can be used to treat pain, optionally pain associated with osteoarthritis. The compositions described herein comprising Compound 1 can be used to treat inflammation, optionally inflammation associated with osteoarthritis. The compositions described herein comprising Compound 1 can be used to treat osteoarthritis.

[0203] Treating Acute Pain

[0204] As the synovitis model induces acute pain, compounds effective in this model are effective in perioperative pain.

[0205] The IRAK4 inhibitors described herein, optionally Compound 1, can be used in methods for the treatment and / or prevention of pain, optionally perioperative pain, postoperative pain, or a combination thereof.

[0206] Compound 1 can be used in methods of treat and preventing pain and inflammation, for example associated with perioperative and postoperative pain management.

[0207] Compositions

[0208] The compositions described herein can comprise an effective amount of an IRAK4 inhibitor described herein, optionally Compound 1. For example, an effective amount of the IRAK4 inhibitor described herein, optionally Compound 1, can be between about 1 mg / kg and 25 mg / kg, about 3 mg / kg and 20 mg / kg, about 5 mg / kg and 15 mg / kg, about 8 mg / kg and 12 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 20 mg / kg. The effective amount of the IRAK4 inhibitor described herein, optionally Compound 1, can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 35 mg / kg.

[0209] The compositions described herein can comprise an effective amount of Compound 1. In one example, an effective amount of Compound 1 can be between about 1 mg / kg and 25 mg / kg, about 3 mg / kg and 20 mg / kg, about 5 mg / kg and 15 mg / kg, about 8 mg / kg and 12 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 20International Patent Application Attorney Docket No.2920951-439977 mg / kg. The effective amount of Compound 1 can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 35 mg / kg.

[0210] The composition described herein may be a pharmaceutical composition. The compositions described herein, including pharmaceutical compositions, can comprise an antibody or antigen-binding fragment described herein and an adjuvant, carrier, buffers, antioxidants, wetting agents, lubricating agents, gelling agents, thickening agents, binding agents, disintegrating agents, humectants, preservatives, diluent, stabilizer, filler, excipient, or a combination thereof.

[0211] Pharmaceutical excipients and additives useful in the compositions described herein can also include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, terra-, and oligosaccharides; derivatized sugars including but not limited to alditols, aldonic acids, esterified sugars, or combinations thereof; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination in ranges of 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin including but not limited to human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, or combinations thereof. Representative amino acid components, which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, or combinations thereof.

[0212] Carbohydrate excipients suitable for use in the compositions described herein include monosaccharides including but not limited to fructose, maltose, galactose, glucose, D- mannose, sorbose, or combinations thereof; disaccharides, including but not limited to lactose, sucrose, trehalose, cellobiose, or combinations thereof; polysaccharides, including but not limited to raffinose, melezitose, maltodextrins, dextrans, starches, or combinations thereof; and alditols, including but not limited to mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), myoinositol or combinations thereof.

[0213] The compositions described herein further can comprise but are not limited to pharmaceutically acceptable carriers including but not limited to coloring agents, emulsifying agents, suspending agents, ethanol, EDTA, citrate buffer, flavoring, and water.

[0214] Chelators including but not limited to EDTA and EGTA can optionally be added to the pharmaceutical compositions to reduce aggregation. These additives are particularly useful if a pump or plastic container is used to administer the pharmaceutical composition.International Patent Application Attorney Docket No.2920951-439977 The presence of pharmaceutically acceptable surfactant mitigates the propensity for the composition to aggregate.

[0215] The compositions described herein also can comprise the preservatives methylparaben (also known as 4-hydroxybenzoic acid methyl ester, methyl p-hydroxybenzoate; or METHYL CHEMOSEPT), ethylparaben (also known as 4-hydroxybenzoic acid ethyl ester; ethyl phydroxybenzoate; or ETHYL PARASEPT), propylparaben (also known as 4- hydroxybenzoic acid propyl ester; propyl p-hydroxybenzoate; NIPASOL; or PROPYL CHEMOSEPT) and / or butylparaben (also known as 4-hydroxybenzoic acid propyl ester; propyl p-hydroxybenzoate; or BUTYL CHEMOSEPT).

[0216] Emulsifiers that may be used in the compositions described herein include, but are not limited to ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0217] The pharmaceutical compositions comprising Compound 1 can also include a buffer or a pH adjusting agent. Typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts including but not limited to salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers.

[0218] Additionally, the pharmaceutical compositions described herein can include polymeric excipients / additives including but not limited to polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, including but not limited to hydroxypropyl- β-cyclodextrin), polyethylene glycols, flavoring agents, anti-microbial agents, sweeteners, antioxidants, anti-static agents, surfactants (e.g., polysorbates including but not limited to “Tween® 20” and “Tween® 80”), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA or EGTA). These and additional known pharmaceutical excipients and / or additives suitable for use in the present invention are known in the art.

[0219] Other excipients, e.g., isotonicity agents, buffers, antioxidants, preservative enhancers, can be optionally added to the diluent. An isotonicity agent including but not limited to glycerin, is commonly used at known concentrations. A physiologically tolerated buffer is preferably added to provide improved pH control. Suitable buffers include phosphate buffers, sodium phosphate and phosphate buffered saline (PBS).International Patent Application Attorney Docket No.2920951-439977

[0220] The IRAK4 inhibitors described herein, optionally Compound 1, can be solubilized or suspended in a preconcentrate (before dilutions with a diluent), added to the preconcentrate prior to dilution, added to the diluted preconcentrate, or added to a diluent prior to mixing with the preconcentrate. The IRAK4 inhibitors described herein, optionally Compound 1, can also be co-administered as part of an independent dosage form, for therapeutic effect. Optionally, the IRAK4 inhibitors described herein, optionally Compound 1, can be present in a first, solubilized amount, and a second, non-solubilized (suspended) amount.

[0221] Compound 1 can be solubilized or suspended in a preconcentrate (before dilutions with a diluent), added to the preconcentrate prior to dilution, added to the diluted preconcentrate, or added to a diluent prior to mixing with the preconcentrate. Compound 1 can also be co-administered as part of an independent dosage form, for therapeutic effect. Optionally, Compound 1 can be present in a first, solubilized amount, and a second, non- solubilized (suspended) amount.

[0222] The pharmaceutical compositions described herein can also include additional therapeutic agents including but not limited to, hydrophilic drugs, hydrophobic drugs, hydrophilic macromolecules, cytokines, peptidomimetics, peptides, proteins, sera, antibodies, vaccines, nucleosides, nucleotides, nucleoside analogs, genetic materials, or combinations thereof.

[0223] The additional therapeutic agent can be solubilized or suspended in a preconcentrate (before dilutions with a diluent), added to the preconcentrate prior to dilution, added to the diluted preconcentrate, or added to a diluent prior to mixing with the preconcentrate. The additional therapeutic agent can also be co-administered as part of an independent dosage form, for therapeutic effect. Optionally, the additional therapeutic agent(s) can be present in a first, solubilized amount, and a second, non-solubilized (suspended) amount. Such additional to a mammal, including but not limited to drugs, nutrients, and diagnostic agents.

[0224] For oral administration in the form of a tablet, optionally a chewable tablet, capsule, the IRAK4 inhibitors described herein, optionally Compound 1, can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier including but not limited to ethanol, glycerol, water or combinations thereof. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture. Suitable binders include, without limitation, starch; gelatin; natural sugars including but not limited to glucose or beta-lactose; corn sweeteners; natural and synthetic gums including but not limited to acacia, tragacanth, or sodium alginate,International Patent Application Attorney Docket No.2920951-439977 carboxymethylcellulose; polyethylene glycol; waxes or combinations thereof. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, or combinations thereof. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, or combinations thereof. Flavorants can be added to the tablets, optionally chewable tablets. Flavorants can include but are not limited meat flavors, optionally poultry, or fish flavours or a combination thereof.

[0225] For oral administration in the form of a tablet, optionally a chewable tablet, capsule, Compound 1 can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier including but not limited to ethanol, glycerol, water or combinations thereof. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture. Suitable binders include, without limitation, starch; gelatin; natural sugars including but not limited to glucose or beta-lactose; corn sweeteners; natural and synthetic gums including but not limited to acacia, tragacanth, or sodium alginate, carboxymethylcellulose; polyethylene glycol; waxes or combinations thereof. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, or combinations thereof. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, or combinations thereof. Flavorants can be added to the tablets, optionally chewable tablets. Flavorants can include but are not limited meat flavors, optionally poultry, or fish flavours or a combination thereof.

[0226] The pharmaceutical compositions described herein suitable for oral administration may be presented as discrete units including but not limited to capsules, dragées, cachets or tablets each containing a predetermined amount of the IRAK4 inhibitors described herein, optinally Compound 1; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion, and as a bolus.

[0227] The pharmaceutical compositions described herein suitable for oral administration may be presented as discrete units including but not limited to capsules, dragées, cachets or tablets each containing a predetermined amount of Compound 1; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion, and as a bolus.

[0228] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitableInternational Patent Application Attorney Docket No.2920951-439977 machine, the IRAK4 inhibitors described herein, optionally Compound 1, in a free-flowing form including but not limited to a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered IRAK4 inhibitors described herein, optionally Compound 1, moistened with an inert liquid diluent. The tablets may be optionally coated or scored and may be formulated so as to provide a slow or controlled release of the IRAK4 inhibitors described herein, optionally Compound 1.

[0229] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, Compound 1 in a free-flowing form including but not limited to a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered Compound 1 moistened with an inert liquid diluent. The tablets may be optionally coated or scored and may be formulated so as to provide a slow or controlled release of Compound 1. Dosages

[0230] The pharmaceutical compositions described herein can be administered to a subject in a manner known in the art. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0231] The IRAK4 inhibitors described herein, optionally Compound 1, can be present in any suitable amount within the pharmaceutical compositions described herein. Those of skill in the art can readily determine suitable concentrations of the IRAK4 inhibitors described herein, optionally Compound 1, to include in the pharmaceutical compositions depending on various factors including dosage and route of administration.

[0232] Compound 1 can be present in any suitable amount within the pharmaceutical compositions described herein. Those of skill in the art can readily determine suitable concentrations of Compound 1 to include in the pharmaceutical compositions depending on various factors including dosage and route of administration.

[0233] The compositions described herein may comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 mg / kg of the IRAK4 inhibitors described herein, optionally Compound 1.

[0234] The compositions described herein may comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 mg / kg of Compound 1.International Patent Application Attorney Docket No.2920951-439977

[0235] The pharmaceutical compositions may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. Doses maybe administered for one week, one month, or over the course of several months, 3, 6, 9 or 12 months, or intervals known in the art and determined to be clinically relevant. Doses may be continued throughout the life of the patient, or discontinues when clinical judgment warrants. The daily dosage of the formulations may be varied over a range from about 1-25 mg / kg per day, about 5-15 mg / kg per day, 2.5-17.5 mg / kg per day, or equivalent doses as determine by a practitioner, to achieve a serum concentration that is clinically relevant.

[0236] The compositions described herein can be administered by the following routes, including, but not limited to oral,

[0237] parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, iontophoretic means, transdermal means, or a combination of routes. A composition comprises Compound 1 can formulated for oral administration. EXAMPLES EXAMPLE 1 N-[6-(2-Hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide F(2-methoxyethyl)-5-({[6-(trifluoromethyl)pyridin-2- yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-2) were dissolved in 500 µl of THF and admixed with 887 µl (0.89 mmol) of a 1 M methylmagnesium bromide solution in THF. The reaction mixture was stirred at 25°C for 60 min. Subsequently, 1 ml of a saturated aqueous ammonium chloride solution was added cautiously and the mixture wasInternational Patent Application Attorney Docket No.2920951-439977 filtered. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, filtered through a hydrophobic filter and concentrated. The residue was dissolved in 3 ml of DMSO and purified by preparative HPLC. The product-containing fractions were freeze-dried.20 mg of the title compound were obtained. UPLC-MS (Method A1): Rt= 1.08 min MS (ESIpos): m / z = 423 (M+H)+1H NMR (300 MHz, DMSO-d6): δ [ppm] = 1.62 (s, 6 H), 3.22 (s, 3 H), 3.82 (t, 2 H), 4.55 (t, 2 H), 5.96 (s, 1 H), 7.57 (s, 1 H), 8.16 (d1 H), 8.29 - 8.42 (m, 2 H), 8.42 - 8.50 (m, 1 H), 8.71 1 H), 12.36 (s, 1 H) EXAMPLE 2 N-[6-(Hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide F Oaluminium hydride were suspended in 1 ml of THF and the mixture was cooled to 0°C.75 mg (0.17 mmol) of methyl 2-(2-methoxyethyl)-5-({[6- (trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-2) dissolved in 500 µl of THF were added dropwise and the mixture was stirred at 25°C for 60 min. The mixture was diluted with water and extracted twice with ethyl acetate, and the combined organic phases were washed with sodium chloride solution, filtered through a hydrophobic filter, concentrated and dried under reduced pressure. This gave 13 mg of the title compound. UPLC-MS (Method A2): Rt = 0.99 min MS (ESIpos): m / z = 394 (M+H)+1H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.23 (s, 3 H), 3.83 (t, 2 H), 4.56 (t, 2 H), 4.69 (d, 2 H), 5.77 (t, 1 H), 7.57 (s, 1 H), 8.19 (d, 1 H), 8.33 - 8.41 (m, 2 H), 8.43 - 8.47 (m, 1 H), 8.51 (s, 1 H), 11.20 (s, 1 H) EXAMPLE 3 N-[6-(2-Hydroxypropan-2-yl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamideInternational Patent Application Attorney Docket No.2920951-439977 F O N (3-methoxypropyl)-5-({[6-(trifluoromethyl)pyridin-2-- (Intermediate 4-3) were dissolved in 500 µl of THF and admixed with 859 µl (0.86 mmol) of a 1 M methylmagnesium bromide solution in THF. The reaction mixture was stirred at 25°C for 60 min. Subsequently, 1 ml of a saturated ammonium chloride solution was added cautiously and the mixture was filtered. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, filtered through a hydrophobic filter and concentrated. The residue was dissolved in 3 ml of DMSO and purified by preparative HPLC. The product-containing fractions were freeze-dried.25 mg of the title compound were obtained. UPLC-MS (Method A1): Rt= 1.13 min MS (ESIpos): m / z = 437 (M+H)+1H NMR (400 MHz, DMSO-d6): δ [ppm] = 1.62 (s, 6 H), 2.14 (quin, 2 H), 3.23 (s, 3 H), 3.26 - (m, 2 H), 4.44 (t, 2 H), 5.95 (s, 1 H), 7.58 (s, 1 H), 8.16 (d, 1 H), 8.31 - 8.40 (m, 2 H), - 8.48 (m, 1 H), 8.72 (s, 1 H), 12.36 (s, 1 H). EXAMPLE 4 N-[6-(Hydroxymethyl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide Fwere suspended in THF and the mixture was cooled to 0°C.75 mg (0.17 mmol) of methyl 2-(3-methoxypropyl)-5-({[6- (trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-3) in THF were added dropwise and the mixture was allowed to come to room temperature within 30 min. The mixture was diluted with water and filtered, the residue was washed with ethyl acetate and the filtrate was extracted with ethyl acetate. The combined ethyl acetateInternational Patent Application Attorney Docket No.2920951-439977 phases were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was purified by preparative HPLC.1H NMR (300 MHz, DMSO-d6): δ [ppm] = 2.14 (quin, 2 H), 3.23 (s, 3 H), 3.29 (t, 2 H), 4.45 (t, 2 H), 4.68 (d, 2 H), 5.77 (t, 1 H), 7.58 (s, 1 H), 8.18 (d, 1 H), 8.32 - 8.48 (m, 3 H), 8.51 (s, 1 H), 11.21 (s, 1 H). EXAMPLE 5 N-[2-(2-Hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide Stage A:

[0242] Preparation of N-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-(2-hydroxypropan-2- yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide F O

[0243] 100 mg (0.19 mmol) of methyl 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-({[6- (trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-5) were dissolved in 1 ml of THF and admixed with 669 µl (0.67 mmol) of a 1 M methylmagnesium bromide solution in THF. The reaction mixture was stirred at 25°C for 60 min. Another 287 µl (0.29 mmol) of a 1 M methylmagnesium bromide solution in THF were added and the mixture was stirred at 25°C for 3 h. Subsequently, 20 ml of a saturated ammonium chloride solution were added cautiously and the mixture was filtered. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, dried over magnesium sulphate, filtered, concentrated and dried under reduced pressure. This gave 50 mg of N-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-(2-hydroxypropan-2-yl)-2H- indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. UPLC-MS (Method A2): Rt= 1.51 min MS (ESIpos): m / z = 523(M+H)+1H NMR (300 MHz, DMSO-d6): δ [ppm] = -0.17 - -0.09 (m, 6 H), 0.78 (s, 9 H), 1.62 (s, 6 H), 4.04 (t, 2 H), 4.47 (t, 2 H), 5.98 (s, 1 H), 7.57 (s, 1 H), 8.16 (d, 1 H), 8.29 (s, 1 H), 8.37 (t, 1 H), 8.45 (d, 1 H), 8.73 (s, 1 H), 12.38 (s, 1 H).International Patent Application Attorney Docket No.2920951-439977 Stage B: F O {[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide were dissolved in 1.0 ml of THF and admixed with 144 µl (0.14 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted twice with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, filtered through a hydrophobic filter and concentrated. This gave 36 mg of N-[2-(2-hydroxyethyl)-6- (2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 5).1H-NMR (400MHz, DMSO-d6): d [ppm] = 1.62 (s, 6H), 3.86 (q, 2H), 4.43 (t, 2H), 4.95 (t, 1H), 5.94 (s, 1H), 7.57 (s, 1H), 8.16 (dd, 1H), 8.30 (s, 1H), 8.37 (t, 1H), 8.45 (d, 1H), 8.72 (s, 1H), 12.36 (s, 1H). UPLC-MS (Method A2): Rt= 0.97 min (UV detector: TIC), mass found 408.00. EXAMPLE 6 N-[6-(2-Hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide Stage A:

[0245] Preparation of N-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan- 2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide FInternational Patent Application Attorney Docket No.2920951-439977

[0246] 50 mg (0.09 mmol) of methyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-({[6- (trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-6) were dissolved in 500 µl of THF and admixed with 326 µl (0.33 mmol) of a 1 M methylmagnesium bromide solution in THF. The reaction mixture was stirred at 25°C for 60 min. Subsequently, 20 ml of a saturated ammonium chloride solution were added cautiously and the mixture was extracted twice with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter, concentrated and dried under reduced pressure. The residue was purified by preparative HPLC.40 mg of N-[2-(3-{[tert- butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide were obtained. UPLC-MS (Method A1): Rt = 1.58 min MS (ESIpos): m / z = 537(M+H)+1H NMR (300 MHz, DMSO-d6): δ [ppm] = 0.02 - 0.05 (m, 6 H), 0.84 - 0.91 (m, 9 H), 1.62 (s, 6 H), 2.02 - 2.18 (m, 2 H), 3.55 - 3.62 (m, 2 H), 4.45 (t, 2 H), 5.96 (s, 1 H), 7.57 (s, 1 H), 8.16 (d, 1 H), 8.31 (s, 1 H), 8.33 - 8.42 (m, 1 H), 8.45 (d, 1 H), 8.72 (s, 1 H), 12.37 (s, 1 H). Stage B: F[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2- hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide were dissolved in 500 µl of THF and admixed with 207 µl (0.21 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF. The reaction mixture was stirred at 25°C for 2 h. The mixture was diluted with water and extracted twice with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, filtered and concentrated. After purification by preparative HPLC, 10 mg of N-[6-(2-hydroxypropan-2- yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 6, contained secondary component) were obtained. UPLC-MS (Method A2): Rt= 1.00 min MS (ESIpos): m / z = 423 (M+H)+1H NMR selected signals (400 MHz, DMSO-d6): δ [ppm] = 1.61 (s), 2.00 - 2.12 (m), 3.38 (t,International Patent Application Attorney Docket No.2920951-439977 2 H), 4.44 (t, 2 H), 4.62 (br. s., 1 H), 5.93 (br. s., 1 H), 7.55 (s, 1 H), 8.13 (d, 1 H), 8.27 - 8.38 (m, 2 H), 8.43 (d, 1 H), 8.71 (s, 1 H), 12.30 (br. s., 1 H). EXAMPLE 7 N-[2-(2-Hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide Stage A:

[0248] N-[2-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]- 6-(trifluoromethyl)pyridine-2-carboxamide F

[0249] 100 mg (0.19 mmol) of methyl 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-({[6- (trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-5) were dissolved in 1 ml of THF and admixed with 191 µl (0.38 mmol) of a 2 M lithium borohydride solution. The mixture was left to stir at 25°C for 24 h.14 mg (0.38 mmol) of sodium borohydride and 500 µl of methanol were added, and the mixture was stirred at 25°C for 4 h. Another 14 mg (0.38 mmol) of sodium borohydride were added, and the mixture was stirred at 25°C for 24 h. Water was added cautiously to the reaction mixture and the organic phase was removed. The mixture was then extracted twice with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was taken up in 2 ml of DMSO and purified by preparative HPLC. This gave 30 mg of N-[2-(2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide. UPLC-MS (Method A2): Rt = 1.44 min MS (ESIpos): m / z = 495(M+H)+1H NMR (300 MHz, DMSO-d6): δ [ppm] = -0.16 - -0.12 (m, 6 H), 0.75 - 0.79 (m, 9 H), 4.05 (t, 2 H), 4.48 (t, 2 H), 4.69 (d, 2 H), 5.75 - 5.77 (m, 1 H), 7.57 (s, 1 H), 8.18 (dd, 1 H), 8.30 -International Patent Application Attorney Docket No.2920951-439977 8.33 (m, 1 H), 8.38 (t, 1 H), 8.45 (d, 1 H), 8.51 (s, 1 H), 11.20 (s, 1 H). Stage B: F O

[0250] 33 mg (0.07 mmol) of N-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6- (hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide were dissolved in 1 ml of THF and admixed with 100 µl (0.10 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF. The reaction mixture was stirred at 25°C for 1 h. The mixture was diluted with water and extracted twice with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, filtered through a hydrophobic filter, concentrated and dried under reduced pressure.25 mg of N-[2-(2- hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2- carboxamide (Example 7) were obtained. UPLC-MS (Method A2): Rt= 0.87 min MS (ESIpos): m / z = 381 (M+H)+1H NMR (300 MHz, DMSO-d6): δ [ppm] = 3.87 (q, 2 H), 4.44 (t, 2 H), 4.69 (d, 2 H), 4.98 (t, - - - -International Patent Application Attorney Docket No.2920951-439977

[0251] 50 mg (0.12 mmol) of methyl 2-(oxetan-3-ylmethyl)-5-({[6-(trifluoromethyl)pyridin- 2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-1) were dissolved in 500 µl of THF and admixed with 576 µl (0.58 mmol) of a 1 M methylmagnesium bromide solution in THF.

[0252] The reaction mixture was stirred at 25°C for 60 min. Subsequently, 20 ml of a saturated aqueous ammonium chloride solution were added cautiously and the mixture was concentrated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, dried over magnesium sulphate, filtered and concentrated. The residue was dissolved in 2.0 ml of DMSO and purified by preparative HPLC. The product- containing fractions were freeze-dried.30 mg of the title compound were obtained. UPLC-MS (Method A2): Rt = 1.03 min MS (ESIpos): m / z = 435 (M+H)+1H NMR (400 MHz, DMSO-d6): δ [ppm] = 1.62 (s, 6 H), 3.45 - 3.61 (m, 1 H), 4.48 (t, 2 H), 4.66 (dd, 2 H), 4.72 (d, 2 H), 5.94 (s, 1 H), 7.57 (s, 1 H), 8.16 (d, 1 H), 8.33 - 8.42 (m, 2 H), 8.42 - 8.47 (m, 1 H), 8.72 (s, 1 H), 12.36 (s, 1 H). EXAMPLE 9 N-[6-(Hydroxymethyl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide F O

[0253] 75 mg (0.17 mmol) of methyl 2-(oxetan-3-ylmethyl)-5-({[6-(trifluoromethyl)pyridin- 2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-1) were dissolved in 1 ml of a mixture of THF / methanol (1:1), and 8 mg (0.21 mmol) of sodium borohydride were added. The mixture was left to stir at 25°C for 60 min. The reaction mixture was concentrated, and the residue was admixed with water. The suspension was stirred vigorously for 15 min, and the solids were filtered off with suction, washed twice with water and twice with diethyl ether, and dried under reduced pressure.48 mg of the title compound were obtained. UPLC-MS (Method A2): Rt= 0.94 min MS (ESIpos): m / z = 407 (M+H)+International Patent Application Attorney Docket No.2920951-4399771H NMR (300 MHz, DMSO-d6): δ [ppm] = 3.55 (s, 1 H), 4.48 (t, 2 H), 4.61 - 4.77 (m, 6 H), 7.57 (s, 1 H), 8.18 (dd, 1 H), 8.33 - 8.49 (m, 3 H), 8.51 (s, 1 H), 11.21 (s, 1 H). EXAMPLE 10 N-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-2H-indazol-5-yl}-6- (trifluoromethyl)pyridine-2-carboxamide F O O

[0254] A mixture of 500 mg (1.32 mmol) of N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]- 6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1), 569 mg of potassium carbonate and 114 mg of potassium iodide in 5.0 ml of DMF was stirred at room temperature for 15 min.414 mg of 1-bromo-3-(methylsulphonyl)propane were added and the mixture was stirred at room temperature overnight. Water was added, the mixture was twice extracted with ethyl acetate and the extracts were washed with sodium chloride solution and concentrated. The residue was purified by column chromatography (dichloromethane / methanol gradient). The product fraction was stirred with diethyl ether, filtered and dried.59 mg of the title compound were obtained. UPLC-MS (Method A2): Rt = 1.02 min MS (ESIpos): m / z = 485 (M+H)+1H-NMR (300MHz, DMSO-d6): δ [ppm]= 1.63 (s, 6H), 2.26 - 2.42 (m, 2H), 2.99 (s, 3H), 3.06 - 3.16 (m, 2H), 4.55 (t, 2H), 5.96 (s, 1H), 7.60 (s, 1H), 8.16 (d, 1H), 8.33 - 8.48 (m, 3H), 8.73 (s, 1H), 12.37 (s, 1H). EXAMPLE 11 N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide F 3International Patent Application Attorney Docket No.2920951-439977

[0255] Preparation Method 1

[0256] 705 mg (1.57 mmol) of methyl 2-(3-hydroxy-3-methylbutyl)-5-({[6- (trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-4) were initially charged in 10 ml of THF and cooled in an ice-water cooling bath.2.6 ml (5.0 equivalents) of 3M methylmagnesium bromide solution (in diethyl ether) were added and the mixture was left to stir while cooling with an ice bath for 1 h and at room temperature for 4.5 h. Another 1 equivalent of the methylmagnesium bromide solution was added and the mixture was left to stir at room temperature for 20.5 h. Another 1 equivalent again of the methylmagnesium bromide solution was added and the mixture was left to stir at room temperature for 22 h. The reaction mixture was admixed with saturated aqueous ammonium chloride solution, stirred and extracted three times with ethyl acetate. The combined organic phases were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. This gave 790 mg of a residue which was purified by means of preparative HPLC. This gave 234 mg of the title compound and 164 mg of a product fraction which was stirred with diethyl ether. After filtration with suction followed by drying, a further 146 mg of the title compound were obtained. UPLC-MS (Method A1): Rt= 1.10 min (UV detector: TIC), mass found 450.00.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.14 (s, 6H), 1.61 (s, 6H), 1.99 - 2.08 (m, 2H), 4.42 - 4.55 (m, 3H), 5.93 (s, 1H), 7.56 (s, 1H), 8.15 (dd, 1H), 8.32 - 8.39 (m, 2H), 8.41 - 8.47 (m, 1H), 8.70 (s, 1H), 12.34 (s, 1H).

[0257] Preparation Method 2

[0258] A mixture of 500 mg (1.37 mmol) of N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]- 6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1), 569 mg of potassium carbonate and 114 mg of potassium iodide in 5 ml of DMF was stirred at room temperature for 15 min.344 mg (1.5 equivalents) of 4-bromo-2-methylbutan-2-ol were added and the mixture was heated to 100°C for 2 h. Another 0.5 equivalent of 4-bromo-2-methylbutan-2-ol was added and the mixture was stirred at room temperature for 16 h. The mixture was admixed with water and extracted twice with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution and filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography purification on silica gel (hexane / ethyl acetate). This gave 100 mg of a product fraction which was stirredInternational Patent Application Attorney Docket No.2920951-439977 with diethyl ether. The solid was filtered and dried.60 mg of the title compound were obtained.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.14 (s, 6 H), 1.61 (s, 6H), 1.99 - 2.07 (m, 2 H), 4.43 - 4.52 (m, 3 H) 5.94 (s, 1 H) 7.57 (s, 1 H) 8.15 (dd, 1H) 8.33 - 8.40 (m, 2 H), 8.42 - 8.48 (m, 1 H), 8.71 (s, 1 H), 12.35 (s, 1 H) EXAMPLE 12 N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6- (trifluoromethyl)pyridine-2-carboxamide F O

[0259] 160 mg (0.44 mmol) of N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1) were suspended together with 182 mg of potassium carbonate and 36 mg of potassium iodide in 1.0 ml of DMF, and the mixture was stirred at room temperature for 15 min. Then 123 mg of 2-bromoethyl methyl sulphone (0.66 mmol) were added and the mixture was stirred at room temperature overnight. Water was added, the mixture was extracted twice with ethyl acetate and the extracts were washed with saturated aqueous sodium chloride solution, filtered through a hydrophobic filter and concentrated. Purification of the residue by preparative HPLC gave 20 mg of the title compound. UPLC (Method A2): Rt = 1.01 min; MS (ESIpos): m / z = 471 (M+H)+1H NMR (400 MHz, DMSO-d6): δ [ppm]= 1.63 (s, 6 H), 2.90 (s, 3 H), 3.85 (t, 2 H), 4.86 (t, 2 H), 5.97 (s, 1 H), 7.59 (s, 1 H), 8.13 - 8.19 (m, 1 H), 8.37 (s, 1 H), 8.41 - 8.48 (m, 2 H), 8.74 (s, 1 H), 12.37 (s, 1 H). EXAMPLE 13 6-(Difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H- indazol-5-yl]pyridine-2-carboxamideInternational Patent Application Attorney Docket No.2920951-439977 F O N

[0260] Preparation

[0261] A mixture of 250 mg of 6-(difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-1H-indazol- 5-yl]pyridine-2-carboxamide (crude product of Intermediate 5-2), 144 mg of potassium iodide and 239 mg of potassium carbonate in 2.5 ml of DMF was stirred at room temperature for 15 min.145 mg (0.87 mmol) of 4-bromo-2-methylbutan-2-ol were added, the mixture was stirred at 110°C for 3 h, another 96 mg of 4-bromo-2-methylbutan-2-ol were added and the mixture was stirred at 110°C for 4 h. Water was added, the mixture was extracted twice with ethyl acetate and the extract was washed with semisaturated aqueous sodium chloride solution, filtered through a hydrophobic filter and concentrated. Purification was effected by column chromatography on silica gel (hexane / ethyl acetate).61 mg of the title compound were obtained. UPLC-MS (Method A1): Rt = 1.00 min (UV detector: TIC), mass found 432.00.1H-NMR (300MHz, DMSO-d6): δ [ppm]= 1.14 (s, 6H), 1.63 (s, 6H), 1.97 - 2.08 (m, 2H), 4.41 - 4.55 (m, 3H), 5.99 (s, 1H), 7.03 (t, 1H), 7.56 (s, 1H), 7.94 – 8.00 (m, 1H), 8.24 - 8.38 (m, 3H), 8.71 (s, 1H), 12.49 (s, 1H). Preparation Method 2

[0262] Analogously to the preparation of Example 11 (Preparation Method 1), 3.00 g of methyl 5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-2-(3-hydroxy-3-methylbutyl)- 2H-indazole-6-carboxylate (Intermediate 4-11) were reacted with 3M methylmagnesium bromide solution (in diethyl ether). After purification of the crude product by stirring with diethyl ether, filtering followed by preparative HPLC, 1.37 g of the title compound were obtained. EXAMPLE 14 6-(Difluoromethyl)-N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H- indazol-5-yl}pyridine-2-carboxamideInternational Patent Application Attorney Docket No.2920951-439977 F O N

[0263] A mixture of 250 mg - 2-yl)-1H-indazol- 5-yl]pyridine-2-carboxamide (crude product of Intermediate 5-2), 144 mg of potassium iodide and 239 mg of potassium carbonate in 2.5 ml of DMF was stirred at room temperature for 15 min.162 mg of 2-bromoethyl methyl sulphone (0.87 mmol) were added and the mixture was stirred at 110°C for 3 h. Water was added, the mixture was extracted twice with ethyl acetate and the extract was washed with semisaturated aqueous sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was purified by preparative HPLC and the product fractions were additionally purified by column chromatography purification on silica gel (hexane / ethyl acetate).40 mg of the title compound were obtained.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.65 (s, 6H), 2.90 (s, 3H), 3.85 (t, 2H), 4.85 (t, 2H), 6.03 (s, 1H), 7.04 (t, 1H), 7.59 (s, 1H), 7.98 (d, 1H), 8.25 - 8.36 (m, 2H), 8.43 (s, 1H), 8.75 (s, 1H), 12.52 (s, 1H). EXAMPLE 15 6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5- yl]pyridine-2-carboxamide

[0264] Stage A:

[0265] Preparation of N-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan- 2-yl)-2H-indazol-5-yl]-6-(difluoromethyl)pyridine-2-carboxamideInternational Patent Application Attorney Docket No.2920951-439977

[0266] A mixture of 250 mg of 6-(difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-1H-indazol- 5-yl]pyridine-2-carboxamide (Intermediate 5-2), 48 mg of potassium iodide and 239 mg of potassium carbonate in 2.5 ml of DMF was stirred at room temperature for 15 min.219 mg (0.87 mmol, 1.5 equivalents) of (3-bromopropoxy)(tert-butyl)dimethylsilane were added and the mixture was stirred at 110°C for 3 h. Another 1 equivalent of (3-bromopropoxy)(tert- butyl)dimethylsilane was added and the mixture was stirred at 100°C for 4 h. Water was added, the mixture was extracted with ethyl acetate and the extract was washed with aqueous sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate).92 mg of the title compound were obtained.

[0267] Stage B:

[0268] Analogously tomg of N-[2-(3-{[tert- butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6- (difluoromethyl)pyridine-2-carboxamide were reacted with 0.53 ml of a 1 M solution of tetrabutylammonium fluoride in THF within 1 h. Aqueous workup as in Example 6 and purification by preparative HPLC gave 46 mg of the title compound. UPLC-MS (Method A1): Rt = 0.92 min (UV detector: TIC), mass found 404.00.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.64 (s, 6H), 2.05 (quin, 2H), 3.35 - 3.46 (m, 2H), 4.45 (t, 2H), 4.64 (t, 1H), 5.99 (s, 1H), 7.04 (t, 1H), 7.57 (s, 1H), 7.95 – 7.99 (m, 1H), 8.25 - 8.36 (m, 3H), 8.73 (s, 1H), 12.50 (s, 1H). EXAMPLE 16 N-[6-(2-Hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamideInternational Patent Application Attorney Docket No.2920951-439977 F O F F F

[0269] A mixture of 2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1) in 3 ml of DMF was admixed with 0.11 ml (0.87 mmol) of 1,1,1-trifluoro-4-iodobutane and 239 mg of potassium carbonate, and the mixture was stirred at 80°C for 6 h. After addition of water, the mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, filtered through a hydrophobic filter and concentrated. The crude product was purified by preparative HPLC.19 mg of the title compound were obtained. UPLC-MS (Method A1): Rt= 1.27 min (UV detector: TIC), mass found 474.15.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.62 (s, 6H), 2.10 - 2.33 (m), 4.49 (t, 2H), 5.94 (s, 1H), 7.59 (s, 1H), 8.13 - 8.18 (m, 1H), 8.32 - 8.41 (m, 2H), 8.41 - 8.47 (m, 1H), 8.72 (s, 1H), 12.35 (s, 1H). EXAMPLE 17 N-{6-(2-Hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]-2H-indazol-5-yl}-6- (trifluoromethyl)pyridine-2-carboxamide F F F

[0270] 150 mg (0.33indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1) were initially charged in 2 ml of THF.58 mg (0.40 mmol) of 3-(trifluoromethoxy)propan-1-ol, 131 mg of triphenylphosphine and 71 µl of diisopropyl azodicarboxylate (DIAD, CAS 2446-83-5) were added and the mixture was stirred at room temperature for 19 h.0.83 ml of sodium hydroxide solution (2M) was added and the mixture was stirred at 40°C for 5 h. The mixture was diluted with water and extracted three times with ethyl acetate, and the combined organic phases wereInternational Patent Application Attorney Docket No.2920951-439977 concentrated and purified by preparative HPLC.16 mg of the title compound were obtained as a crude product. UPLC-MS (Method A2): Rt = 1.26 min (UV detector: TIC), mass found 490.14.1H-NMR (400MHz, DMSO-d6, selected signals): δ [ppm]= 1.61 (s, 6H), 1.84 (d, 1H), 2.32 (quint., 2H), 4.08 (t, 2H), 4.51 (t, 2H), 7.58 (s, 1H), 8.15 (d, 1H), 8.31 – 8.39 (m, 2H), 8.44 (d, 1H), 8.72 (s, 1H), 12.35 (s, 1H). EXAMPLE 18 N-{6-(2-Hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]-2H-indazol-5-yl}-6- (trifluoromethyl)pyridine-2-carboxamide F F O F F

[0271] Analogously toMethod 1), 52 mg (0.10 mmol) of methyl 2-[3-(2,2,2-trifluoroethoxy)propyl]-5-({[6-(trifluoromethyl)pyridin-2- yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-10) in 3 ml of THF were reacted with 2 × 171 µl of 3M magnesium bromide solution in diethyl ether. Purification by preparative HPLC gave 12 mg of the title compound. UPLC-MS (Method A1): Rt = 1.25 min (UV detector: TIC), mass found 504.16.1H-NMR (500 MHz, DMSO-d6): δ [ppm] = 1.63 (s, 6H), 2.20(quin, 2H), 3.58(t, 2H),4.05(q, 2H), 4.47(t, 2H),5.94(s, 1H), 7.58 (s, 1H), 8.15 (dd, 1H), 8.32 (s, 1H), 8.36 (t, 1H), 8.45(d, 1H), 8.73 (s, 1H), 12.36 (s,1H). EXAMPLE 19 5-Fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6- methylpyridine-2-carboxamide F

[0272] 228 mg (0.312-yl)carbonyl]amino}- 2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate (Intermediate 4-8) were initially charged in 4.5 ml of THF and cooled with an ice cooling bath.0.63 ml of 3M methylmagnesium bromide solution (in diethyl ether) was added and the mixture was left to stir while cooling with an ice bath for 2 h and at room temperature for 21 h. The reactionInternational Patent Application Attorney Docket No.2920951-439977 mixture was admixed with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were concentrated. The residue was purified by preparative HPLC.82 mg of the title compound were obtained. UPLC-MS (Method A2): Rt= 1.03 min (UV detector: TIC), mass found 414.21.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.13 (s, 6H), 1.63 (s, 6H), 1.99 - 2.05 (m, 2H), 2.55 - 2.59 (m, 3H), 4.42 - 4.50 (m, 3H), 5.95 (s, 1H), 7.54 (s, 1H), 7.83 (t, 1H), 8.05 (dd, 1H), 8.31 (s, 1H), 8.68 (s, 1H), 12.33 (s, 1H). EXAMPLE 20 N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6- methylpyridine-2-carboxamide O

[0273] 278 mg (0.48 mmol) of methyl 2-(3-hydroxy-3-methylbutyl)-5-{[(6-methylpyridin-2- yl)carbonyl]amino}-2H-indazole-6-carboxylate (Intermediate 4-9) were initially charged in 5.0 ml of THF and cooled with an ice cooling bath.0.97 ml of 3M methylmagnesium bromide solution (in diethyl ether) was added and the mixture was left to stir while cooling with an ice bath for 2 h and at room temperature for 20.5 h. Another 0.48 ml of 3M methylmagnesium bromide solution was added and the mixture was left to stir at room temperature for 67 h. The mixture was admixed with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate, and the extracts were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was purified by preparative HPLC.111 mg of the title compound were obtained. UPLC-MS (Method A2): Rt= 0.97 min (UV detector: TIC), mass found 396.22.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.15 (s, 6H), 1.64 (s, 6H), 2.00 - 2.08 (m, 2H), 2.61 (s, 3H), 4.41 - 4.59 (m, 3H), 5.92 (s, 1H), 7.50 (dd, 1H), 7.56 (s, 1H), 7.90 - 7.99 (m, 2H), 8.33 (s, 1H), 8.70 (s, 1H), 12.39 (s, 1H). EXAMPLE 21 6-(2-Hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H- indazol-5-yl]pyridine-2-carboxamideInternational Patent Application Attorney Docket No.2920951-439977 H C H C O F N F F

[0274] A solution of 72 mg 2-yl)pyridin-2- yl]carbonyl}amino)-2-(4,4,4-trifluorobutyl)-2H-indazole-6-carboxylate (Intermediate 4-7) in 10 ml of THF was cooled in an ice / water cooling bath.0.26 ml of 3M methylmagnesium bromide solution in diethyl ether was added and the mixture was stirred for 2 h and then at room temperature for 20 h. Another 1 equivalent of the 3M methylmagnesium bromide solution was added and the mixture was stirred at room temperature for 24 h. Saturated aqueous ammonium chloride solution was added, the mixture was three times extracted with ethyl acetate and the extracts were washed with sodium chloride solution and concentrated. Preparative HPLC gave 22 mg (31% of theory) of the title compound. UPLC-MS (Method A2): Rt = 1.15 min (UV detector: TIC), mass found 464.20.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.56 (s, 6H), 1.64 (s, 6H), 2.07 - 2.34 (m, 4H), 4.49 (t, 2H), 5.32 (s, 1H), 6.05 (s, 1H), 7.60 (s, 1H), 7.87 (dd, 1H), 7.99 - 8.05 (m, 2H), 8.35 (s, 1H), 8.79 (s, 1H), 12.45 (s, 1H). EXAMPLE 22 N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6- (trifluoromethyl)pyridine-2-carboxamide

[0275] 250 mg (0.69indazol-5-yl]-6- (trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1) were initially charged in 5 ml of DMSO.159 mg (0.96 mmol) of 1-(2-bromoethyl)cyclopropanol, 285 mg of potassium carbonate and 171 mg of potassium iodide were added and the mixture was stirred at 100°C for 5 h. Water was added and the mixture was extracted three times with ethyl acetate. TheInternational Patent Application Attorney Docket No.2920951-439977 combined organic phases were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was purified by preparative HPLC (column: Waters XBridge C185µ 100x30mm, eluent A: water + 0.1% by volume of formic acid (99%), eluent B: acetonitrile). Freeze-drying gave 45 mg of the title compound.1H-NMR (500MHz, DMSO-d6): δ [ppm]= 0.18 - 0.22 (m, 2H), 0.48 - 0.52 (m, 2H), 1.62 (s, 6H), 2.08 (t, 2H), 4.54 - 4.60 (m, 2H), 5.36 (s, 1H), 5.96 (s, 1H), 7.57 (s, 1H), 8.16 (dd, 1H), 8.34 - 8.39 (m, 2H), 8.45 (d, 1H), 8.72 (s, 1H), 12.36 (s, 1H). EXAMPLE 23 TESTING COMPOUND 1 (FORMULA I) FORMULATIONS

[0276] Evaluation of efficacy of Compound 1 administered orally at two dose rates (5 mg / kg and 15 mg / kg) in an induced acute synovitis model in dogs.

[0277] Induced Acute Synovitis Model

[0278] In an induced acute synovitis model in dogs, sodium urate suspension is injected into a stifle joint of the dogs. This induces pain, inflammation, and loss of function for approximately 8–12 hours in most dogs.

[0279] Gait Analysis At each time point following the induction of synovitis using a single intra-articular injection of a uric acid crystal suspension, dogs were assessed with gait analysis.

[0280] Gait analysis was measured by trotting the animals at a constant speed over the pressure walkway five times per time point. The study was a blinded, placebo controlled, 3-phase cross-over design in 15 dogs.

[0281] Dogs were dosed once daily for five consecutive days with placebo (empty gelatin capsules), 15mg / kg Compound 1, or 5mg / kg Compound 1. Each treatment was administered to the 15 dogs over the study duration (5 dogs per treatment, per phase), with a minimum of 16 days washout between phases.

[0282] In each phase, pain and inflammation was induced in each dog at approximately one hour after treatment on the fifth treatment day Gait analysis was performed before each uric acid injection and 5, 6, 7, 8, 9, 10, and 12 hours post injection. Results

[0283] Surprisingly, Compound 1 treated dogs showed minimal to no pain and lameness following synovitis induction which is a magnitude of effect that we have not documented with any other class of drugs outside of NSAIDs. Compound 1 strongly relieved acute pain and improved lameness significantly better than placebo and showed better effectiveness inInternational Patent Application Attorney Docket No.2920951-439977 this setting as compared to historical data and published data for non-NSAID modes of action. As depicted in FIG.1 placebo treated dogs were minimally to completely non-weight bearing within 4 hours of synovitis induction, while Compound 1 treated dogs were completely normally weight-bearing or had very minimal lameness at both 5 mg / kg and 15mg / kg of treatment. Statistically significant (p<0.05) improvement in pain and inflammation was observed as improved weight-bearing lameness compared to the placebo through hour 8 in 15 mg / kg treated dogs and hour 10 in 5 mg / kg treated dogs.

[0284] Although the invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it should be understood that certain changes and modifications may be practiced within the scope of the appended claims. Modifications of the above-described modes for carrying out the invention that would be understood in view of the foregoing disclosure or made apparent with routine practice or implementation of the invention to persons of skill in veterinary medicine, pharmacokinetics, and / or related fields are intended to be within the scope of the following claims.

[0285] All publications (e.g., Non-Patent Literature), patents, patent application publications, and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All such publications (e.g., Non- Patent Literature), patents, patent application publications, and patent applications are herein incorporated by reference to the same extent as if each individual publication, patent, patent application publication, or patent application was specifically and individually indicated to be incorporated by reference.

[0286] While the foregoing invention has been described in connection with this preferred embodiment, it is not to be limited thereby but is to be limited solely by the scope of the claims which follow.

Claims

International Patent Application Attorney Docket No.2920951-439977 CLAIMS 1. A method for treating or preventing pain in a mammal comprising administering an effective amount of an IRAK4 inhibitor.

2. The method of claim 1, wherein the pain is associated with osteoarthritis.

3. A method for treating or preventing inflammation in a mammal comprising administering an effective amount of an IRAK4 inhibitor.

4. The method of claim 1, wherein the inflammation is associated with osteoarthritis.

5. A method of treating or preventing osteoarthritis in a mammal comprising administering a composition comprising an effective amount of an IRAK4 inhibitor, wherein the IRAK4 inhibitor is a compound of the general formula (I) R5(I) in which:R1is C1-C6-alkyl, where 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, R7SO2, R7SO or R8O group, or a group selected from: where *R2and R3always have the same definition and are both either hydrogen or C1-C6-alkyl; R4is 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 of halogen and hydroxyl; R5is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6- alkyl; R6is 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 SO2;International Patent Application Attorney Docket No.2920951-439977 R7is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C3-C6-cycloalkyl; or R7is C3-C6-cycloalkyl; R8is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof.

6. The method of claim 5, wherein R1is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R6, R7SO2, R7SO or R8O group; R2and R3always have the same definition and are both either hydrogen or C1-C3-alkyl; R4is halogen, cyano or C1-C3-alkyl, where the C1-C3-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl; R5is hydrogen, fluorine, chlorine or C1-C3-alkyl; R6is oxetanyl or tetrahydrofuranyl; R7is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms; R8is an unsubstituted C1-C4-alkyl group or a tri-fluorine-substituted C1-C4-alkyl group.

7. The method of claim 5 or 6, wherein R4is difluoromethyl, trifluoromethyl or methyl.

8. The method of any one of claims 5-7, wherein R5is hydrogen or fluorine.

9. The method of any one of claims 5-8, wherein R2and R3are both either hydrogen or methyl.

10. The method of claim 6, wherein R1is C2-C6-alkyl, where 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, R7SO2, or R8O, or R1is an oxetanyl-substituted C1-C3-alkyl group; R2and R3always have the same definition and are both either hydrogen or methyl; R4is 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; R5is hydrogen, fluorine or C1-C3-alkyl; R7is C1-C3-alkyl; R8is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or mono-, di- or tri-International Patent Application Attorney Docket No.2920951-439977 fluorine-substituted.

11. The method of claim 10, in which R1is a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or is a methyl-SO2-substituted C2-C4-alkyl group or is an oxetan-3-yl-substituted C1-C2-alkyl group; R2and R3always have the same definition and are both hydrogen or methyl; R4is methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl; R5is hydrogen, fluorine or methyl.

12. The method of claim 10, in which R1is 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; R2and R3are both methyl or hydrogen; R4is difluoromethyl, trifluoromethyl or methyl; R5is hydrogen or fluorine.

13. The method of claim 12, in which R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is difluoromethyl or trifluoromethyl; R5is hydrogen.

14. The method of claim 12, in which R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is methyl; R5is fluorine, where R5is in the ortho position to R4.

15. The method of any one of claims 1-14, wherein the IRAK4 inhibitor is: 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;International Patent Application Attorney Docket No.2920951-439977 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-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-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; N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-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-[2-(methylsulphonyl)ethyl]-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-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl]-6-methylpyridine-2-carboxamide;International Patent Application Attorney Docket No.2920951-439977 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; or N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}- 6-(trifluoromethyl)pyridine-2-carboxamide.

16. The method of claim 1 or 5, wherein the IRAK4 inhibitor is Compound 1: . 17.amount of an IRAK4 inhibitor treats pain associated with osteoarthritis.

18. The method of any one of claims 1-17, wherein the composition comprising an effective amount of an IRAK4 inhibitor treats inflammation associated with osteoarthritis.

19. The method of any one of claims 1-18, wherein the mammal is a dog, cat, horse, pig, cow, sheep, or goat.

20. The method of claim 19, wherein the mammal is a dog.

21. The method of any one of claims 1-20, wherein the effective amount is between about 1 and 25 mg / kg.

22. The method of any one of claims 1-21, wherein the effective amount is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg / kg.

23. The method of any one of claims 1-21, wherein the effective amount is about 5 mg / kg.

24. The method of any one of claims 1-21, wherein the effective amount is about 15 mg / kg.

25. The method of any one of claims 1-24, wherein the composition is administered 1, 2, 3, 4, or 5 times a day.

26. The method of any one of claims 1-24, wherein the composition is administered every other day.International Patent Application Attorney Docket No.2920951-439977 27. The method of any one of claims 1-26, wherein the composition is administered once a day.

28. The method of any one of claims 1-27, wherein the composition is a pharmaceutical composition comprising an effective amount of the IRAK4 inhibitor and a carrier.

29. The method of claim 28, wherein the carrier is an excipient, lubricant, antioxidant, emulsifier, stabilizer, solvent, diluent, buffer, vehicle, or a combination thereof.

30. The method of any one of claims 1-29, wherein the composition is in the form of a tablet, optionally a chewable tablet.

31. The method of any one of claims 1-30, wherein the composition is administered intravenously, intramuscularly, orally, buccally, or a combination thereof.

32. The method of any one of claims 1-31, wherein the composition is administered orally.

33. A method for treating pain in mammal comprising administering a composition comprising an effective amount of an IRAK4 inhibitor, wherein the IRAK4 inhibitor is a compound of the general formula (I) R5(I) in which:R1is C1-C6-alkyl, where 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, R7SO2, R7SO or R8O group, or a group selected from: where *R2and R3always have the same definition and are both either hydrogen or C1-C6-alkyl; R4is 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 of halogen and hydroxyl; R5is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6-International Patent Application Attorney Docket No.2920951-439977 alkyl; R6is 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 SO2; R7is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C3-C6-cycloalkyl; or R7is C3-C6-cycloalkyl; R8is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof.

34. The method of claim 33, wherein R1is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R6, R7SO2, R7SO or R8O group; R2and R3always have the same definition and are both either hydrogen or C1-C3-alkyl; R4is halogen, cyano or C1-C3-alkyl, where the C1-C3-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl; R5is hydrogen, fluorine, chlorine or C1-C3-alkyl; R6is oxetanyl or tetrahydrofuranyl; R7is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms; R8is an unsubstituted C1-C4-alkyl group or a tri-fluorine-substituted C1-C4-alkyl group.

35. The method of claim 33 or 34, wherein R4is difluoromethyl, trifluoromethyl or methyl.

36. The method of any one of claims 33-35, wherein R5is hydrogen or fluorine.

37. The method of any one of claims 33-36, wherein R2and R3are both either hydrogen or methyl.

38. The method of claim 34, wherein R1is C2-C6-alkyl, where 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, R7SO2, or R8O, or R1is an oxetanyl-substituted C1-C3-alkyl group; R2and R3always have the same definition and are both either hydrogen or methyl; R4is 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 substitutedInternational Patent Application Attorney Docket No.2920951-439977 by one hydroxyl group and three fluorine atoms; R5is hydrogen, fluorine or C1-C3-alkyl; R7is C1-C3-alkyl; R8is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or mono-, di- or tri- fluorine-substituted.

39. The method of claim 38, in which R1is a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or is a methyl-SO2-substituted C2-C4-alkyl group or is an oxetan-3-yl-substituted C1-C2-alkyl group; R2and R3always have the same definition and are both hydrogen or methyl; R4is methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl; R5is hydrogen, fluorine or methyl.

40. The method of claim 38, in which R1is 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; R2and R3are both methyl or hydrogen; R4is difluoromethyl, trifluoromethyl or methyl; R5is hydrogen or fluorine.

41. The method of claim 40, in which R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is difluoromethyl or trifluoromethyl; R5is hydrogen.

42. The method of claim 40, in which R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is methyl; R5is fluorine, where R5is in the ortho position to R4.

43. The method of any one of claims 33-42, wherein the IRAK4 inhibitor is:International Patent Application Attorney Docket No.2920951-439977 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-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-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; N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-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-[2-(methylsulphonyl)ethyl]-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;International Patent Application Attorney Docket No.2920951-439977 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-methylbutyl)-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; or N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}- 6-(trifluoromethyl)pyridine-2-carboxamide.

44. The method of claim 33, wherein the IRAK4 inhibitor is Compound 1 .

45. The46. The method of claim 4451, wherein the pain is perioperative 47. The method of claim 45 or 46, wherein the mammal is a dog, cat, horse, pig, cow, sheep, or goat.

48. The method of claim 47, wherein the mammal is a dog.

49. The method of claim 47, wherein the mammal is a cat.

50. The method of any one of claims 33-49, wherein the effective amount is between about 1 and 25 mg / kg of the IRAK4 inhibitor.

51. The method of any one of claims 33-50, wherein the effective amount is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg / kg of the IRAK4 inhibitor.

52. The method of any one of claims 33-51, wherein the effective amount is about 5 mg / kg of the IRAK4 inhibitor.International Patent Application Attorney Docket No.2920951-439977 53. The method of any one of claims 33-52, wherein the effective amount is about 15 mg / kg of the IRAK4 inhibitor.

54. The method of any one of claims 33-53, wherein the composition is administered 1, 2, 3, 4, or 5 times a day.

55. The method of any one of claims 33-54, wherein the composition is administered once a day.

56. The method of any one of claims 33-55, wherein the composition is administered every other day.

57. The method of any one of claims 33-56, wherein the composition is a pharmaceutical composition comprising an effective amount of the IRAK4 inhibitor and a carrier.

58. The method of claim 57, wherein the carrier is an excipient, lubricant, antioxidant, emulsifier, stabilizer, solvent, diluent, buffer, vehicle, or a combination thereof.

59. The method of any one of claims 33-58, wherein the composition is in the form of a tablet, optionally a chewable tablet.

60. The method of any one of claims 33-59, wherein the composition is administered intravenously, intramuscularly, orally, buccally, or a combination thereof.

61. The method of any one of claims 33-60, wherein the composition is administered orally.

62. A method for treating inflammation in a mammal comprising a composition comprising administering an effective amount of wherein the IRAK4 inhibitor is a compound of the general formula (I) R5(I) in which:R1is C1-C6-alkyl, where 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, R7SO2, R7SO or R8O group, or a group selected from: where *International Patent Application Attorney Docket No.2920951-439977 R2and R3always have the same definition and are both either hydrogen or C1-C6-alkyl; R4is 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 of halogen and hydroxyl; R5is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6- alkyl; R6is 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 SO2; R7is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C3-C6-cycloalkyl; or R7is C3-C6-cycloalkyl; R8is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the salts thereof.

63. The method of claim 62, wherein R1is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R6, R7SO2, R7SO or R8O group; R2and R3always have the same definition and are both either hydrogen or C1-C3-alkyl; R4is halogen, cyano or C1-C3-alkyl, where the C1-C3-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl; R5is hydrogen, fluorine, chlorine or C1-C3-alkyl; R6is oxetanyl or tetrahydrofuranyl; R7is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms; R8is an unsubstituted C1-C4-alkyl group or a tri-fluorine-substituted C1-C4-alkyl group.

64. The method of claim 62 or 63, wherein R4is difluoromethyl, trifluoromethyl or methyl.

65. The method of any one of claims 62-64, wherein R5is hydrogen or fluorine.

66. The method of any one of claims 62-65, wherein R2and R3are both either hydrogen orInternational Patent Application Attorney Docket No.2920951-439977 methyl.

67. The method of claim 63, wherein R1is C2-C6-alkyl, where 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, R7SO2, or R8O, or R1is an oxetanyl-substituted C1-C3-alkyl group; R2and R3always have the same definition and are both either hydrogen or methyl; R4is 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; R5is hydrogen, fluorine or C1-C3-alkyl; R7is C1-C3-alkyl; R8is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or mono-, di- or tri- fluorine-substituted.

68. The method of claim 67, in which R1is a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or is a methyl-SO2 -substituted C2-C4-alkyl group or is an oxetan-3-yl-substituted C1-C2-alkyl group; R2and R3always have the same definition and are both hydrogen or methyl; R4is methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl; R5is hydrogen, fluorine or methyl.

69. The method of claim 68, in which R1is 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; R2and R3are both methyl or hydrogen; R4is difluoromethyl, trifluoromethyl or methyl; R5is hydrogen or fluorine.

70. The method of claim 69, in which R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is difluoromethyl or trifluoromethyl;International Patent Application Attorney Docket No.2920951-439977 R5is hydrogen.

71. The method of claim 69, in which R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is methyl; R5is fluorine, where R5is in the ortho position to R4.

72. The method of any one of claims 62-71, wherein the IRAK4 inhibitor is: 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-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-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; N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-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;International Patent Application Attorney Docket No.2920951-439977 6-(Difluoromethyl)-N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-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-methylbutyl)-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; or N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}- 6-(trifluoromethyl)pyridine-2-carboxamide.

73. The method of claim 62, wherein the IRAK4 inhibitor is Compound 1 . 74.

75. The method of claim 62, wherein the inflammation is associated with degenerative joint disease (DJD).International Patent Application Attorney Docket No.2920951-439977 76. The method of claim 62, wherein the inflammation is associated with inflammatory bowel disease (IBD), diabetes mellitus, kidney disease, intervertebral disc disease, and allergic inflammation, or a combination thereof.

77. The method of claim 62, wherein the mammal is a dog, cat, horse, pig, cow, sheep, or goat.

78. The method of claim 77, wherein the mammal is a dog.

79. The method of claim 77, wherein the mammal is a cat.

80. The method of any one of claims 62-79, wherein the effective amount is between about 1 and 25 mg / kg of the IRAK4 inhibitor.

81. The method of any one of claims 62-80, wherein the effective amount is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg / kg of the IRAK4 inhibitor.

82. The method of any one of claims 62-81, wherein the effective amount is about 5 mg / kg of the IRAK4 inhibitor.

83. The method of any one of claims 62-81, wherein the effective amount is about 15 mg / kg of the IRAK4 inhibitor.

84. The method of any one of claims 62-81, wherein the composition is administered 1, 2, 3, 4, or 5 times a day.

85. The method of any one of claims 62-84, wherein the composition is administered once a day.

86. The method of any one of claims 62-84, wherein the composition is administered every other day.

87. The method of any one of claims 62-86, wherein the composition is a pharmaceutical composition comprising an effective amount of the IRAK4 inhibitor and a carrier.

88. The method of claim 87, wherein the carrier is an excipient, lubricant, antioxidant, emulsifier, stabilizer, solvent, diluent, buffer, vehicle, or a combination thereof.

89. The method of any one of claims 62-88, wherein the composition is in the form of a tablet, optionally a chewable tablet.

90. The method of any one of claims 62-89, wherein the composition is administered intravenously, intramuscularly, orally, buccally, or a combination thereof.

91. The method of any one of claims 62-90, wherein the composition is administered orally.

92. A method for treating or preventing degenerative joint disease (DJD) in a mammal comprising administering an effective amount of an IRAK4 inhibitor.International Patent Application Attorney Docket No.2920951-439977 93. A method for treating or preventing degenerative joint disease (DJD) in a mammal comprising a composition comprising administering an effective amount of an IRAK4 inhibitor, wherein the IRAK4 inhibitor is a compound of the general formula (I) R5(I) in which: 1R is C1-C6-alkyl, where the group or mono- or polysubstituted identically or differently by halogen, hydroxyl, an unsubstituted or mono- or poly-halogen-substituted C3-C6-cycloalkyl, or an R6, R7SO2, R7SO or R8O group, or a group selected from: where *R2and R3always have the same definition and are both either hydrogen or C1-C6-alkyl; R4is 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 of halogen and hydroxyl; R5is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C1-C6- alkyl; R6is 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 SO2; R7is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C3-C6-cycloalkyl; or R7is C3-C6-cycloalkyl; R8is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen; and the diastereomers, enantiomers, metabolites, salts, solvates or solvates of the saltsInternational Patent Application Attorney Docket No.2920951-439977 thereof.

94. The method of claim 93, wherein R1is C1-C6-alkyl, where the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl or an R6, R7SO2, R7SO or R8O group; R2and R3always have the same definition and are both either hydrogen or C1-C3-alkyl; R4is halogen, cyano or C1-C3-alkyl, where the C1-C3-alkyl group is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl; R5is hydrogen, fluorine, chlorine or C1-C3-alkyl; R6is oxetanyl or tetrahydrofuranyl; R7is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms; R8is an unsubstituted C1-C4-alkyl group or a tri-fluorine-substituted C1-C4-alkyl group.

95. The method of claim 93 or 94, wherein R4is difluoromethyl, trifluoromethyl or methyl.

96. The method of any one of claims 93-95, wherein R5is hydrogen or fluorine.

97. The method of any one of claims 93-96, wherein R2and R3are both either hydrogen or methyl.

98. The method of claim 94, wherein R1is C2-C6-alkyl, where 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, R7SO2, or R8O, or R1is an oxetanyl-substituted C1-C3-alkyl group; R2and R3always have the same definition and are both either hydrogen or methyl; R4is 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; R5is hydrogen, fluorine or C1-C3-alkyl; R7is C1-C3-alkyl; R8is C1-C4-alkyl, where the C1-C4-alkyl group is unsubstituted or mono-, di- or tri- fluorine-substituted.

99. The method of claim 97, in which R1is a C2-C5-alkyl group substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl or is a methyl-SO2-substituted C2-C4-alkyl group or is an oxetan-3-yl-substituted C1-C2-alkyl group; R2and R3always have the same definition and are both hydrogen or methyl;International Patent Application Attorney Docket No.2920951-439977 R4is methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl; R5is hydrogen, fluorine or methyl.

100. The method of claim 99, in which R1is 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; R2and R3are both methyl or hydrogen; R4is difluoromethyl, trifluoromethyl or methyl; R5is hydrogen or fluorine.

101. The method of claim 99, in which R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is difluoromethyl or trifluoromethyl; R5is hydrogen.

102. The method of claim 100, in which R1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 3-(methylsulphonyl)propyl or 2-(methylsulphonyl)ethyl; R2and R3are both methyl; R4is methyl; R5is fluorine, where R5is in the ortho position to R4.

103. The method of any one of claims 92-102, wherein the IRAK4 inhibitor is: 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;International Patent Application Attorney Docket No.2920951-439977 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-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-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; N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-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-[2-(methylsulphonyl)ethyl]-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-methylbutyl)-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; or N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}- 6-(trifluoromethyl)pyridine-2-carboxamide.International Patent Application Attorney Docket No.2920951-439977 104. The method of claim 93, wherein the IRAK4 inhibitor is Compound 1 . 105.pig, cow, sheep, or goat.

106. The method of claim 105, wherein the mammal is a dog.

107. The method of claim 105, wherein the mammal is a cat.

108. The method of any one of claims 92-107, wherein the effective amount is between about 1 and 25 mg / kg of the IRAK4 inhibitor.

109. The method of any one of claims 92-108, wherein the effective amount is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg / kg of the IRAK4 inhibitor.

110. The method of any one of claims 92-109, wherein the effective amount is about 5 mg / kg of the IRAK4 inhibitor.

111. The method of any one of claims 92-109, wherein the effective amount is about 15 mg / kg of the IRAK4 inhibitor.

112. The method of any one of claims 92-111, wherein the composition is administered 1, 2, 3, 4, or 5 times a day.

113. The method of any one of claims 92-112, wherein the composition is administered once a day.

114. The method of any one of claims 92-113, wherein the composition is administered every other day.

115. The method of any one of claims 92-114, wherein the composition is a pharmaceutical composition comprising an effective amount of the IRAK4 inhibitor and a carrier.

116. The method of claim 115, wherein the carrier is an excipient, lubricant, antioxidant, emulsifier, stabilizer, solvent, diluent, buffer, vehicle, or a combination thereof.International Patent Application Attorney Docket No.2920951-439977 117. The method of any one of claims 92-116, wherein the composition is in the form of a tablet, optionally a chewable tablet.

118. The method of any one of claims 92-117, wherein the composition is administered intravenously, intramuscularly, orally, buccally, or a combination thereof.

119. The method of any one of claims 92-118, wherein the composition is administered orally.

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