Methods and compositions for the control of pain and inflammation

Abstract

Compositions comprising IRAK4 inhibitors and methods of use for treating pain and pain-associated inflammation in mammals are provided.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED ART) This international patent application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 418,192, filed October 21, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Osteoarthritis (OA) is the most common form of arthritis in dogs, affecting approximately one-quarter of the population. Osteoarthritis is a chronic joint disease characterized by loss of articular cartilage, thickening of the joint capsule, and new bone formation around the joint (osteohyperplasia). Osteoarthritis symptoms include pain and limb dysfunction. Most cases of canine osteoarthritis occur secondary to developmental orthopedic conditions, such as cranial cruciate ligament disease, hip dysplasia, elbow dysplasia, osteochondritis dissecans (OCD), and patellar luxation. Osteoarthritis can occur without a clear primary cause and may be genetically and age-related. Other contributing factors to osteoarthritis include weight, obesity, sex, exercise, and diet. See the American College of Veterinary Surgeons website, "Osteoarthritis in Dogs" (2022).

[0003] Thus, there is a need for improved methods and compositions for the control and treatment of pain and inflammation in mammals (eg, dogs). Summary of the Invention

[0004] In one aspect, the IRAK4 inhibitors described herein may be used in methods for the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0005] In one aspect, the IRAK4 inhibitors described herein can be used in methods for the treatment and / or prevention of degenerative joint disease (DJD).

[0006] In one aspect, the IRAK4 inhibitors described herein may be formulated into a medicament 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.

[0007] In one aspect, the IRAK4 inhibitors described herein can be formulated into medicaments for use in the treatment and / or prevention of degenerative joint disease (DJD).

[0008] In one aspect, the IRAK4 inhibitors described herein may 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.

[0009] In one embodiment, the IRAK4 inhibitors described herein can be formulated into compositions for the treatment and / or prevention of degenerative joint disease (DJD).

[0010] In one embodiment, a method of treating or preventing pain in a mammal may comprise administering a composition comprising an effective amount of an IRAK4 inhibitor, the IRAK4 inhibitor being a compound of general formula (I):

[0011] [ka] (In the formula, R 1 is C1-C6-alkyl, wherein the C1-C6-alkyl group is halogen, hydroxyl, unsubstituted or mono- or polyhalogen-substituted C3-C6-cycloalkyl, or R 6 , R 7 SO2, R 7 SO or R 8O group or groups selected from the following:

[0012] [ka] where * represents the point of attachment of the group to the rest of the molecule; R 2 and R 3 always has the same definition and is either hydrogen or C1-C6 alkyl, R 4 is halogen, cyano, unsubstituted or single or multiple, identically or differently substituted C1-C6-alkyl or unsubstituted or single or multiple, identically or differently substituted C3-C6-cycloalkyl, the substituents being selected from the group of halogen and hydroxyl, R 5 is hydrogen, halogen, or unsubstituted or mono- or polyhalogen-substituted C1-C6 alkyl; R 6 is an unsubstituted or monosubstituted or dimethyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms containing a heteroatom or heterogroup from the group O, S, SO and SO2, R 7 is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted, mono- or polysubstituted by halogen, hydroxyl or C3-C6-cycloalkyl, or R 7 is C3-C6-cycloalkyl, R 8 is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted or mono- or polysubstituted by halogens, and its diastereomers, enantiomers, metabolites, salts, solvates, or solvates of the salts thereof.

[0013] In one aspect, a method of treating or preventing osteoarthritis in a mammal can include administering a composition comprising an effective amount of an IRAK4 inhibitor, wherein the IRAK4 inhibitor is a compound of general formula (I):

[0014] [ka] (In the formula, R 1 is C1-C6-alkyl, wherein the C1-C6-alkyl group is halogen, hydroxyl, unsubstituted or mono- or polyhalogen-substituted C3-C6-cycloalkyl, or R 6 , R 7 SO2, R 7 SO or R 8 O group or groups selected from the following:

[0015] [ka] where * represents the point of attachment of the group to the rest of the molecule; R 2 and R 3 always has the same definition and is either hydrogen or C1-C6 alkyl, R 4 is halogen, cyano, unsubstituted or single or multiple, identically or differently substituted C1-C6-alkyl or unsubstituted or single or multiple, identically or differently substituted C3-C6-cycloalkyl, the substituents being selected from the group of halogen and hydroxyl, R 5 is hydrogen, halogen, or unsubstituted or mono- or polyhalogen-substituted C1-C6 alkyl; R 6 is an unsubstituted or monosubstituted or dimethyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms containing a heteroatom or heterogroup from the group O, S, SO and SO2, R 7is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted, mono- or polysubstituted by halogen, hydroxyl or C3-C6-cycloalkyl, or R 7 is C3-C6-cycloalkyl, R 8 is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted or mono- or polysubstituted by halogens, and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof.

[0016] In one aspect, R 1 is C1-C6-alkyl, where the C1-C6-alkyl group is fluorine, hydroxyl, or R 6 , R 7 SO2, R 7 SO, or R 8 unsubstituted, mono- or polysubstituted by identical or different O groups, R 2 and R 3 always has the same definition and is either hydrogen or C1-C3 alkyl, R 4 is halogen, cyano, or C1-C3-alkyl, the C1-C3-alkyl groups being identically or differently unsubstituted, mono- or polysubstituted by halogen or hydroxyl, R 5 is hydrogen, fluorine, chlorine or C1-C3-alkyl, R 6 is oxetanyl or tetrahydrofuranyl, R 7 is C1-C4-alkyl, in which the C1-C4-alkyl group is unsubstituted, monosubstituted by hydroxyl or cyclopropyl or substituted by three fluorine atoms, R 8 is an unsubstituted C1-C4-alkyl group or a tri-fluorine substituted C1-C4-alkyl group.

[0017] In one aspect, R 4 is difluoromethyl, trifluoromethyl, or methyl.

[0018] In one aspect, R 5 is hydrogen or fluorine.

[0019] In one aspect, R 2 and R 3 are both either hydrogen or methyl.

[0020] In one aspect, R 1 is C2-C6-alkyl, wherein the C2-C6-alkyl group is unsubstituted, or the C2-C6-alkyl group is mono-, di- or trifluorine-substituted, or the C2-C6-alkyl group is hydroxyl, R 6 , R 7 SO2 or R 8 monosubstituted by O or R 1 is an oxetanyl-substituted C1-C3-alkyl group, R 2 and R 3 always has the same definition and is both hydrogen or methyl, R 4 is an unsubstituted or mono- or polyhalogen-substituted C1-C3-alkyl radical, or a C1-C3-alkyl radical substituted by one hydroxyl group, or a C1-C3-alkyl radical substituted by one hydroxyl group and three fluorine atoms, R 5 is hydrogen, fluorine or C1-C3-alkyl, R 7 is C1-C3-alkyl, R 8 is C1-C4-alkyl, wherein the C1-C4-alkyl group is unsubstituted or mono-, di- or trifluorine-substituted.

[0021] In one aspect, R1 is a C2-C5-alkyl radical substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl, or a methyl-SO2-substituted C2-C4-alkyl radical, or an oxetan-3-yl-substituted C1-C2-alkyl radical, R 2 and R 3 always has the same definition and is both hydrogen or methyl, R 4 are methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl; R 5 is hydrogen, fluorine, or methyl.

[0022] In one aspect, R 1 is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulfonyl)ethyl, or 3-(methylsulfonyl)propyl; R 2 and R 3 are both methyl or hydrogen, R 4 is difluoromethyl, trifluoromethyl, or methyl; R 5 is hydrogen or fluorine.

[0023] In one aspect, R 1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl, R 2 and R 3 are both methyl, R 4 is difluoromethyl or trifluoromethyl, R 5 is hydrogen.

[0024] In one aspect, R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl, R 2 and R 3 are both methyl, R 4 is methyl, R 5 is fluorine, where R 5 is R 4 It is in the ortho position relative to

[0025] In one 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-(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-(methylsulfonyl)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-(methylsulfonyl)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-(methylsulfonyl)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.

[0026] In one embodiment, the IRAK4 inhibitor is Compound 1:

[0027] [ka]

[0028] In one embodiment, a composition comprising an effective amount of an IRAK4 inhibitor treats pain associated with osteoarthritis.

[0029] In one embodiment, a composition comprising an effective amount of an IRAK4 inhibitor treats inflammation associated with osteoarthritis.

[0030] In one aspect, a method for treating pain in a mammal can include administering a composition comprising an effective amount of an IRAK4 inhibitor, the IRAK4 inhibitor being a compound of general formula (I):

[0031] [ka] (In the formula, R 1 is C1-C6-alkyl, wherein the C1-C6-alkyl group is halogen, hydroxyl, unsubstituted or mono- or polyhalogen-substituted C3-C6-cycloalkyl, or R 6 , R 7 SO2, R 7 SO or R 8 O group or groups selected from the following:

[0032] [ka] where * represents the point of attachment of the group to the rest of the molecule; R 2 and R 3 always has the same definition and is either hydrogen or C1-C6 alkyl, R 4is halogen, cyano, unsubstituted or single or multiple, identically or differently substituted C1-C6-alkyl or unsubstituted or single or multiple, identically or differently substituted C3-C6-cycloalkyl, the substituents being selected from the group of halogen and hydroxyl, R 5 is hydrogen, halogen, or unsubstituted or mono- or polyhalogen-substituted C1-C6 alkyl; R 6 is an unsubstituted or monomethyl- or dimethyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms containing a heteroatom or heterogroup from the group O, S, SO and SO2, R 7 is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted, mono- or polysubstituted by halogen, hydroxyl or C3-C6-cycloalkyl, or R 7 is C3-C6-cycloalkyl, R 8 is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted or mono- or polysubstituted by halogens, and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof.

[0033] In one aspect, R 1 is C1-C6-alkyl, where the C1-C6-alkyl group is fluorine, hydroxyl, or R 6 , R 7 SO2, R 7 SO, or R 8 unsubstituted, mono- or polysubstituted by identical or different O groups, R 2 and R 3 always has the same definition and is either hydrogen or C1-C3 alkyl, R 4is halogen, cyano, or C1-C3-alkyl, the C1-C3-alkyl groups being identically or differently unsubstituted, mono- or polysubstituted by halogen or hydroxyl, R 5 is hydrogen, fluorine, chlorine or C1-C3-alkyl, R 6 is oxetanyl or tetrahydrofuranyl, R 7 is C1-C4-alkyl, wherein the C1-C4-alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms, R 8 is an unsubstituted C1-C4-alkyl group or a tri-fluorine substituted C1-C4-alkyl group.

[0034] In one aspect, R 4 is difluoromethyl, trifluoromethyl, or methyl.

[0035] In one aspect, R 5 is hydrogen or fluorine.

[0036] In one aspect, R 2 and R 3 are both either hydrogen or methyl.

[0037] In one aspect, R 1 is C2-C6-alkyl, wherein the C2-C6-alkyl group is unsubstituted, or the C2-C6-alkyl group is mono-, di- or trifluorine-substituted, or the C2-C6-alkyl group is hydroxyl, R 6 , R 7 SO2 or R 8 monosubstituted by O or R 1 is an oxetanyl-substituted C1-C3-alkyl group, R 2 and R 3always has the same definition and is both hydrogen or methyl, R 4 is an unsubstituted or mono- or polyhalogen-substituted C1-C3-alkyl radical, or a C1-C3-alkyl radical substituted by one hydroxyl group, or a C1-C3-alkyl radical substituted by one hydroxyl group and three fluorine atoms, R 5 is hydrogen, fluorine or C1-C3-alkyl, R 7 is C1-C3-alkyl, R 8 is C1-C4-alkyl, wherein the C1-C4-alkyl group is unsubstituted or mono-, di- or trifluorine-substituted.

[0038] In one aspect, R 1 is a C2-C5-alkyl radical substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl, or a methyl-SO2-substituted C2-C4-alkyl radical, or an oxetan-3-yl-substituted C1-C2-alkyl radical, R 2 and R 3 always has the same definition and is both hydrogen or methyl, R 4 are methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl; R 5 is hydrogen, fluorine, or methyl.

[0039] In one aspect, R 1is 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-(methylsulfonyl)ethyl, or 3-(methylsulfonyl)propyl; R 2 and R 3 are both methyl or hydrogen, R 4 is difluoromethyl, trifluoromethyl, or methyl; R 5 is hydrogen or fluorine.

[0040] In one aspect, R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl, R 2 and R 3 are both methyl, R 4 is difluoromethyl or trifluoromethyl, R 5 is hydrogen.

[0041] In one aspect, R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl, R 2 and R 3 are both methyl, R 4 is methyl, R 5 is fluorine, where R 5 is R4 It is in the ortho position relative to

[0042] In one 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-(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-(methylsulfonyl)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-(methylsulfonyl)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-(methylsulfonyl)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.

[0043] In one embodiment, the IRAK4 inhibitor is Compound 1.

[0044] [ka]

[0045] In one embodiment, the pain is associated with osteoarthritis.

[0046] In one aspect, the pain is perioperative.

[0047] In one aspect, a method for treating inflammation in a mammal can include administering an effective amount of an IRAK4 inhibitor comprising a compound of general formula (I), wherein the IRAK4 inhibitor is a compound of general formula (I):

[0048] [ka] (In the formula, R 1is C1-C6-alkyl, wherein the C1-C6-alkyl group is halogen, hydroxyl, unsubstituted or mono- or polyhalogen-substituted C3-C6-cycloalkyl, or R 6 , R 7 SO2, R 7 SO or R 8 O group or groups selected from the following:

[0049] [ka] where * represents the point of attachment of the group to the rest of the molecule; R 2 and R 3 always has the same definition and is either hydrogen or C1-C6 alkyl, R 4 is halogen, cyano, unsubstituted or single or multiple, identically or differently substituted C1-C6-alkyl or unsubstituted or single or multiple, identically or differently substituted C3-C6-cycloalkyl, the substituents being selected from the group of halogen and hydroxyl, R 5 is hydrogen, halogen, or unsubstituted or mono- or polyhalogen-substituted C1-C6 alkyl; R 6 is an unsubstituted or monosubstituted or dimethyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms containing a heteroatom or heterogroup from the group O, S, SO and SO2, R 7 is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted, mono- or polysubstituted by halogen, hydroxyl or C3-C6-cycloalkyl, or R 7 is C3-C6-cycloalkyl, R 8 is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted or mono- or polysubstituted by halogens, and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof.

[0050] In one aspect, R 1 is C1-C6-alkyl, where the C1-C6-alkyl group is fluorine, hydroxyl, or R 6 , R 7 SO2, R 7 SO, or R 8 unsubstituted, mono- or polysubstituted by identical or different O groups, R 2 and R 3 always has the same definition and is either hydrogen or C1-C3 alkyl, R 4 is halogen, cyano or C1-C3-alkyl, said C1-C3-alkyl groups being identically or differently unsubstituted, mono- or polysubstituted by halogen or hydroxyl, R 5 is hydrogen, fluorine, chlorine or C1-C3-alkyl, R 6 is oxetanyl or tetrahydrofuranyl, R 7 is C1-C4-alkyl, wherein the C1-C4-alkyl group is unsubstituted, monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms, R 8 is an unsubstituted C1-C4-alkyl group or a tri-fluorine substituted C1-C4-alkyl group.

[0051] In one aspect, R 4 is difluoromethyl, trifluoromethyl, or methyl.

[0052] In one aspect, R 5 is hydrogen or fluorine.

[0053] In one aspect, R 2 and R 3are both either hydrogen or methyl.

[0054] In one aspect, R 1 is C2-C6-alkyl, wherein the C2-C6-alkyl group is unsubstituted, or the C2-C6-alkyl group is mono-, di- or trifluorine-substituted, or the C2-C6-alkyl group is hydroxyl, R 6 , R 7 SO2 or R 8 monosubstituted by O or R 1 is an oxetanyl-substituted C1-C3-alkyl group, R 2 and R 3 always has the same definition and is both hydrogen or methyl, R 4 is an unsubstituted or mono- or polyhalogen-substituted C1-C3-alkyl radical, or a C1-C3-alkyl radical substituted by one hydroxyl group, or a C1-C3-alkyl radical substituted by one hydroxyl group and three fluorine atoms, R 5 is hydrogen, fluorine or C1-C3-alkyl, R 7 is C1-C3-alkyl, R 8 is C1-C4-alkyl, wherein the C1-C4-alkyl group is unsubstituted or mono-, di- or trifluorine-substituted.

[0055] In one aspect, R 1 is a C2-C5-alkyl radical substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl, or a methyl-SO2-substituted C2-C4-alkyl radical, or an oxetan-3-yl-substituted C1-C2-alkyl radical, R 2 and R 3always has the same definition and is both hydrogen or methyl, R 4 are methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl; R 5 is hydrogen, fluorine, or methyl.

[0056] In one aspect, R 1 is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulfonyl)ethyl, or 3-(methylsulfonyl)propyl; R 2 and R 3 are both methyl or hydrogen, R 4 is difluoromethyl, trifluoromethyl, or methyl; R 5 is hydrogen or fluorine.

[0057] In one aspect, R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl, R 2 and R 3 are both methyl, R 4 is difluoromethyl or trifluoromethyl, R 5 is hydrogen.

[0058] In one aspect, R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl, R 2 and R 3 are both methyl, R 4 is methyl, R 5 is fluorine, where R 5 is R 4 It is in the ortho position relative to

[0059] In one 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-(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-(methylsulfonyl)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-(methylsulfonyl)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-(methylsulfonyl)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 It can be N-{2-[2-(1-hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide.

[0060] In one embodiment, the IRAK4 inhibitor can be Compound 1.

[0061] [ka]

[0062] In one embodiment, the inflammation is associated with osteoarthritis.

[0063] In one aspect, the inflammation is associated with degenerative joint disease (DJD).

[0064] In one aspect, the inflammation is associated with inflammatory bowel disease (IBD), diabetes mellitus, kidney disease, disc disease, and allergic inflammation.

[0065] In one aspect, a method for treating or preventing degenerative joint disease (DJD) in a mammal can include a composition comprising administering an effective amount, wherein the IRAK4 inhibitor is a compound of general formula (I):

[0066] [ka] (In the formula, R 1 is C1-C6-alkyl, wherein the C1-C6-alkyl group is halogen, hydroxyl, unsubstituted or mono- or polyhalogen-substituted C3-C6-cycloalkyl, or R 6 , R 7 SO2, R 7 SO or R 8 O group or groups selected from the following:

[0067] [ka] where * represents the point of attachment of the group to the rest of the molecule; R 2 and R 3 always has the same definition and is either hydrogen or C1-C6 alkyl, R 4 is halogen, cyano, unsubstituted or single or multiple, identically or differently substituted C1-C6-alkyl or unsubstituted or single or multiple, identically or differently substituted C3-C6-cycloalkyl, the substituents being selected from the group of halogen and hydroxyl, R 5 is hydrogen, halogen, or unsubstituted or mono- or polyhalogen-substituted C1-C6 alkyl; R 6 is an unsubstituted or monosubstituted or dimethyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms containing a heteroatom or heterogroup from the group O, S, SO and SO2, R7 is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted, mono- or polysubstituted by halogen, hydroxyl or C3-C6-cycloalkyl, or R 7 is C3-C6-cycloalkyl, R 8 is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted or mono- or polysubstituted by halogens, and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof.

[0068] In one aspect, R 1 is C1-C6-alkyl, where the C1-C6-alkyl group is fluorine, hydroxyl, or R 6 , R 7 SO2, R 7 SO, or R 8 unsubstituted, mono- or polysubstituted by identical or different O groups, R 2 and R 3 always has the same definition and is either hydrogen or C1-C3 alkyl, R 4 is halogen, cyano, or C1-C3-alkyl, the C1-C3-alkyl groups being identically or differently unsubstituted, mono- or polysubstituted by halogen or hydroxyl, R 5 is hydrogen, fluorine, chlorine or C1-C3-alkyl, R 6 is oxetanyl or tetrahydrofuranyl, R 7 is C1-C4-alkyl, wherein the C1-C4-alkyl group is unsubstituted, monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms, R 8is an unsubstituted C1-C4-alkyl group or a tri-fluorine substituted C1-C4-alkyl group.

[0069] In one aspect, R 4 is difluoromethyl, trifluoromethyl, or methyl.

[0070] In one aspect, R 5 is hydrogen or fluorine.

[0071] In one aspect, R 2 and R 3 are both either hydrogen or methyl.

[0072] In one aspect, R 1 is C2-C6-alkyl, wherein the C2-C6-alkyl group is unsubstituted, or the C2-C6-alkyl group is mono-, di- or trifluorine-substituted, or the C2-C6-alkyl group is hydroxyl, R 6 , R 7 SO2 or R 8 monosubstituted by O or R 1 is an oxetanyl-substituted C1-C3-alkyl group, R 2 and R 3 always has the same definition and is both hydrogen or methyl, R 4 is an unsubstituted or mono- or polyhalogen-substituted C1-C3-alkyl radical, or a C1-C3-alkyl radical substituted by one hydroxyl group, or a C1-C3-alkyl radical substituted by one hydroxyl group and three fluorine atoms, R 5 is hydrogen, fluorine or C1-C3-alkyl, R 7 is C1-C3-alkyl, R 8 is C1-C4-alkyl, wherein the C1-C4-alkyl group is unsubstituted or mono-, di- or trifluorine-substituted.

[0073] In one aspect, R 1 is a C2-C5-alkyl radical substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl, or a methyl-SO2-substituted C2-C4-alkyl radical, or an oxetan-3-yl-substituted C1-C2-alkyl radical, R 2 and R 3 always has the same definition and is both hydrogen or methyl, R 4 are methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl; R 5 is hydrogen, fluorine, or methyl.

[0074] In one aspect, R 1 is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulfonyl)ethyl, or 3-(methylsulfonyl)propyl; R 2 and R 3 are both methyl or hydrogen, R 4 is difluoromethyl, trifluoromethyl, or methyl; R 5 is hydrogen or fluorine.

[0075] In one aspect, R 1is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl, R 2 and R 3 are both methyl, R 4 is difluoromethyl or trifluoromethyl, R 5 is hydrogen.

[0076] In one aspect, R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl, R 2 and R 3 are both methyl, R 4 is methyl, R 5 is fluorine, where R 5 is R 4 It is in the ortho position relative to

[0077] In one 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-(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-(methylsulfonyl)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-(methylsulfonyl)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-(methylsulfonyl)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.

[0078] In one embodiment, the IRAK4 inhibitor can be Compound 1.

[0079] [ka]

[0080] In one aspect, the mammal is a dog, cat, horse, pig, cow, sheep, or goat. The mammal can be a dog.

[0081] In one embodiment, the effective amount is about 1-25 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.

[0082] In one embodiment, the effective amount is about 1 to 25 mg / kg of a compound described herein. An 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. An effective amount can be about 5 mg / kg of a compound described herein. An effective amount can be about 15 mg / kg of a compound described herein.

[0083] In one embodiment, the composition is administered once, twice, three times, four times, or five times daily.

[0084] In one embodiment, the composition is administered every other day.

[0085] In one embodiment, the composition is administered once daily.

[0086] In one embodiment, the composition is a pharmaceutical composition comprising an effective amount of an IRAK4 inhibitor and a carrier, which can be an excipient, lubricant, antioxidant, emulsifier, stabilizer, solvent, diluent, buffer, vehicle, or a combination thereof.

[0087] In one embodiment, the composition is in the form of a tablet, optionally a chewable tablet.

[0088] In one aspect, the composition is administered intravenously, intramuscularly, orally, buccally, or a combination thereof. The composition can be administered orally. [Brief explanation of the drawings]

[0089] [Figure 1] FIG. 1 shows an exemplary IRAK4 inhibitor (Compound 1) using Compound 1 in a uric acid synovitis model in dogs comparing two exemplary doses, 15 mg / kg and 5 mg / kg, to placebo. Detailed Description of the Invention

[0090] Various exemplary aspects have been described in detail and may be further illustrated by the examples provided. Additional survivable variations can be readily envisioned.

[0091] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0092] As used throughout this description and the claims that follow, the meanings of "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0093] As used herein, "effective amount" broadly refers to the amount of a compound, antibody, antigen, or cell that, when administered to a patient to treat a disease, is sufficient to affect such treatment of the disease. An effective amount may be a prophylactically effective amount and / or a prophylactically effective amount. An effective amount may be an amount effective to reduce the incidence of signs / symptoms, an amount effective to reduce the severity of the incidence of signs / symptoms, an amount effective to eliminate the incidence of signs / symptoms, an amount effective to delay the onset of signs / symptoms, an amount effective to prevent the onset of signs / symptoms, and / or an amount effective to provide a prophylactic effect on the onset of signs / symptoms. An "effective amount" may vary depending on the disease and its severity, as well as the age, weight, medical history, susceptibility, and pre-existing conditions of the patient being treated. For purposes of this specification, the term "effective amount" is synonymous with "therapeutically effective amount."

[0094] As used herein, "mammal" broadly refers to any and all warm-blooded vertebrates of the class mammary, characterized by hair on the skin and, in females, milk-producing mammary glands for nourishing young animals. Mammals include, but are not limited to, humans, domestic and farm animals, as well as zoo, sport, or pet animals. Examples of mammals include, but are not limited to, alpacas, armadillos, capybaras, cats, camels, chimpanzees, chinchillas, cows, 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.

[0095] "Treatment" broadly refers to both therapeutic and prophylactic or preventative treatment. "Treatment" also refers to the prescribing of a medication, drug, or treatment to a patient by a healthcare professional (such as a physician, physician assistant, nurse practitioner, pharmacist, etc.). Those in need of treatment include those already with the disorder as well as those in whom the disorder is to be prevented. As used herein, the term "treatment" broadly refers to treating a disease, arresting or reducing the onset of a disease or its clinical symptoms, and / or alleviating a disease, causing regression of a disease or its clinical symptoms. Therapy includes preventing, treating, ameliorating, reducing, alleviating, and / or providing relief from the disease, signs, and / or symptoms of a disease. Therapy includes the alleviation of signs and / or symptoms in patients with ongoing signs and / or symptoms of a disease. Therapy also encompasses "prevention." For purposes of therapy, the term "reduction" broadly refers to a clinically significant decrease in signs and / or symptoms. Therapy includes the treatment of recurrent or recurrent signs and / or symptoms. Therapy includes, but is not limited to, preventing the appearance of signs and / or symptoms at any time, reducing existing signs and / or symptoms, and eliminating existing signs and / or symptoms. Therapy includes treatment of chronic diseases ("maintenance") and acute diseases. For example, treatment includes treating or preventing recurrence, or the recurrence of signs and / or symptoms.

[0096] IRAK-4 inhibitor compounds Nonsteroidal anti-inflammatory drugs (NSAIDs) are the standard of care for the management of clinical signs associated with osteoarthritis in dogs, but are associated with significant gastrointestinal, hepatic, and renal side effects.

[0097] 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 inhibitors. IRAK4 is expressed by many cells and mediates signaling of Toll-like receptors (TLRs), with the exception of TLR3 and the interleukin (IL)-1β family of receptors, which consists of 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.

[0098] IRAK4 inhibitors include inhibitors of IRAK4, as described herein.

[0099] The IRAK4 inhibitors described herein include, but are not limited to, those described in U.S. Patent No. 10,793,545 and U.S. Patent Application No. 17 / 570,550. The IRAK4 inhibitors described herein can be used alone and / or in combination with other active ingredients to treat pain and / or inflammation, and include compounds of general formula (I):

[0100] [ka] (In the formula, R 1 is C1-C6-alkyl, where the C1-C6-alkyl group is halogen, hydroxyl, unsubstituted or mono- or poly-halogen-substituted C3-C6 cycloalkyl, or R 6 , R 7 SO2, R 7 SO or R 8 O group, or unsubstituted, mono- or polysubstituted with, identically or differently, groups selected from the following:

[0101] [ka] where * represents the point of attachment of the group to the rest of the molecule; R 2 and R 3 always has the same definition and is either hydrogen or C1-C6 alkyl, R 4 is halogen, cyano, unsubstituted or single or multiple, identically or differently substituted C1-C6-alkyl or unsubstituted or single or multiple, identically or differently substituted C3-C6-cycloalkyl, the substituents being selected from the group of halogen and hydroxyl, R 5 is hydrogen, halogen, or unsubstituted or mono- or poly-halogen-substituted C1-C6 alkyl, optionally wherein halogen is fluorine; R 6 is an unsubstituted or monosubstituted or dimethyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms containing a heteroatom or heterogroup from the group O, S, SO and SO2, R 7 is C1-C6-alkyl, wherein the C1-C6-alkyl group is unsubstituted or mono- or polysubstituted, similarly or differently, by halogen, hydroxyl or C3-C6-cycloalkyl, or R 7 is C3-C6-cycloalkyl, R 8 is C1-C6-alkyl, in which the C1-C6-alkyl groups are identically or differently unsubstituted or mono- or polysubstituted by halogens, and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof, but are not limited to these.

[0102] Exemplary IRAK4 inhibitors described herein include, but are not limited to, the IRAK4 inhibitors described in U.S. Patent No. 10,793,545 and U.S. Patent Application No. 17 / 570,550. IRAK4 inhibitors described herein. A preferred IRAK4 inhibitor is Compound 1:

[0103] [ka]

[0104] An exemplary test was carried out in acute dog uric acid synovitis pain model, which induces severe lameness.Surprisingly, compound 1 is more effective than placebo in reducing acute pain and improving lameness considerably, and also shows equal or better efficacy than expected in this model.Dogs treated with compound 1 show minimal pain and lameness after synovitis induction, or no pain at all, which is the magnitude of effect that has not been recorded in any other class of drugs other than NSAIDs.

[0105] In the case of the mentioned uses of the synthetic intermediates and examples of the invention described below, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown precise stoichiometric composition obtained by the respective preparation and / or purification process. Unless specified in more detail, it is often referred to as, for example, "hydrochloride salt," "trifluoroacetate salt," "sodium salt," or "x HCl," "x CF3COOH," "x Na + " and other additions to names and structural formulas are therefore not to be understood in a stoichiometric sense in the case of such salts, but are merely descriptive in terms of the salt-forming components present therein.

[0106] This applies correspondingly if the described preparation and / or purification processes give rise to synthetic intermediates or working examples, or salts thereof, of unknown stoichiometric composition (if they are of a defined type), for example in the form of solvates such as hydrates.

[0107] The compounds are compounds of formula (I), and salts, solvates and solvates of the salts thereof, compounds of the formulae encompassed by formula (I) and mentioned below, and salts, solvates and solvates of the salts thereof, and compounds encompassed by formula (I) and mentioned below as embodiments as embodiments and salts thereof, if the compounds are not already salts, solvates and solvates of the salts thereof.

[0108] Preferred salts in the context of the compositions described herein are physiologically acceptable salts of the compounds. However, the compositions described herein also encompass salts that are not themselves suitable for pharmaceutical use but may be used, for example, to isolate or purify the compounds.

[0109] Physiologically acceptable salts of the present compounds include acid addition salts of mineral acids, carboxylic acids, and sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid.

[0110] Physiologically acceptable salts of the present compounds also include salts of conventional bases, by way of example and preferably 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 preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, and N-methylpiperidine.

[0111] Solvates in the context of the present compounds are described as forms of the present compounds that form a complex in the solid or liquid state by coordinating with solvent molecules. Hydrates are a specific form of solvates in which the coordination involves water.

[0112] Depending on their structure, the compounds described herein may exist in different stereoisomeric forms, i.e., in the form of configurational isomers, or, where appropriate, conformational isomers (including enantiomers and / or diastereomers, atropisomers). The present compounds encompass the use of enantiomers and diastereomers, as well as their respective mixtures. Stereoisomerically homogeneous components can be isolated from such mixtures of enantiomers and / or diastereomers in a known manner, and chromatographic processes are preferably used for this purpose, in particular HPLC chromatography on achiral or chiral phases.

[0113] Where the present compounds can occur in tautomeric forms, the methods and compositions described herein encompass the use of all tautomeric forms.

[0114] Methods and compositions described herein also encompass the use of all suitable isotopic variants of the compound.Isotopic variants of the compound are understood to mean compounds in which at least one atom in the compound is replaced with another atom of the same atomic number, but has atomic mass different from the atomic mass that usually or mainly occurs in nature.The examples of isotopes that can be incorporated into the compound are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example: 2 H (deuterium), 3 H (tritium), 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F,36 Cl, 82 Br, 123 I, 124 I, 129 I, and 131 I. Certain isotopic variants of the present compounds, especially those incorporating one or more radioisotopes, can be useful, for example, for examining the mechanism of action or distribution of active ingredients in the body. This is particularly advantageous because it is easy to compare the preparation and detectability. 3 H or 14 This is because the compound labeled with C isotope is suitable for this purpose.In addition, the incorporation of isotopes such as deuterium can bring about certain therapeutic benefits, such as increasing the metabolic stability of compound, for example, extending the half-life in the body, or reducing the required active dose.The isotopic variant of this compound can be prepared by processes known to those skilled in the art, for example, by using the corresponding isotopic modification of each reagent and / or starting compound according to the procedures described in the methods and examples described below.

[0115] The methods and compositions described herein provide for the use of all possible crystalline and polymorphic forms of the compounds, which may exist either as a single polymorph or as a mixture of multiple polymorphs in all concentration ranges.

[0116] The methods and compositions described herein also encompass the use of prodrugs of the compounds described herein. The term prodrug in this context refers to a compound that may itself be biologically active or inactive, but that is converted (e.g., metabolically or hydrolytically) to present the compound during its residence time in the body.

[0117] In the context of the methods and compositions described herein, unless otherwise specified, the substituents have the following meanings:

[0118] Alkylrepresents a straight-chain or branched alkyl group having the specified number of carbon atoms. 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. Methyl, ethyl, n-propyl, n-butyl, 2-methylbutyl, 3-methylbutyl, and 2,2-dimethylpropyl are preferred.

[0119] cycloalkyl is a monocyclic saturated alkyl group having the number of carbon atoms specified in each instance. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0120] Alkoxy represents a linear or branched alkoxy group having the specified number of carbon atoms. 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. Particularly preferred are linear or branched alkoxy groups having 1 to 4 carbon atoms. Examples that may be mentioned as preferred are methoxy, ethoxy, n-propoxy, 1-methylpropoxy, n-butoxy, and isobutoxy.

[0121] halogen is fluorine, chlorine, and bromine, preferably fluorine.

[0122] Hydroxyl is OH.

[0123] Monocyclic saturated heterocyclesis a monocyclic saturated heterocycle having 4 to 6 ring atoms and containing a heteroatom or heterogroup from the group O, S, SO, and SO2. Heterocycles containing a heteroatom or heterogroup from the group O, SO, and SO2 are preferred. Examples include oxetane, tetrahydrofuran, tetrahydro-2H-pyran-4-yl, 1,1-dioxidetetrahydro-2H-thiopyran-3-yl, 1,1-dioxidetetrahydro-2H-thiopyran-2-yl, 1,1-dioxidetetrahydro-2H-thiopyran-4-yl, 1,1-dioxidetetrahydrothiophen-3-yl, 1,1-dioxidetetrahydrothiophen-2-yl, 1,1-dioxidethietan-2-yl, or 1,1-dioxidethietan-3-yl. Particularly preferred here are oxetane and tetrahydrofuran. Very particular preference is given to oxetan-3-yl.

[0124] The symbol * at a bond indicates the site of attachment in the molecule.

[0125] When a group in the compounds described herein is substituted, the group may be mono- or polysubstituted unless otherwise specified. All groups that occur more than once are defined independently of each other. Substitution with one, two, or three identical or different substituents is preferred.

[0126] R 1 Preferred embodiments of are C2-C6 alkyl groups substituted with 1, 2, or 3 fluorine atoms. Particularly preferred are 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl. Very particularly preferred is the 4,4,4-trifluorobutyl group.

[0127] Even more preferable R 1An embodiment of is a C2-C6-alkyl group substituted by one or two hydroxyl groups, or one C1-C3-alkoxy, or tri-fluorine-substituted C1-C3-alkoxy. Particularly preferred are C2-C5-alkyl groups substituted by hydroxyl, C1-C3-alkoxy, trifluoromethoxy, or 2,2,2-trifluoroethoxy. Very particularly preferred are 3-hydroxy-3-methylbutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, or 2-hydroxyethyl. Particularly preferred is the 3-hydroxy-3-methylbutyl group.

[0128] More preferably, R 1 is a C2-C6-alkyl group substituted with a C1-C6-alkyl-SO2 group. Methyl-SO2-substituted C2-C4-alkyl groups are particularly preferred. R 1 Particularly preferred for are 2-(methylsulfonyl)ethyl or 3-(methylsulfonyl)propyl. From the latter group, 2-(methylsulfonyl)ethyl is particularly preferred.

[0129] More preferably, R 1 is a C1-C3 alkyl group substituted with oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyran-4-yl, 1,1-dioxidetetrahydro-2H-thiopyran-3-yl, 1,1-dioxidetetrahydro-2H-thiopyran-2-yl, 1,1-dioxidetetrahydro-2H-thiopyran-4-yl, 1,1-dioxidetetrahydrothiophen-3-yl, 1,1-dioxidetetrahydrothiophen-2-yl, 1,1-dioxidethietan-2-yl, or 1,1-dioxidethietan-3-yl. Particularly preferred is a C1-C3 alkyl group substituted with an oxetane group. R 1 Particularly preferred is an oxetan-3-ylmethyl group.

[0130] R 2 and R 3always have the same definition, hydrogen or methyl being preferred, with methyl being particularly preferred.

[0131] R 4 is preferably an unsubstituted or mono- or polyhalogen-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.

[0132] R 4 Particularly preferred for R are the 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. 4 Particularly preferred are a methyl group, a trifluoromethyl group, and a difluoromethyl group, with a trifluoromethyl group being particularly preferred.

[0133] R 5 Preferred embodiments of R are hydrogen, fluorine, chlorine, or C1-C3-alkyl. 5 More preferably, R is hydrogen, fluorine, or methyl. Most preferably, R 5 is hydrogen or fluorine.

[0134] Particularly preferably, R 4 is methyl or trifluoromethyl, and R 5 is fluorine. Very particularly preferred are compounds in which R 4 is methyl and R 5 is fluorine and R 5 R 4 It is a compound that is in the ortho position to

[0135] R 6For the above, preferred embodiments include oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyran-4-yl, 1,1-dioxidetetrahydro-2H-thiopyran-3-yl, 1,1-dioxidetetrahydro-2H-thiopyran-2-yl, 1,1-dioxidetetrahydro-2H-thiopyran-4-yl, 1,1-dioxidetetrahydrothiophen-3-yl, 1,1-dioxidetetrahydrothiophen-2-yl, 1,1-dioxidethietan-2-yl, or 1,1-dioxidethietan-3-yl. Particularly preferred here is oxetanyl. Very particular preference is given to oxetan-3-yl.

[0136] R 7 is bonded exclusively to the functional groups -SO2- and -SO-, i.e., R 7 A substituted -SO2- or SO group. In this context, R 7 is preferably C1-C4-alkyl, the C1-C4-alkyl group being unsubstituted, monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms. 7 More preferably, R is a cyclopropyl group. 7 Particularly preferred is methyl, ethyl, or hydroxyethyl. 7 Very particularly preferred for is methyl.

[0137] This is R7SO2- or R 7 In the case of a C1-C6-alkyl group substituted by SO-, R 1 In the context of R, C-C-alkyl-SO or C-C-alkyl substituted by C-C-alkyl-SO is preferred. 1 Particular preference is given to methylsulfonylethyl and methylsulfonylpropyl, with very particular preference given here to methylsulfonylethyl.

[0138] R 8is preferably an unsubstituted C1-C4-alkyl group or a tri-fluorine-substituted C1-C4-alkyl group. Particularly preferred is methyl, ethyl, trifluoromethyl or 2,2,2-trifluoroethyl. Very particularly preferred is methyl, trifluoromethyl or 2,2,2-trifluoroethyl.

[0139] Preferably, a compound of formula (I), wherein: R 1 is C1-C6-alkyl, where the C1-C6-alkyl group is fluorine, hydroxyl, or R 6 , R 7 SO2, R 7 SO, or R 8 unsubstituted, mono- or polysubstituted by identical or different O groups, R 2 and R 3 always has the same definition and is either hydrogen or C1-C3 alkyl, R 4 is halogen, cyano, or C1-C3-alkyl, the C1-C3-alkyl groups being identically or differently unsubstituted, mono- or polysubstituted by halogen or hydroxyl, R 5 is hydrogen, fluorine, chlorine or C1-C3-alkyl, R 6 is oxetanyl or tetrahydrofuranyl, R 7 is C1-C4-alkyl, wherein the C1-C4-alkyl group is unsubstituted, monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms, R 8 is unsubstituted C1-C4-alkyl or tri-fluorine substituted C1-C4-alkyl), and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof.

[0140] Additionally preferred is a compound of formula (I), wherein: R 1 is C2-C6-alkyl, wherein C2-C6-alkyl is unsubstituted or C2-C6-alkyl is mono-, di-, or tri-fluorine-substituted or C2-C6-alkyl is hydroxyl, R 6 , R 7 SO2 or R 8 monosubstituted by O or R 1 is an oxetanyl-substituted C1-C3-alkyl, R 2 and R 3 always has the same definition and is both hydrogen or methyl, R 4 is an unsubstituted or mono- or polyhalogen-substituted C1-C3-alkyl radical, or a C1-C3-alkyl radical substituted by one hydroxyl group, or a C1-C3-alkyl radical substituted by one hydroxyl group and three fluorine atoms, R 5 is hydrogen, fluorine or C1-C3-alkyl, R 7 is C1-C3-alkyl, R 8 is C1-C4-alkyl, wherein the C1-C4-alkyl group is unsubstituted or mono-, di- or trifluorine-substituted, and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof. Furthermore, the IRAK4 inhibitors described herein can be used in methods for the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0141] Also particularly preferred is a compound of the following general formula (I) for use in the treatment and / or prevention of osteoarthritis, including pain and / or inflammation associated with osteoarthritis, in an animal: R 1 is a C2-C5-alkyl radical substituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl, or a methyl-SO2-substituted C2-C4-alkyl radical, or an oxetan-3-yl-substituted C1-C2-alkyl radical, R 2 and R 3 always has the same definition and is both hydrogen or methyl, R 4 are methyl, ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl; R 5 is hydrogen, fluorine, or methyl), and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof. Furthermore, the IRAK4 inhibitors described herein can be used in methods for the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0142] Very particularly preferred is a compound of the formula: R 1is 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-(methylsulfonyl)ethyl, or 3-(methylsulfonyl)propyl; R 2 and R 3 are both methyl or hydrogen, R 4 is difluoromethyl, trifluoromethyl, or methyl; R 5 is hydrogen or fluorine), and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof. Furthermore, the IRAK4 inhibitors described herein can be used in methods for the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0143] Also very especially preferred is a compound of the formula: R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl, R 2 and R 3 are both methyl, R 4 is difluoromethyl or trifluoromethyl, R 5 is hydrogen), and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof. Furthermore, the IRAK4 inhibitors described herein can be used in methods for the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0144] Additionally, particularly preferred is a compound of the formula: R 1 is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl, R 2 and R 3 are both methyl, R 4 is methyl, R 5 is fluorine, where R 5 is R 4 (ortho to and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof. Furthermore, the IRAK4 inhibitors described herein can be used in methods for the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0145] The present disclosure particularly relates to the following compounds for use in the treatment and / or prevention of osteoarthritis, including pain and / or inflammation, in an animal: (1) N-[6-(2-hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (2) N-[6-(hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (3) N-[6-(2-hydroxypropan-2-yl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (4) N-[6-(hydroxymethyl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (5) N-[2-(2-hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (6) N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (7) N-[2-(2-hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (8) N-[6-(2-hydroxypropan-2-yl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (9) N-[6-(hydroxymethyl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (10) N-{6-(2-hydroxypropan-2-yl)-2-[3-(methylsulfonyl)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-(methylsulfonyl)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-(methylsulfonyl)ethyl]-2H-indazol-5-yl}pyridine-2-carboxamide (15) 6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]pyridine-2-carboxamide (16) N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (17) N-{6-(2-hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (18) N-{6-(2-hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (19) 5-Fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide (20) N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide (21) 6-(2-hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]pyridine-2-carboxamide (22) N-{2-[2-(1-hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide, Additionally, the IRAK4 inhibitors described herein can be used in methods for the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0146] The present disclosure further provides a compound of general formula (III):

[0147] [ka] (In the formula, R 1 is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulfonyl)ethyl, 3-(methylsulfonyl)propyl, or 2-(1-hydroxycyclopropyl)ethyl; R 4 is difluoromethyl, trifluoromethyl, or methyl; R 5 is hydrogen or fluorine), and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof. Additionally, the IRAK4 inhibitors described herein can be used in methods for the treatment and / or prevention of osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof.

[0148] Preferably and especially the following compounds of general formula (III) for use in the treatment and / or prevention of osteoarthritis, including pain and / or inflammation associated with osteoarthritis, in animals: Methyl 5-{[(5-fluoro-6-methylpyridin-2-yl)carbonyl]amino}-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate, and 2-(3-hydroxy-3-methylbutyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate methyl ester Furthermore, the IRAK4 inhibitors described herein can be used in methods for the 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).

[0149] The IRAK4 inhibitors described herein may 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.

[0150] The IRAK4 inhibitors described herein can be formulated into medicaments for use in the treatment and / or prevention of degenerative joint disease (DJD).

[0151] The IRAK4 inhibitors described herein may 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.

[0152] The IRAK4 inhibitors described herein can be formulated into compositions for the treatment and / or prevention of degenerative joint disease (DJD).

[0153] The compounds of general formula (III) are suitable for the preparation of some of the compounds of general formula (I). Furthermore, the compounds of general formula (III) are inhibitors of interleukin-1 receptor-associated kinase-4 (IRAK4).

[0154] Compounds of general formula (III) can be prepared from compounds of general formula (II):

[0155] [ka] During the ceremony, R 1 is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulfonyl)ethyl, 3-(methylsulfonyl)propyl, or 2-(1-hydroxycyclopropyl)ethyl; R 4 is difluoromethyl, trifluoromethyl, or methyl; R 5 is hydrogen or fluorine, By reaction of (II) with an appropriately substituted alkyl halide or alkyl 4-methylbenzenesulfonate in the presence of potassium carbonate.

[0156] Furthermore, compounds of general formula (I) can be prepared from compounds of formula (III):

[0157] [ka] During the ceremony, R 1 are 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-(methylsulfonyl)propyl 2-(1-hydroxycyclopropyl)ethyl, R 2 and R 3 is methyl, R 4 is difluoromethyl, trifluoromethyl, or methyl; R 5 is hydrogen or fluorine, It was purified by Grignard reaction with methylmagnesium bromide.

[0158] As described below, Compound 1 provides similar efficacy to NSAIDs in dogs with osteoarthritis, but with a much improved safety profile, allowing more dogs to be aggressively and appropriately treated for pain and disability associated with, for example, osteoarthritis.

[0159] Preparation of compounds The preparation of this compound is exemplified by the following synthetic scheme.

[0160] The starting material used in the synthesis of this compound is a carboxylic acid (intermediate V3), which is commercially available or can be prepared by or in analogy with 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 by proceeding from carboxylic acid esters (intermediates V2) by hydrolysis (e.g., reaction of ethyl 6-(hydroxymethyl)pyridine-2-carboxylate with aqueous sodium hydroxide in methanol, see WO2004113281) or, in the case of tert-butyl esters, by reaction with an acid, such as hydrogen chloride or trifluoroacetic acid (see, e.g., Dalton Transactions, 2014, 43, 19, 7176-7190). Carboxylic acids V3 can also be used in the form of their alkali metal salts. Intermediates V2 can also be prepared, optionally, from intermediates V1 bearing chlorine and substituent X by reaction in a carbon monoxide atmosphere. 1Bromine or iodine as a palladium compound, optionally under high 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, in a solvent such as ethanol or methanol, with the addition of, for example, dimethyl sulfoxide (for preparation methods, see, for example, WO2012112743, WO2005082866, Chemical Communications (Cambridge, England), 2003, 15, 1948-1949, WO200661715). Intermediate V1 is commercially available or can be prepared by routes known from the literature. Exemplary preparation methods are detailed in WO2012061926, 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.

[0161] Synthetic Scheme 1

[0162] [ka] X 1 is chlorine, bromine, or iodine. R d is methyl, ethyl, benzyl, or tert-butyl. R 4 , R 5 are each as defined in general formula (I).

[0163] Methyl 5-amino-1H-indazole-6-carboxylate (intermediate 2) can be obtained from methyl 1H-indazole-6-carboxylate (intermediate 0) by nitration and reduction of the nitro group of intermediate 1 with hydrogen in the presence of palladium on charcoal in analogy to WO 2008 / 001883, according to synthetic scheme 2. For the preparation of intermediate 3 proceeding from intermediate 2, 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) can be used. For example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride can be converted to 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)methaniminium hexafluorophosphate (HATU, CAS It is possible to use TBTU (148893-10-1), propanephosphonic anhydride (as a solution in ethyl acetate or DMF, CAS 68957-94-8), or di-1H-imidazol-1-ylmethanone (CDI) as a coupling reagent, in combination with a base such as triethylamine or N-ethyl-N-isopropylpropan-2-amine, in each case added to the reaction mixture. Preferred is the use of TBTU and N-ethyl-N-isopropylpropan-2-amine in THF.

[0164] Synthetic Scheme 2

[0165] [ka] Substituent R 4 , R 5 are each as defined in general formula (I).

[0166] Proceeding from intermediate 3, it is possible to prepare 2-substituted indazole derivatives (intermediate 4) (see Synthesis Scheme 3). Useful reactions for this purpose include reactions with optionally substituted alkyl chlorides, bromides, iodides, or alkyl 4-methylbenzenesulfonates. The alkyl halides or alkyl 4-methylbenzenesulfonates used are commercially available or can be prepared analogously to routes known from the literature (for the preparation of alkyl 4-methylbenzenesulfonates, an example is the reaction of an appropriate alcohol with 4-methylbenzenesulfonyl chloride in the presence of triethylamine or pyridine; see, for example, Bioorganic and Medicinal Chemistry, 2006, 14, 12, 4277-4294). Optionally, when using alkyl chlorides or bromides, it is also possible to add an alkali metal iodide, such as potassium iodide or sodium iodide. The base used may be, for example, potassium carbonate, cesium carbonate, or sodium hydride. In the case of reactive alkyl halides, N-cyclohexyl-N-methylcyclohexanamine may be used in some cases. Useful solvents include, for example, 1-methylpyrrolidin-2-one, DMF, DMSO, or THF. Optionally, the alkyl halide or alkyl 4-methylbenzenesulfonate used may have functional groups that have been optionally protected in advance with a protecting group (see also PGM Wuts, TW Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541). For example, when an alkyl halide or alkyl 4-methylbenzenesulfonate having one or more hydroxyl groups is used, these hydroxyl groups may optionally be protected with a tert-butyl(dimethyl)silyl group or a similar silicon-containing protecting group well known to those skilled in the art.Alternatively, the hydroxyl group may also be protected by a tetrahydro-2H-pyran (THP) group, or by an acetyl or benzoyl group. The protecting group used can then be removed following the synthesis of intermediate 4, or otherwise after the synthesis of (I). For example, if a tert-butyl(dimethylsilyl) group is used as a protecting group, it can be removed using, for example, tetrabutylammonium fluoride in a solvent such as THF. The THP protecting group can be removed, for example, using 4-methylbenzenesulfonic acid (optionally in monohydrate form). The acetyl or benzoyl group can be removed by treatment with aqueous sodium hydroxide.

[0167] Optionally, the alkyl halide or alkyl 4-methylbenzenesulfonate used may contain a functional group that can be converted by oxidation or reduction reactions known to those skilled in the art (see, for example, Science of Synthesis, Georg Thieme Verlag). For example, if the functional group is a sulfide group, it can be oxidized to a sulfoxide or sulfone group by methods well known in the literature. In the case of a sulfoxide group, it can also be oxidized to a sulfone group. For these oxidation steps, for example, 3-chloroperbenzoic acid (CAS 937-14-4) can be used (in this regard, for the oxidation of 2-(methylsulfanyl)ethyl-1H-pyrazole derivatives to 2-(methylsulfinyl)ethyl-1H-pyrazole derivatives, and further oxidation of 2-(methylsulfanyl)ethyl-1H-pyrazole derivatives to 2-(methylsulfonyl)ethyl-1H-pyrazole derivatives, see, for example, US201094000). If the alkyl halide or tosylate used contains a keto group, it can be reduced to an alcohol group by reduction methods known to those skilled in the art (e.g., for the use of sodium borohydride, see Chemische Berichte, 1980, 113, 1907-1920). These oxidation or reduction steps can be achieved subsequent to the synthesis of intermediate 4 or otherwise after the synthesis of the present compound of general formula (I). Alternatively, intermediate 4 can be prepared via a Mitsunobu reaction (e.g., KCK Swamy et al. Chem. Rev. 2009, 109, 2551-2651) involving intermediate 3 and an optionally substituted alkyl alcohol. Various phosphines, such as triphenylphosphine, tributylphosphine, or 1,2-diphenylphosphinoethane, can be used in combination with diisopropyl azodicarboxylate (CAS 2446-83-5) or other diazene derivatives mentioned in the literature (KCK Swamy et al. Chem. Rev. 2009, 109, 2551-2651). Preferred is the use of triphenylphosphine and diisopropyl azodicarboxylate.If the alkyl alcohol has a functional group, as in the case of the above-mentioned reaction with alkyl halides, this can be achieved by known protecting group strategies (further pointers are given in PGM Wuts, TW Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541), and by an oxidation or reduction step, as in the case of the above-mentioned reaction with alkyl halides, corresponding to the synthesis of intermediate 4 or after the synthesis of the present compounds of general formula (I). Proceeding from intermediate 4, R 2 and R 3 is defined as C1-C6-alkyl 2 and R 3 have the same definition) can be obtained by Grignard reaction (for example, the reaction of 1H-indazole-6-carboxylic acid methyl derivatives with methylmagnesium bromide in EP 2489663). For the Grignard reaction, it is possible to use alkylmagnesium halides. Particularly preferred are methylmagnesium chloride or methylmagnesium bromide in THF or diethyl ether, or else in a mixture of THF and diethyl ether. Alternatively, from intermediate 4, R 2 and R 3 is defined as C1-C6-alkyl 2 and R 3 have the same definition) may be obtained by reaction with alkyllithium reagents (for example, the reaction of isopropyllithium or tert-isopropyllithium with methyl 2-amino-4-chloro-1-methyl-1H-benzimidazole-7-carboxylate derivatives in WO2006116412). Proceeding from intermediate 4, reduction with lithium aluminum hydride in THF, lithium borohydride in THF, or sodium borohydride in THF, or a mixture of lithium and sodium borohydride, optionally with the addition of methanol, gives R 2 and R3 It is possible to prepare the present compounds of general formula (I) where is defined as H.

[0168] Synthetic Scheme 3

[0169] [ka] Substituent R 1 , R 2 , R 3 , R 4 , R 5 are each as defined in general formula (I).

[0170] From intermediate 3, R 2 and R 3 Intermediate 5 (R 2 and R 3 have the same definition) can be obtained by Grignard reaction (see, for example, Synthesis Scheme 4). For this purpose, it is possible to use a suitable alkylmagnesium halide, such as methylmagnesium chloride or methylmagnesium bromide, in THF or diethyl ether or a mixture of THF and diethyl ether.

[0171] Then, proceeding from intermediate 5, R 2 and R 3 It is possible to prepare the moiety (Ia) of the compound (I) in which R is defined as C1-C6-alkyl. 2 and R 3 have the same definition). To this end, similar to Synthetic Scheme 3 (preparation of intermediate 3), a useful reaction is the reaction of intermediate 5 with an optionally substituted alkyl chloride, bromide, iodide, or alkyl 4-methylbenzenesulfonate. Protecting group strategies similar to those described in Synthetic Scheme 3 can be used.

[0172] Alternatively, R 2 and R 3Preparation of a part (Ia) of the compound (I) where R is defined as C1-C6-alkyl 2 and R 3 have the same definition), the Mitsunobu reaction of intermediate 5 can be used with optionally substituted alkyl alcohols (similar to synthesis scheme 3).

[0173] R in the compound of formula (Ia) 1 If contains a suitable functional group, then, as in Synthetic Scheme 3, oxidation or reduction reactions can optionally be used to prepare further compounds of this invention.

[0174] Synthetic Scheme 4

[0175] [ka]

[0176] Substituent R 1 , R 4 , R 5 are each as defined in general formula (I). 2 and R 3 always have the same definition, both are C1-C6 alkyl.

[0177] Proceeding from intermediate 1, intermediate 4 can be prepared in an alternative manner (see Synthetic Scheme 5). First, intermediate 1 is converted to intermediate 6 by the method of Synthetic Scheme 3 (Preparation of intermediate 4 from intermediate 3).

[0178] Intermediate 6 can then be converted to intermediate 7 by reducing the nitro group. For example, the nitro group can be reduced using palladium on carbon under a hydrogen atmosphere (see, for example, 6-isopropoxy-5-nitro-1H-indazole to 6-isopropoxy-1H-indazol-5-amine WO2013174744), or by using iron and ammonium chloride in water and ethanol (see, for example, Journal of the Chemical Society, 1955, 2412-2419), or by using tin(II) chloride (CAS 7772-99-8). The use of iron and ammonium chloride in water and ethanol is preferred. The preparation of intermediate 4 from intermediate 7 can be achieved similarly to Synthesis Scheme 2 (preparation of intermediate 3 from intermediate 2).

[0179] As described for Synthetic Scheme 3, a protecting group strategy can also be optionally used in the case of Synthetic Scheme 5. Optionally, proceeding from intermediate 6 or intermediate 7 as described for Synthetic Scheme 3, it is further possible to carry out oxidation or reduction reactions known to those skilled in the art (see, for example, Science of Synthesis, Georg Thieme Verlag).

[0180] Synthetic Scheme 5

[0181] [ka]

[0182] Substituent R 1 , R 4 , R 5 are each as defined in general formula (I).

[0183] Synthesis of exemplary compounds Abbreviations and Clarifications

[0184] [Table 1] The term "sodium chloride solution" always means saturated aqueous sodium chloride solution. Chemical names of intermediates and examples were generated using ACD / LABS (batch version 12.01.) software.

[0185] method In some cases, the compounds and their precursors and / or intermediates were analyzed by LC-MS.

[0186] Method A1: UPLC (MeCN-HCOOH): Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm, Eluent A: water + 0.1% by volume 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.

[0187] Method A2: UPLC (MeCN-NH): Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm, Eluent A: water + 0.2% (v / v) 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.

[0188] Method A3: (LC-MS) Instrument: Agilent 1290 Infinity LC; Column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm, Eluent A: water + 0.05% formic acid (volume), Eluent B: acetonitrile + 0.05% formic acid (volume), 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.

[0189] Method A4: (LC-MS) Instrument: Waters Acquity; Column: Kinetex (Phenomenex), 50 x 2 mm, Eluent A: water + 0.05% by volume formic acid, Eluent B: acetonitrile + 0.05% by volume 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 compounds and their precursors and / or intermediates were purified by the following exemplary preparative HPLC method.

[0190] Method P1: System: Waters Automated Purification System: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBridge C18 5 μm 100 × 30 mm, Eluent A: water + 0.1% formic acid (volume), Eluent B: acetonitrile, Gradient: 0–8 min 10–100% B, 8–10 min 100% B, Flow Rate: 50 ml / min, Temperature: Room temperature, Solution: Up to 250 mg / max DMSO or DMF up to 2.5 ml; Injection: 1 × 2.5 ml; Detection: DAD scan range 210–400 nm, MS ESI+, ESI-, scan range 160–1000 m / z.

[0191] Method P2: System: Waters Automated Purification System: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100; Column: XBridge C18 5 μm 10 x 30 mm, Eluent A: water + 0.2% ammonia (32%) by volume, Eluent B: methanol, Gradient: 0-8 min 30-70% B, Flow rate: 50 ml / min, Temperature: room temperature, Detection: DAD scan range 210-400 nm, MS ESI+, ESI-, scan range 160-1000 m / z, ELSD.

[0192] Method P3: System: Labomatic, Pump: HD-5000, Automated Fractionator: LABOCOL Vario-4000, UV Detector: Knauer UVD 2.1S; Column: XBridge C18 5 μm 100 × 30 mm, Eluent A: Water + 0.2% (volume) 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 Rate: 60 ml / min, Temperature: Room temperature, Solution: Max. 250 mg / 2 ml DMSO, Injection: 2 × 2 ml, Detection: UV 218 nm; Software: SCPA PrepCon5.

[0193] Method P4: system: Labomatic, pump: HD-5000, autosampler: LABOCOL Vario-4000, UV detector: Knauer UVD 2.1S; column: Chromatorex RP C18 10 μm 125 × 30 mm, eluent A: water + 0.1% formic acid (volume), eluent B: acetonitrile, gradient: 0–15 min 65–100% B, flow rate: 60 mL / min, temperature: room temperature, solution: max. 250 mg / 2 mL DMSO, injection: 2 × 2 mL, detection: UV 254 nm; software: SCPA PrepCon5.

[0194] Method P5: System: Sepiatec: Prep SFC100, Column: Chiralpak IA 5 μm 250 x 20 mm, Eluent A: carbon dioxide, Eluent B: ethanol, Gradient: isocratic 20% B, Flow rate: 80 ml / min, Temperature: 40 °C, Solution: max. 250 mg / 2 ml DMSO, Injection: 5 x 0.4 mL, Detection: UV 254 nm.

[0195] Method P6: System: Agilent: Prep 1200, 2 x Prep Pumps, 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 Rate: 25 mL / min, Temperature: 25 °C, Solution: 187 mg / 8 mL ethanol / methanol, Injection: 8 x 1.0 mL, Detection: UV 280 nm.

[0196] Method P7: System: Labomatic, Pump: HD-5000, Automated Fractionator: LABOCOL Vario-4000, UV Detector: Knauer UVD 2.1S; Column: XBridge C18 5 μm 100 × 30 mm, Eluent A: water + 0.1% by volume formic acid, Eluent B: acetonitrile, Gradient: 0–3 min: 65% B isocratic, 3–13 min: 65–100% B, Flow Rate: 60 ml / min, Temperature: Room temperature, Solution: Max. 250 mg / 2 ml DMSO, Injection: 2 × 2 ml, Detection: UV 254 nm.

[0197] Method P8: System: Agilent: Prep 1200, 2 x preparative pumps, 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 rate: 25 mL / min, Temperature: 25 °C, Solution: 600 mg / 7 ml N,N-dimethylformamide, Injection: 10 x 0.7 ml, Detection: UV 254 nm.

[0198] In some cases, the substance mixture was purified by column chromatography on silica gel.

[0199] For the preparation of some of the compounds described herein, as well as their precursors and / or intermediates, column chromatographic purification ("flash chromatography") can be carried out on silica gel using Biotage's Isolera® devices. This can be done using cartridges manufactured by Biotage, such as "SNAP Cartridges, KP_SIL" cartridges of different sizes, and "Interchim Puriflash Silica HP 15UM Flash Column" cartridges of different sizes manufactured by Interchim.

[0200] Starting materials Intermediate V2-1 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylic acid methyl ester

[0201] [ka]

[0202] 2.00 g (9.26 mmol) of 2-(6-bromopyridin-2-yl)propan-2-ol (CAS 638218-78-7) was dissolved in 20 ml of methanol and 20 ml of DMSO. Then, 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 with carbon monoxide three times at room temperature and stirred under a carbon monoxide atmosphere of 13 bar for 30 minutes. The carbon monoxide atmosphere was removed by applying a vacuum, and the mixture was stirred at 100 °C under a carbon monoxide atmosphere of 14 bar for 24 hours. The autoclave was depressurized, water was added to the reaction mixture, and the reaction mixture was extracted three times with ethyl acetate, washed with saturated aqueous sodium bicarbonate and sodium chloride solutions, filtered through a hydrophobic filter, and concentrated. This yielded 1.60 g of crude product. UPLC-MS (Method A1):R t=0.76 min (UV detector: TIC), actual mass: 195.00.

[0203] Intermediate V3-1 Potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate

[0204] [ka]

[0205] 1.60 g of the crude product of intermediate 0-1 was first placed in 15 ml of methanol, 0.74 g of potassium hydroxide was added, and the mixture was stirred for 16.5 hours at 50° C. After concentration, this gave 2.1 g of a residue, which was used without further purification. UPLC-MS (Method A1):R t =0.47 min (UV detector: TIC), actual mass: 181.00.

[0206] Intermediate 1-1 5-Nitro-1H-indazole-6-carboxylic acid methyl ester

[0207] [ka]

[0208] 4.60 g (26.1 mmol) of methyl 1H-indazole-6-carboxylate (CAS number: 170487-40-8) was dissolved in 120 ml of sulfuric acid (96%) and cooled to −15° C. in a three-necked flask equipped with a CPG stirrer, a dropping funnel, and an internal thermometer. Over a period of 15 minutes, pre-prepared and cooled nitric acid (10 ml of 96% sulfuric acid in 5 ml of 65% nitric acid) was added dropwise to this solution. After the addition was complete, the mixture was stirred for another hour (internal temperature −13° C.). The reaction mixture was added to ice, and the precipitate was filtered with suction, washed with water, and dried at 50° C. in a drying cabinet under reduced pressure. 5.49 g of the title compound was obtained. UPLC-MS (Method A2):R t =0.75 minutes MS (ESIpos): m / z = 222 (M+H) + 1 H 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).

[0209] Intermediate 2-1 5-Amino-1H-indazole-6-carboxylic acid methyl ester

[0210] [ka]

[0211] 4.40 g (19.8 mmol) of methyl 5-nitro-1H-indazole-6-carboxylate (Intermediate 1-1) was dissolved in 236 ml of methanol and hydrogenated over 1.06 g (0.99 mmol) of palladium on activated carbon at 25° C. under standard hydrogen pressure for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was washed with methanol and concentrated to give 3.53 g of the title compound. 1 H 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).

[0212] Intermediate 3-1 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate methyl ester

[0213] [ka]

[0214] 4.95 g (25.9 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid was initially placed 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 minutes. 4.50 g (23.5 mmol) of methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 2-1) was then added, and the mixture was stirred at 25 ° C for 24 hours. The reaction mixture was filtered with suction through a membrane filter, and the solid was washed with THF and water and dried overnight in a drying cabinet. 7.60 g of the title compound was obtained. UPLC-MS (Method A2):R t =1.16 minutes MS (ESIpos): m / z = 365 (M+H) + 1 H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.97 (s, 3 H), 8.13 - 8.27 (m, 2 H), 8.30 (s, 1 H), 8.33 - 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).

[0215] Intermediate 3-2 5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate methyl ester

[0216] [ka]

[0217] 2.85 g (23.5 mmol) of 6-(difluoromethyl)pyridine-2-carboxylic acid was initially placed 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. Then, 3.00 g (15.7 mmol) of methyl 5-amino-1H-indazole-6-carboxylate was added, and the mixture was stirred at room temperature overnight. The reaction mixture was mixed with water, and the precipitate was filtered with suction and washed repeatedly with water and dichloromethane. This yielded 1.53 g (27% of theory) of the title compound. The filtrate phases were separated, and the organic phase was concentrated, mixed with a small amount of dichloromethane, suspended in an ultrasonic bath, and the precipitate was filtered 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).

[0218] Intermediate 3-3 5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate methyl ester

[0219] [ka]

[0220] 2.10 g of potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate (Intermediate V3-1) was initially placed 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 minutes. Then, 1.83 g (9.58 mmol) of methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 2-1) was added, and the mixture was stirred at room temperature for 19 hours. The mixture was mixed with water and ethyl acetate, the undissolved solids were filtered, the filtrate phases 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). After removal of the solvent, 1.56 g of the title compound was obtained as a yellow foam. UPLC-MS (Method A1):R t =1.00 min (UV detector: TIC smooth), actual mass: 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).

[0221] Intermediate 4-1 2-(Oxetan-3-ylmethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate methyl ester

[0222] [ka]

[0223] 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 1.10 g (7.99 mmol) of potassium carbonate and 221 mg (1.33 mmol) of potassium iodide were added. The mixture was stirred at 25° C. for 30 minutes. 603 mg (3.99 mmol) of 3-bromomethyloxetane was added, and the mixture was stirred at 25° C. for 24 hours. 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 was obtained. UPLC-MS (Method A2):R t =1.24 minutes MS (ESIpos): m / z = 435(M+H) + 1 H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.49 - 3.64 (m, 1 H), 3.95 (s, 3 H), 4.49 (t, 2 H), 4.68 (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).

[0224] Intermediate 4-2 2-(2-Methoxyethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate methyl ester

[0225] [ka]

[0226] 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 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 with stirring. The reaction mixture was stirred at 25 ° C. for 24 hours, 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 was obtained. UPLC-MS (Method A1):R t =1.24 minutes MS (ESIpos): m / z = 423 (M+H) + 1 H 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).

[0227] Intermediate 4-3 2-(3-Methoxypropyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate methyl ester

[0228] [ka]

[0229] 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 with stirring. The reaction mixture was stirred at 25 ° C. for 72 hours, 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). 28 mg of the title compound was obtained. UPLC-MS (Method A1):R t =1.29 minutes MS (ESIpos): m / z = 437 (M+H) + 1 H 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).

[0230] Intermediate 4-4 2-(3-hydroxy-3-methylbutyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate methyl ester Preparation method 1

[0231] [ka]

[0232] 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 placed in 9 ml of DMF, and the mixture was stirred for 15 minutes. Then, 0.62 ml of 4-bromo-2-methylbutan-2-ol was added, and the mixture was stirred at 60 °C for 16 hours. The mixture was mixed with water, 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):R t =1.21 min (UV detector: TIC), actual mass: 450.00. 1 H-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)

[0233] Preparation method 2 1.95 g (7.03 mmol) of methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate (Intermediate 7-1) was initially placed 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 hours. Water was added, and the mixture was extracted three times with ethyl acetate. 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 was obtained. UPLC-MS (Method A1):R t =1.23 min (UV detector: TIC), actual mass: 450.00.

[0234] Intermediate 4-5 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate methyl ester

[0235] [ka] 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 placed in 50 mL of DMF, and 1.10 g (7.99 mmol) of potassium carbonate and 221 mg (1.33 mmol) of potassium iodide were added with stirring, and the mixture was stirred at 25 ° C. for 30 minutes. Then, 857 μl (3.99 mmol) of (2-bromoethoxy)(tert-butyl)dimethylsilane was added, and the mixture was stirred at 25 ° C. for 24 hours. 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 was obtained. UPLC-MS (Method A1):R t =1.58 minutes MS (ESIpos): m / z = 523 (M+H) + 1 H 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, 3 H), 9.07 (s, 1 H), 12.53 (s, 1 H).

[0236] Intermediate 4-6 2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate methyl ester

[0237] [ka]

[0238] Similarly to Intermediate 4-5, 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 10 ml of DMF, 1.14 g (8.24 mmol) of potassium carbonate, and 228 mg (1.37 mmol) of potassium iodide with stirring, and the mixture was stirred at 25 ° C. for 30 minutes. Then, 1.04 g (4.12 mmol) of (3-bromopropoxy)(tert-butyl)dimethylsilane was added, and the mixture was stirred at 25 ° C. for 24 hours. The reaction mixture was filtered, and the filter cake 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 afforded 428 mg of the title compound. UPLC-MS (Method A1):R t =1.63 minutes MS (ESIpos): m / z = 537(M+H) + 1 H NMR (400 MHz, DMSO-d6): δ [ppm] = -0.02 - 0.06 (m, 6 H), 0.87 (s, 9 H), 2.14 (quin, 2 H), 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 (m, 3 H), 8.49 - 8.53 (m, 1 H), 9.06 (s, 1 H).

[0239] Intermediate 4-7 5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-2-(4,4,4-trifluorobutyl)-2H-indazole-6-carboxylate

[0240] [ka]

[0241] 300 mg (0.80 mmol) of methyl 5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (Intermediate 3-3) was initially placed 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 hours. 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):R t =1.26 min (UV detector: TIC), actual mass: 464.17.

[0242] Intermediate 4-8 5-{[(5-fluoro-6-methylpyridin-2-yl)carbonyl]amino}-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate

[0243] [ka]

[0244] 195 mg (0.46 mmol) of methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate (Intermediate 7-1) was reacted with 78 mg (0.50 mmol) of 5-fluoro-6-methylpyridine-2-carboxylic acid, similar to Intermediate 4-4 (Preparation Method 2), within 19.5 hours. After a similar aqueous workup, 228 mg of crude product was obtained. UPLC-MS (Method A1):R t =1.20 min (UV detector: TIC), actual mass: 414.00.

[0245] Intermediate 4-9 2-(3-hydroxy-3-methylbutyl)-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazole-6-carboxylate methyl ester

[0246] [ka]

[0247] 195 mg (0.45 mmol) of methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate (Intermediate 7-1) was reacted with 70 mg (0.50 mmol) of 6-methylpyridine-2-carboxylic acid in a similar manner to the preparation of Intermediate 4-4 (Preparation Method 2) within 19.5 hours. After a similar aqueous workup, 278 mg of the title compound was obtained as a crude product. UPLC-MS (Method A1):R t =1.14 min (UV detector: TIC), actual mass: 396.00.

[0248] Intermediate 4-10 2-[3-(2,2,2-trifluoroethoxy)propyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate methyl ester

[0249] [ka]

[0250] 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 hours. 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):R t =1.39 min (UV detector: TIC), actual mass: 504.12.

[0251] Intermediate 4-11 5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate

[0252] [ka]

[0253] 2.00 g of methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate (Intermediate 7-1) was initially placed 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 No. 125700-67-6), and 1.5 ml of N-ethyl-N-isopropylpropan-2-amine were added, and the mixture was stirred at room temperature for 24 hours. Water was added, and the mixture was extracted three times with ethyl acetate. 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 afforded 3.05 g of the title compound as a yellow solid. UPLC-MS (Method A1): Rt = 1.15 min (UV detector TIC), observed mass: 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).

[0254] Intermediate 5-1 N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0255] [ka]

[0256] To a solution of 1.50 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, cooled in an ice-water cooling bath, 6.9 ml (5 equivalents) of a 3 M solution of methylmagnesium bromide in diethyl ether was carefully added. The mixture was stirred with cooling in an ice bath for 1 hour and at room temperature for 19.5 hours. Another 2 equivalents of methylmagnesium bromide solution was added, and the mixture was stirred at room temperature for another 24 hours. 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 was 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).

[0257] Intermediate 5-2 6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]pyridine-2-carboxamide

[0258] [ka]

[0259] In a manner similar to the preparation of intermediate 5-1, 2.40 g (6.93 mmol) of methyl 5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (intermediate 3-2) in 10 ml THF was reacted with three portions of a 3 M methylmagnesium bromide solution in diethyl ether (6.9 ml, then stirred at room temperature for 45 minutes; 11.6 ml, then stirred at room temperature for 2 hours; 6.9 ml, then stirred at room temperature for 2 hours). After refinement for intermediate 5-1, 2.39 g of crude product was obtained, which was used further without further purification.

[0260] Intermediate 6-1 2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-carboxylate methyl ester

[0261] [ka]

[0262] 5.00 g (22.6 mmol) of methyl 5-nitro-1H-indazole-6-carboxylate (Intermediate 1-1) was initially placed 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 hours. Water was added, and the mixture was extracted three times with ethyl acetate. 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 resulting solid was stirred with diethyl ether, filtered with suction, washed with diethyl ether, and dried. 2.49 g of the title compound was obtained. UPLC-MS (Method A1):R t =0.93 min (UV detector: TIC), actual mass: 307.00. 1 H-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).

[0263] Intermediate 7-1 5-Amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylic acid methyl ester

[0264] [ka]

[0265] 4.53 g of iron and 217 mg of 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 hours. The mixture was filtered through Celite, washed three times with ethanol, the filtrate was concentrated, and the residue was mixed with water. Extraction was carried out three times with ethyl acetate (sodium chloride solution was added to improve phase separation). 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):R t =0.67 min (UV detector: TIC), actual mass: 277.00. 1 H-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).

[0266] Treatment of osteoarthritis The IRAK4 inhibitors described herein, including but not limited to Compound 1, can be used in methods for treating and preventing osteoarthritis, pain, optionally pain associated with osteoarthritis, inflammation, optionally inflammation associated with osteoarthritis, or a combination thereof. The compositions 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, 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, including but not limited to Compound 1, can be used to treat osteoarthritis.

[0267] Compound 1 can be used, for example, in methods for treating and preventing pain and inflammation associated with osteoarthritis. Compositions described herein that include Compound 1 can be used to treat pain, optionally pain associated with osteoarthritis. Compositions described herein that include Compound 1 can be used to treat inflammation, optionally inflammation associated with osteoarthritis. Compositions described herein that include Compound 1 can be used to treat osteoarthritis.

[0268] Treating acute pain Since the synovitis model induces acute pain, compounds effective in this model are effective in treating intraoperative pain.

[0269] The IRAK4 inhibitors described herein, optionally Compound 1, may be used in methods for the treatment and / or prevention of pain, optionally perioperative pain, postoperative pain, or a combination thereof.

[0270] Compound 1 can be used in methods for treating and preventing pain and inflammation, for example, associated with intra- and post-operative pain management.

[0271] composition The compositions described herein can include an effective amount of an IRAK4 inhibitor described herein, optionally Compound 1. For example, an effective amount of an IRAK4 inhibitor described herein, optionally Compound 1, can be about 1 mg / kg to 25 mg / kg, about 3 mg / kg to 20 mg / kg, about 5 mg / kg to 15 mg / kg, about 8 mg / kg to 12 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 20 mg / kg. An effective amount of an 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.

[0272] The compositions described herein can include an effective amount of Compound 1. In one example, an effective amount of Compound 1 can be about 1 mg / kg to 25 mg / kg, about 3 mg / kg to 20 mg / kg, about 5 mg / kg to 15 mg / kg, about 8 mg / kg to 12 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 20 mg / kg. An 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.

[0273] The compositions described herein may be pharmaceutical compositions. The compositions described herein, including pharmaceutical compositions, may include an antibody or antigen-binding fragment described herein, as well as an adjuvant, carrier, buffer, antioxidant, wetting agent, lubricant, gelling agent, thickener, binder, disintegrant, wetting agent, preservative, diluent, stabilizer, filler, excipient, or a combination thereof.

[0274] Pharmaceutical excipients and additives useful in the compositions described herein also include proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides, including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides; derivatized saccharides, including but not limited to alditols, aldonic acids, esterified saccharides, or combinations thereof; and polysaccharides or sugar polymers), which may be present alone or in combinations ranging from 1 to 99.99% by weight or volume. Exemplary protein excipients include serum albumins, including but not limited to human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, or combinations thereof. Representative amino acid components that may also function in buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, or combinations thereof.

[0275] 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, maltodextrin, dextran, starch, or combinations thereof), and alditols (including but not limited to mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), myo-inositol, or combinations thereof).

[0276] The compositions described herein may further comprise pharmaceutically acceptable carriers, including, but not limited to, coloring agents, emulsifying agents, suspending agents, ethanol, EDTA, citrate buffer, flavoring agents, and water.

[0277] Chelating agents, including but not limited to EDTA and EGTA, can be optionally added to the pharmaceutical composition to reduce aggregation.These additives are particularly useful when the pharmaceutical composition is administered using a pump or plastic container.The presence of a pharmaceutically acceptable surfactant reduces the tendency of the composition to aggregate.

[0278] The compositions described herein may also include 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 p-hydroxybenzoate, or ETHYL PARASEPT), propylparaben (also known as 4-hydroxybenzoic acid propyl ester and propyl p-hydroxybenzoate, NIPASOL, or PROPYL CHEMOSEPT), and / or butylparaben (also known as 4-hydroxybenzoic acid propyl ester, propyl p-hydroxybenzoate, or BUTYL CHEMOSEPT).

[0279] 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, dimethylformamide, oils, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0280] The pharmaceutical composition containing Compound 1 may also contain a buffer or pH adjuster. Typically, the buffer is a salt prepared from an organic acid or organic base. Representative buffers include organic acid salts, including, but not limited to, citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid salts, Tris, tromethamine hydrochloride, or phosphate buffers.

[0281] Additionally, the pharmaceutical compositions described herein may contain polymeric excipients / additives, including, but not limited to, polyvinylpyrrolidone, Ficoll (polymeric sugars), dextrates (e.g., cyclodextrins, including but not limited to hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic 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.

[0282] Other excipients, such as tonicity agents, buffers, antioxidants, and preservative enhancers, can be optionally added to the diluent. Tonicity agents, including but not limited to glycerin, are commonly used at known concentrations. It is preferable to add a physiologically acceptable buffer to improve pH control. Suitable buffers include phosphate buffer, sodium phosphate, and phosphate-buffered saline (PBS).

[0283] The IRAK4 inhibitors described herein, optionally Compound 1, can be solubilized or suspended in a preconcentrate (before dilution with a diluent), added to the preconcentrate before dilution, added to the diluted preconcentrate, or added to the diluent before 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.

[0284] Compound 1 can be solubilized or suspended in a preconcentrate (before dilution with a diluent), added to the preconcentrate before dilution, added to the diluted preconcentrate, or added to the diluent before 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.

[0285] The pharmaceutical compositions described herein may also include additional therapeutic agents, including, but not limited to, hydrophilic drugs, hydrophobic drugs, hydrophilic macromolecules, cytokines, peptidomimetics, peptides, proteins, serum, antibodies, vaccines, nucleosides, nucleotides, nucleoside analogs, genetic material, or combinations thereof.

[0286] The additional therapeutic agent may be solubilized or suspended in the preconcentrate (before dilution with the diluent), added to the preconcentrate before dilution, added to the diluted preconcentrate, or added to the diluent before mixing with the preconcentrate. The additional therapeutic agent may also be co-administered as part of a separate dosage form for therapeutic effect. Optionally, the additional therapeutic agent may be present in a first solubilized amount and a second non-solubilized (suspended) amount. Such mammalian additions include, but are not limited to, drugs, nutrients, and diagnostic agents.

[0287] For oral administration in the form of tablets, optionally chewable tablets, or capsules, 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. Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars including 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, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, or combinations thereof. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, or combinations thereof. Flavoring agents can be added to the tablets, optionally chewable tablets, and can include, but are not limited to, meat flavors, optionally poultry, or fish flavors, or combinations thereof.

[0288] For oral administration in the form of tablets, optionally chewable tablets, or capsules, 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. Furthermore, if desired or necessary, suitable binders, lubricants, disintegrants, and coloring agents can also be incorporated into the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars including 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, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, or combinations thereof. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, or combinations thereof. Flavoring agents can be added to tablets, optionally chewable tablets. Flavoring agents may include, but are not limited to, meat flavors, optionally poultry, or fish flavors, or combinations thereof.

[0289] Pharmaceutical compositions described herein suitable for oral administration may be presented as discrete units, including, but not limited to, capsules, dragees, cachets, or tablets, each containing a predetermined amount of an IRAK4 inhibitor described herein, optionally Compound 1, a powder or granules, a solution or suspension in an aqueous liquid or a non-aqueous liquid, or an oil-in-water liquid emulsion or a water-in-oil emulsion, and a bolus.

[0290] Pharmaceutical compositions described herein suitable for oral administration may be presented as discrete units including, but not limited to, capsules, dragees, cachets, or tablets, powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, and boluses, each containing a predetermined amount of Compound 1.

[0291] Tablets 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 an IRAK4 inhibitor 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 agent, or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of a powdered IRAK4 inhibitor described herein, optionally Compound 1, moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated to provide sustained or controlled release of an IRAK4 inhibitor described herein, optionally Compound 1.

[0292] Tablets 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 agent, or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of powdered Compound 1 moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of Compound 1.

[0293] Dosage The pharmaceutical compositions described herein can be administered to a subject in a manner known in the art. The dose administered will depend on the age, health, and weight of the recipient, the type of concomitant therapy, if any, the frequency of treatment, and the nature of the desired effect.

[0294] The IRAK4 inhibitors described herein, optionally Compound 1, can be present in any suitable amount in the pharmaceutical compositions described herein. One of ordinary skill in the art can readily determine the appropriate concentration of the IRAK4 inhibitors described herein, optionally Compound 1, to include in the pharmaceutical composition, depending on various factors, including dosage and route of administration.

[0295] Compound 1 can be present in any suitable amount in the pharmaceutical compositions described herein. Those skilled in the art can easily determine the appropriate concentration of Compound 1 to include in the pharmaceutical composition, depending on various factors, including dosage and route of administration.

[0296] 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 an IRAK4 inhibitor described herein, optionally Compound 1.

[0297] 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.

[0298] The pharmaceutical composition may be administered in a single daily dose, or the total daily dose may be administered in divided doses two, three, or four times daily. Doses may be administered over the course of one week, one month, or several months, three months, six months, nine months, or twelve months, or over intervals known in the art and determined to be clinically relevant. Doses may be continued throughout the patient's lifetime or discontinued as indicated by clinical judgment. The daily dosage of the formulation may vary over a range of about 1 to 25 mg / kg per day, about 5 to 15 mg / kg per day, 2.5 to 17.5 mg / kg per day, or equivalent doses as determined by a physician to achieve clinically meaningful serum concentrations.

[0299] The compositions described herein may be administered by a route including, but not limited to, oral, parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intracapsular, intrachondral, intracavitary, intraperitoneal, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraperiosteal, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, intravaginal, rectal, buccal, sublingual, intranasal, iontophoretic, transdermal, or a combination of routes. The compositions include Compound 1, which may be formulated for oral administration. [Example]

[0300] [Example 1] N-[6-(2-hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0301] [ka]

[0302] 75 mg (0.18 mmol) of methyl 2-(2-methoxyethyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Intermediate 4-2) was dissolved in 500 μl of THF and mixed with 887 μl (0.89 mmol) of a 1 M solution of methylmagnesium bromide in THF. The reaction mixture was stirred at 25° C. for 60 minutes. 1 ml of saturated aqueous ammonium chloride solution was then carefully added, 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 lyophilized to give 20 mg of the title compound. UPLC-MS (Method A1):R t =1.08 minutes MS (ESIpos): m / z = 423 (M+H) + 1 H 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 (s, 1 H), 12.36 (s, 1 H)

[0303] [Example 2] N-[6-(hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0304] [ka]

[0305] 13 mg (0.36 mmol) of lithium aluminum hydride was 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 was added dropwise, and the mixture was stirred at 25 ° C. for 60 minutes. 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):R t =0.99 minutes MS (ESIpos): m / z = 394 (M+H) + 1 H 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)

[0306] [Example 3] N-[6-(2-hydroxypropan-2-yl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0307] [ka]

[0308] 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) was dissolved in 500 μl of THF and mixed with 859 μl (0.86 mmol) of a 1 M solution of methylmagnesium bromide in THF. The reaction mixture was stirred at 25° C. for 60 minutes. 1 ml of saturated ammonium chloride solution was then carefully added, 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 lyophilized. 25 mg of the title compound was obtained. UPLC-MS (Method A1):R t =1.13 minutes MS (ESIpos): m / z = 437 (M+H) + 1 H NMR (400 MHz, DMSO-d6): δ [ppm] = 1.62 (s, 6 H), 2.14 (quin, 2 H), 3.23 (s, 3 H), 3.26 - 3.32 (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), 8.43 - 8.48 (m, 1 H), 8.72 (s, 1 H), 12.36 (s, 1 H).

[0309] [Example 4] N-[6-(hydroxymethyl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0310] [ka]

[0311] 13 mg of lithium aluminum hydride was 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 was added dropwise, and the mixture was allowed to reach room temperature within 30 minutes. The mixture was diluted with water, filtered, the residue was washed with ethyl acetate, and the filtrate was extracted with ethyl acetate. The combined ethyl acetate phases were washed with sodium chloride solution, filtered through a hydrophobic filter, and concentrated. The residue was purified by preparative HPLC. 1 H 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).

[0312] [Example 5] N-[2-(2-hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0313] Phase A: 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

[0314] [ka]

[0315] 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) was dissolved in 1 ml of THF and mixed 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 minutes. Another 287 μl (0.29 mmol) of a 1 M methylmagnesium bromide solution in THF was added, and the mixture was stirred at 25° C. for 3 hours. Then, 20 ml of saturated ammonium chloride solution was carefully added, and the mixture was filtered. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, dried over magnesium sulfate, 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):R t =1.51 minutes MS (ESIpos): m / z = 523 (M+H) + 1 H 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).

[0316] Stage B:

[0317] [ka]

[0318] 50 mg (96 μmol) of N-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide was dissolved in 1.0 ml of THF and mixed with 144 μl (0.14 mmol) of a 1 M tetrabutylammonium fluoride solution in THF. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted twice with ethyl acetate. 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). 1 H-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):R t =0.97 min (UV detector: TIC), actual mass: 408.00.

[0319] [Example 6] N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0320] Phase A: 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

[0321] [ka]

[0322] 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) was dissolved in 500 μl of THF and mixed with 326 μl (0.33 mmol) of a 1 M solution of methylmagnesium bromide in THF. The reaction mixture was stirred at 25° C. for 60 minutes. Then, 20 ml of saturated ammonium chloride solution was carefully added, and the mixture was extracted twice with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter, concentrated under reduced pressure, and dried. 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 was obtained. UPLC-MS (Method A1):R t =1.58 minutes MS (ESIpos): m / z = 537(M+H) + 1 H 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).

[0323] Stage B:

[0324] [ka]

[0325] 37 mg (0.07 mmol) of N-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide was dissolved in 500 μl of THF and mixed with 207 μl (0.21 mmol) of a 1 M tetrabutylammonium fluoride solution in THF. The reaction mixture was stirred at 25 ° C. for 2 hours. The mixture was diluted with water and extracted twice with ethyl acetate. 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, containing secondary components) was obtained. UPLC-MS (Method A2):R t =1.00 minutes MS (ESIpos): m / z = 423 (M+H) + 1 H NMR selected signals (400 MHz, DMSO-d6): δ [ppm] = 1.61 (s), 2.00 - 2.12 (m), 3.38 (t, 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).

[0326] [Example 7] N-[2-(2-hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0327] Phase A: N-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0328] [ka]

[0329] 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) was dissolved in 1 ml of THF and mixed with 191 μl (0.38 mmol) of 2 M lithium borohydride solution. The mixture was stirred at 25 ° C for 24 hours. 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 hours. Another 14 mg (0.38 mmol) of sodium borohydride was added, and the mixture was stirred at 25 ° C for 24 hours. Water was carefully added 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 to give 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):R t =1.44 minutes 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 - 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).

[0330] Stage B:

[0331] [ka]

[0332] 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 was dissolved in 1 ml of THF and mixed 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 hour. The mixture was diluted with water, 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) was obtained. UPLC-MS (Method A2):R t =0.87 minutes 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, 1 H), 5.70 - 5.81 (m, 1 H), 7.57 (s, 1 H), 8.11 - 8.23 (m, 1 H), 8.31 - 8.42 (m, 2 H), 8.43 - 8.49 (m, 1 H), 8.51 (s, 1 H), 11.20 (s, 1 H).

[0333] [Example 8] N-[6-(2-hydroxypropan-2-yl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0334] [ka]

[0335] 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) was dissolved in 500 μl of THF and mixed with 576 μl (0.58 mmol) of a 1 M solution of methylmagnesium bromide in THF.

[0336] The reaction mixture was stirred at 25°C for 60 minutes. Then, 20 ml of saturated aqueous ammonium chloride solution was carefully added, and the mixture was concentrated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 2.0 ml of DMSO and purified by preparative HPLC. The product-containing fractions were lyophilized to obtain 30 mg of the title compound. UPLC-MS (Method A2):R t =1.03 minutes 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).

[0337] [Example 9] N-[6-(hydroxymethyl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0338] [ka]

[0339] 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) was dissolved in 1 ml of a mixture of THF / methanol (1:1), and 8 mg (0.21 mmol) of sodium borohydride was added. The mixture was stirred at 25° C. for 60 minutes. The reaction mixture was concentrated, and the residue was mixed with water. The suspension was stirred vigorously for 15 minutes, and the solid was filtered off with suction, washed twice with water and twice with diethyl ether, and dried under reduced pressure. 48 mg of the title compound was obtained. UPLC-MS (Method A2):R t =0.94 minutes MS (ESIpos): m / z = 407 (M+H) + 1H 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).

[0340] [Example 10] N-{6-(2-hydroxypropan-2-yl)-2-[3-(methylsulfonyl)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

[0341] [ka]

[0342] 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 minutes. 414 mg of 1-bromo-3-(methylsulfonyl)propane was added, and the mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted twice with ethyl acetate. 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 was obtained. UPLC-MS (Method A2):R t =1.02 minutes 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).

[0343] [Example 11] N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0344] [ka]

[0345] Preparation method 1 705 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) was initially charged in 10 ml of THF and cooled in an ice-water cooling bath. 2.6 ml (5.0 equivalents) of a 3 M methylmagnesium bromide solution (in diethyl ether) was added, and the mixture was stirred with cooling in an ice bath for 1 hour and at room temperature for 4.5 hours. Another equivalent of methylmagnesium bromide solution was added, and the mixture was stirred at room temperature for 20.5 hours. Another equivalent of methylmagnesium bromide solution was added again, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was mixed 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 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 and subsequent drying, a further 146 mg of the title compound was obtained. UPLC-MS (Method A1):R t =1.10 min (UV detector: TIC), actual mass: 450.00. 1 H-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).

[0346] Preparation method 2 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 minutes. 344 mg (1.5 equivalents) of 4-bromo-2-methylbutan-2-ol was added, and the mixture was heated to 100 °C for 2 hours. Another 0.5 equivalents of 4-bromo-2-methylbutan-2-ol was added, and the mixture was stirred at room temperature for 16 hours. The mixture was mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, filtered through a hydrophobic filter, and concentrated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate). This gave 100 mg of the product fraction, which was stirred with diethyl ether. The solid was filtered and dried to give 60 mg of the title compound. 1 H-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)

[0347] [Example 12] N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

[0348] [ka]

[0349] 160 mg (0.44 mmol) of N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1) was suspended in 1.0 ml of DMF with 182 mg of potassium carbonate and 36 mg of potassium iodide, and the mixture was stirred at room temperature for 15 minutes. Then, 123 mg of 2-bromoethylmethylsulfone (0.66 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted twice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride, filtered through a hydrophobic filter, and concentrated. Purification of the residue by preparative HPLC afforded 20 mg of the title compound. UPLC (Method A2):R t =1.01 minutes, MS (ESIpos): m / z = 471 (M+H)+ 1 H 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).

[0350] [Example 13] 6-(Difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]pyridine-2-carboxamide

[0351] [ka]

[0352] Preparation method 1 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 minutes. 145 mg (0.87 mmol) of 4-bromo-2-methylbutan-2-ol was added, and the mixture was stirred at 110°C for 3 hours. Another 96 mg of 4-bromo-2-methylbutan-2-ol was added, and the mixture was stirred at 110°C for 4 hours. Water was added, and the mixture was extracted twice with ethyl acetate. The extracts were washed with half-saturated aqueous sodium chloride, filtered through a hydrophobic filter, and concentrated. Purification was carried out by column chromatography on silica gel (hexane / ethyl acetate). 61 mg of the title compound was obtained. UPLC-MS (Method A1):R t =1.00 min (UV detector: TIC), actual mass: 432.00. 1 H-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).

[0353] Preparation method 2 In a manner similar 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 (Intermediates 4-11) was reacted with a 3 M solution of methylmagnesium bromide in diethyl ether. After stirring with diethyl ether and filtration, followed by purification of the crude product by preparative HPLC, 1.37 g of the title compound was obtained.

[0354] [Example 14] 6-(Difluoromethyl)-N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

[0355] [ka]

[0356] 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 minutes. 162 mg of 2-bromoethylmethylsulfone (0.87 mmol) was added, and the mixture was stirred at 110 °C for 3 hours. Water was added, and the mixture was extracted twice with ethyl acetate. The extracts were washed with semi-saturated aqueous sodium chloride solution, filtered through a hydrophobic filter, and concentrated. The residue was purified by preparative HPLC, and the product fraction was further purified by column chromatography on silica gel (hexane / ethyl acetate). 40 mg of the title compound was obtained. 1 H-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).

[0357] [Example 15] 6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]pyridine-2-carboxamide

[0358] Phase A: Preparation of N-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(difluoromethyl)pyridine-2-carboxamide

[0359] [ka] 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 minutes. 219 mg (0.87 mmol, 1.5 equivalents) of (3-bromopropoxy)(tert-butyl)dimethylsilane was added, and the mixture was stirred at 110°C for 3 hours. Another equivalent of (3-bromopropoxy)(tert-butyl)dimethylsilane was added, and the mixture was stirred at 100°C for 4 hours. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride, filtered through a hydrophobic filter, and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate). 92 mg of the title compound was obtained.

[0360] Stage B:

[0361] [ka]

[0362] In Step B, similar to the preparation of Example 6, 92 mg of N-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(difluoromethyl)pyridine-2-carboxamide was reacted with 0.53 ml of a 1 M solution of tetrabutylammonium fluoride in THF within 1 hour. Aqueous workup as described in Example 6 and purification by preparative HPLC gave 46 mg of the title compound. UPLC-MS (Method A1):R t =0.92 min (UV detector: TIC), actual mass: 404.00. 1 H-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).

[0363] [Example 16] N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

[0364] [ka]

[0365] A mixture of 210 mg (0.58 mmol) of N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1) in 3 ml of DMF was mixed 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 hours. After adding 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 was obtained. UPLC-MS (Method A1):R t =1.27 min (UV detector: TIC), actual mass: 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).

[0366] [Example 17] N-{6-(2-hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

[0367] [ka]

[0368] 150 mg (0.33 mmol) of N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1) was 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 hours. 0.83 ml of sodium hydroxide solution (2 M) was added, and the mixture was stirred at 40 °C for 5 hours. The mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were concentrated and purified by preparative HPLC. 16 mg of the title compound was obtained as a crude product. UPLC-MS (Method A2):R t =1.26 min (UV detector: TIC), actual mass: 490.14. 1H-NMR (400 MHz, 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).

[0369] [Example 18] N-{6-(2-hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

[0370] [ka]

[0371] In a similar manner to the preparation of Example 11 (Preparation Method 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 was reacted with 2 × 171 μl of a 3 M magnesium bromide solution in diethyl ether. Purification by preparative HPLC afforded 12 mg of the title compound. UPLC-MS (Method A1):R t =1.25 min (UV detector: TIC), actual mass: 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).

[0372] [Example 19] 5-Fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide

[0373] [ka]

[0374] 228 mg (0.31 mmol) of methyl 5-{[(5-fluoro-6-methylpyridin-2-yl)carbonyl]amino}-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate (Intermediate 4-8) was initially charged in 4.5 ml of THF and cooled in an ice bath. 0.63 ml of 3 M methylmagnesium bromide solution (diethyl ether) was added, and the mixture was stirred in an ice bath for 2 hours and at room temperature for 21 hours while cooling. The reaction mixture was mixed with saturated aqueous ammonium chloride 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 was obtained. UPLC-MS (Method A2):R t =1.03 min (UV detector: TIC), actual mass: 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).

[0375] [Example 20] N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide

[0376] [ka]

[0377] 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) was initially charged in 5.0 ml of THF and cooled in an ice bath. 0.97 ml of 3 M methylmagnesium bromide solution (diethyl ether) was added, and the mixture was stirred in an ice bath for 2 hours and at room temperature for 20.5 hours with cooling. Another 0.48 ml of 3 M methylmagnesium bromide solution was added, and the mixture was stirred at room temperature for 67 hours. The mixture was mixed with saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, and the extract was 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 was obtained. UPLC-MS (Method A2):R t =0.97 min (UV detector: TIC), actual mass: 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).

[0378] [Example 21] 6-(2-hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]pyridine-2-carboxamide

[0379] [ka]

[0380] A solution of 72 mg (0.16 mmol) of methyl 5-({[6-(2-hydroxypropan-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 a 3 M solution of methylmagnesium bromide in diethyl ether was added, and the mixture was stirred for 2 h, then at room temperature for 20 h. Another 1 equivalent of a 3 M solution of methylmagnesium bromide was added, and the mixture was stirred at room temperature for 24 h. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The extracts were washed with sodium chloride solution and concentrated. Preparative HPLC afforded 22 mg (31% of theory) of the title compound. UPLC-MS (Method A2):R t =1.15 min (UV detector: TIC), actual mass: 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).

[0381] [Example 22] N-{2-[2-(1-hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

[0382] [ka]

[0383] 250 mg (0.69 mmol) of N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1) was 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 hours. Water was added, and the mixture was 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 preparative HPLC (column: Waters XBridge C18 5μ 100 × 30 mm, eluent A: water + 0.1% by volume of formic acid (99%), eluent B: acetonitrile). Lyophilization afforded 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).

[0384] [Example 23] Testing of Compound 1 (Formula I) Formulations Evaluation of the 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.

[0385] Induced acute synovitis model In the induced acute synovitis model in dogs, a urinary sodium suspension is injected into the canine synovial joint, which induces pain, inflammation, and loss of function for approximately 8-12 hours in most dogs.

[0386] Gait analysis Dogs were evaluated using gait analysis at various time points after induction of synovitis using a single intra-articular injection of a uric acid crystal suspension.

[0387] Gait analysis was measured by pacing the animals at a constant speed across a pressure channel five times per time point. The study was a blinded, placebo-controlled, three-phase crossover design in 15 dogs.

[0388] Dogs were administered placebo (empty gelatin capsule), 15 mg / kg Compound 1, or 5 mg / kg Compound 1 once daily for 5 consecutive days. Each treatment was administered to 15 dogs over the course of the study (5 dogs per treatment per phase), with at least a 16-day washout between phases.

[0389] At each stage, pain and inflammation were induced in each dog approximately 1 hour after treatment on treatment day 5. Gait analysis was performed before each uric acid injection and 5, 6, 7, 8, 9, 10, and 12 hours after injection.

[0390] result Surprisingly, dogs treated with Compound 1 showed minimal or no pain and lameness after synovitis induction, an effect size not demonstrated with any other class of drugs other than NSAIDs. Compound 1 strongly reduced acute pain and improved lameness significantly better than placebo, demonstrating better efficacy in this setting compared to previous and published data on non-NSAID mechanisms of action. As shown in Figure 1, placebo-treated dogs were minimally or completely unweighted within 4 hours of synovitis induction, while Compound 1-treated dogs were completely weight-bearing or had very minimal lameness at both the 5 mg / kg and 15 mg / kg treatments. Statistically significant (p<0.05) improvements in pain and inflammation were observed as improvements in weight-bearing lameness compared to placebo by 8 hours in 15 mg / kg-treated dogs and by 10 hours in 5 mg / kg-treated dogs.

[0391] Although the present invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will 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 will be understood in light of the foregoing disclosure or that will be apparent to those skilled in the veterinary, pharmacokinetic, and / or related fields through routine practice or implementation of the invention are intended to fall within the scope of the following claims.

[0392] 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.

[0393] While the foregoing invention has been described in connection with this preferred embodiment, it should not be limited thereby, but rather only by the scope of the following claims.

Claims

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

2. 10. 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. 10. The method of claim 1, wherein the inflammation is associated with osteoarthritis.

5. 1. A method for treating or preventing osteoarthritis in a mammal, comprising administering an effective amount of a composition comprising an IRAK4 inhibitor, wherein the IRAK4 inhibitor is a compound of general formula (I): 【Chemistry 1】 (In the formula, R １ But C １ -C ６ -alkyl, and said C １ -C ６ - alkyl group is halogen, hydroxyl, unsubstituted or mono- or poly-halogen substituted C ３ -C ６ -cycloalkyl, or R ６ , R ７ SO ２ , R ７ SO or R ８ O group or is unsubstituted, mono- or polysubstituted by groups selected from the following, which may be the same or different: 【Chemistry 2】 where * represents the point of attachment of the group to the rest of the molecule; R ２ and R ３ always have the same definition and are hydrogen or C １ -C ６ alkyl, R ４ is halogen, cyano, unsubstituted or single or multiple, identical or different substituted C １ -C ６ - alkyl, or unsubstituted or singly or multiply, identically or differently substituted C ３ -C ６ -cycloalkyl, said substituents being selected from the group of halogen and hydroxyl, R ５ is hydrogen, halogen, or unsubstituted or mono- or poly-halogen substituted C １ -C ６ is alkyl, R ６ However, O, S, SO and SO ２ is an unsubstituted or monomethyl- or dimethyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms containing a heteroatom or hetero group from the group R ７ But C １ -C ６ -alkyl, and said C １ -C ６ - the alkyl group is halogen, hydroxyl, or C ３ -C ６ -cycloalkyl, which may be identically or differently unsubstituted, monosubstituted or polysubstituted, or R ７ is C ３ -C ６ -cycloalkyl, R ８ But C １ -C ６ -alkyl, and said C １ -C ６ - alkyl groups which are identically or differently unsubstituted, mono- or polysubstituted by halogens), and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof.

6. R １ But C １ -C ６ -alkyl, and said C １ -C ６ - the alkyl group is fluorine, hydroxyl, or R ６ , R ７ SO ２ , R ７ SO, or R ８ unsubstituted, mono- or polysubstituted by identical or different O groups, R ２ and R ３ always have the same definition and are hydrogen or C １ -C ３ alkyl, R ４ is halogen, cyano, or C １ -C ３ -alkyl, and said C １ -C ３ the alkyl groups are unsubstituted, mono- or polysubstituted, identically or differently, by halogen or hydroxyl, R ５ is hydrogen, fluorine, chlorine, or C １ -C ３ - alkyl, R ６ is oxetanyl or tetrahydrofuranyl, R ７ But C １ -C ４ -alkyl, and said C １ -C ４ the alkyl group is unsubstituted, monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms, R ８ is unsubstituted C １ -C ４ -Alkyl group or tri-fluorine substituted C １ -C ４ The method of claim 5, wherein the alkyl group is -.

7. R ４ The method of claim 5 or 6, wherein is difluoromethyl, trifluoromethyl, or methyl.

8. R ５ The method according to any one of claims 5 to 7, wherein is hydrogen or fluorine.

9. R ２ and R ３ The method of any one of claims 5 to 8, wherein both are either hydrogen or methyl.

10. R １ But C ２ -C ６ -alkyl, and said C ２ -C ６ - the alkyl group is unsubstituted or C ２ -C ６ the alkyl group is mono-, di- or trifluorine substituted, or C ２ -C ６ - the alkyl group is hydroxyl, R ６ , R ７ SO ２ , or R ８ monosubstituted by O or R １ is an oxetanyl-substituted C １ -C ３ - is an alkyl group, R ２ and R ３ always have the same definition and are both either hydrogen or methyl, R ４ is unsubstituted or mono- or poly-halogen-substituted C １ -C ３ - alkyl group or C substituted with one hydroxyl group １ -C ３ - alkyl group or C substituted with one hydroxyl group and three fluorine atoms １ -C ３ - is an alkyl group, R ５ is hydrogen, fluorine, or C １ -C ３ - alkyl, R ７ But C １ -C ３ - alkyl, R ８ But C １ -C ４ -alkyl, and said C １ -C ４ 7. The method of claim 6, wherein the alkyl group is unsubstituted, mono-, di-, or tri-fluorine substituted.

11. R １ is hydroxyl or C １ -C ３ -C substituted by alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl ２ -C ５ - alkyl group or methyl -SO ２ - Substitution C ２ -C ４ -alkyl group or oxetan-3-yl substituted C １ -C ２ - is an alkyl group, R ２ and R ３ always have the same definition and are both hydrogen or methyl, R ４ However, methyl, ethyl, trifluoro-C １ -C ３ -Alkyl, difluoro-C １ -C ３ -alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl; R ５ The method of claim 10, wherein is hydrogen, fluorine, or methyl.

12. R １ is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulfonyl)ethyl, or 3-(methylsulfonyl)propyl; R ２ and R ３ are both methyl or hydrogen, R ４ is difluoromethyl, trifluoromethyl, or methyl; R ５ The method of claim 10, wherein is hydrogen or fluorine.

13. R １ is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl; R ２ and R ３ But both are methyl, R ４ is difluoromethyl or trifluoromethyl, R ５ The method of claim 12 , wherein is hydrogen.

14. R １ is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl; R ２ and R ３ But both are methyl, R ４ is methyl, R ５ is fluorine, and R ５ is R ４ The method of claim 12, wherein the hydroxyl group is in the ortho position relative to

15. 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-(methylsulfonyl)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-(methylsulfonyl)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-(methylsulfonyl)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 The method according to any one of claims 1 to 14, wherein the compound is N-{2-[2-(1-hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide.

16. The method of any one of claims 1 to 5, wherein the IRAK4 inhibitor is compound 1. 【Transformation 3】

17. 17. The method of any one of claims 1 to 16, wherein the composition comprising an effective amount of an IRAK4 inhibitor treats pain associated with osteoarthritis.

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

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

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

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

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

25. 25. The method of any one of claims 1 to 24, wherein the composition is administered once, twice, three times, four times, or five times daily.

26. 25. The method of any one of claims 1 to 24, wherein the composition is administered every other day.

27. 27. The method of any one of claims 1 to 26, wherein the composition is administered once daily.

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

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

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

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

33. 1. A method of treating pain in a mammal, comprising administering a composition comprising an effective amount of an IRAK4 inhibitor, wherein the IRAK4 inhibitor is a compound of general formula (I): 【Chemistry 4】 (In the formula, R １ But C １ -C ６ -alkyl, and said C １ -C ６ - alkyl group is halogen, hydroxyl, unsubstituted or mono- or poly-halogen substituted C ３ -C ６ -cycloalkyl, or R ６ , R ７ SO ２ , R ７ SO or R ８ O group or is unsubstituted, mono- or polysubstituted by groups selected from the following, which may be the same or different: 【Transformation 5】 where * represents the point of attachment of the group to the rest of the molecule; R ２ and R ３ always have the same definition and both are hydrogen or C １ -C ６ alkyl, R ４ is halogen, cyano, unsubstituted or single or multiple, identical or different substituted C １ -C ６ - alkyl, or unsubstituted or singly or multiply, identically or differently substituted C ３ -C ６ -cycloalkyl, the substituents being selected from the group halogen and hydroxyl, R ５ is hydrogen, halogen, or unsubstituted or mono- or poly-halogen substituted C １ -C ６ is alkyl, R ６ However, O, S, SO and SO ２ is an unsubstituted or monomethyl- or dimethyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms containing a heteroatom or hetero group from the group R ７ But C １ -C ６ -alkyl, and said C １ -C ６ - the alkyl group is halogen, hydroxyl, or C ３ -C ６ -cycloalkyl, which may be identically or differently unsubstituted, monosubstituted or polysubstituted, or R ７ is C ３ -C ６ -cycloalkyl, R ８ But C １ -C ６ -alkyl, and said C １ -C ６ - alkyl groups which are identically or differently unsubstituted, mono- or polysubstituted by halogens), and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof.

34. R １ But C １ -C ６ -alkyl, and said C １ -C ６ - the alkyl group is fluorine, hydroxyl, or R ６ , R ７ SO ２ , R ７ SO, or R ８ unsubstituted, mono- or polysubstituted by identical or different O groups, R ２ and R ３ always have the same definition and both are hydrogen or C １ -C ３ alkyl, R ４ is halogen, cyano, or C １ -C ３ -alkyl, and said C １ -C ３ the alkyl groups are identically or differently unsubstituted, mono- or polysubstituted by halogen or hydroxyl, R ５ is hydrogen, fluorine, chlorine, or C １ -C ３ - alkyl, R ６ is oxetanyl or tetrahydrofuranyl, R ７ But C １ -C ４ -alkyl, and said C １ -C ４ the alkyl group is unsubstituted, monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms, R ８ is unsubstituted C １ -C ４ -Alkyl group or tri-fluorine substituted C １ -C ４ The method of claim 33, wherein the - is an alkyl group.

35. R ４ 35. The method of claim 33 or 34, wherein is difluoromethyl, trifluoromethyl, or methyl.

36. R ５ The method of any one of claims 33 to 35, wherein is hydrogen or fluorine.

37. R ２ and R ３ The method of any one of claims 33 to 36, wherein both are either hydrogen or methyl.

38. R １ But C ２ -C ６ -alkyl, and said C ２ -C ６ - the alkyl group is unsubstituted or C ２ -C ６ the alkyl group is mono-, di- or trifluorine substituted, or C ２ -C ６ - the alkyl group is hydroxyl, R ６ , R ７ SO ２ , or R ８ monosubstituted by O or R １ is an oxetanyl-substituted C １ -C ３ - is an alkyl group, R ２ and R ３ always have the same definition and are both either hydrogen or methyl, R ４ is unsubstituted or mono- or poly-halogen-substituted C １ -C ３ - alkyl group or C substituted with one hydroxyl group １ -C ３ - alkyl group or C substituted with one hydroxyl group and three fluorine atoms １ -C ３ - is an alkyl group, R ５ is hydrogen, fluorine, or C １ -C ３ - alkyl, R ７ But C １ -C ３ - alkyl, R ８ But C １ -C ４ -alkyl, and said C １ -C ４ 35. The method of claim 34, wherein the alkyl group is unsubstituted, mono-, di-, or tri-fluorine substituted.

39. R １ is hydroxyl or C １ -C ３ -C substituted by alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl ２ -C ５ - alkyl group or methyl -SO ２ - Substitution C ２ -C ４ -alkyl group or oxetan-3-yl substituted C １ -C ２ - is an alkyl group, R ２ and R ３ always have the same definition and are both hydrogen or methyl, R ４ However, methyl, ethyl, trifluoro-C １ -C ３ -Alkyl, difluoro-C １ -C ３ -alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl; R ５ 39. The method of claim 38, wherein is hydrogen, fluorine, or methyl.

40. R １ is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulfonyl)ethyl, or 3-(methylsulfonyl)propyl; R ２ and R ３ are both methyl or hydrogen, R ４ is difluoromethyl, trifluoromethyl, or methyl; R ５ 39. The method of claim 38, wherein is hydrogen or fluorine.

41. R １ is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl; R ２ and R ３ But both are methyl, R ４ is difluoromethyl or trifluoromethyl, R ５ 41. The method of claim 40, wherein is hydrogen.

42. R １ is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl; R ２ and R ３ But both are methyl, R ４ is methyl, R ５ is fluorine, and R ５ is R ４ 41. The method of claim 40, wherein the aryl group is in the ortho position relative to

43. 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-(methylsulfonyl)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-(methylsulfonyl)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-(methylsulfonyl)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 The method according to any one of claims 33 to 42, wherein the compound is N-{2-[2-(1-hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide.

44. 34. The method of claim 33, wherein the IRAK4 inhibitor is compound 1. 【Transformation 6】

45. 45. The method of any one of claims 33 to 44, wherein the pain is associated with osteoarthritis.

46. The method of claim 4451, wherein the pain is perioperative.

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

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

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

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

51. 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. 52. The method of any one of claims 33-51, wherein the effective amount is about 5 mg / kg of the IRAK4 inhibitor.

53. 53. The method of any one of claims 33-52, wherein the effective amount is about 15 mg / kg of the IRAK4 inhibitor.

54. 54. The method of any one of claims 33-53, wherein the composition is administered once, twice, three times, four times, or five times daily.

55. 55. The method of any one of claims 33 to 54, wherein the composition is administered once daily.

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

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

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

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

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

62. 1. A method of treating inflammation in a mammal, comprising administering an effective amount of a composition, wherein said IRAK4 inhibitor is a compound of general formula (I): 【Transformation 7】 (In the formula, R １ But C １ -C ６ -alkyl, and said C １ -C ６ - alkyl group is halogen, hydroxyl, unsubstituted or mono- or poly-halogen substituted C ３ -C ６ -cycloalkyl, or R ６ , R ７ SO ２ , R ７ SO or R ８ O group or is unsubstituted, mono- or polysubstituted by groups selected from the following, which may be the same or different: 【Transformation 8】 where * represents the point of attachment of the group to the rest of the molecule; R ２ and R ３ always have the same definition and both are hydrogen or C １ -C ６ alkyl, R ４ is halogen, cyano, unsubstituted or single or multiple, identical or different substituted C １ -C ６ - alkyl, or unsubstituted or singly or multiply, identically or differently substituted C ３ -C ６ -cycloalkyl, said substituents being selected from the group of halogen and hydroxyl, R ５ is hydrogen, halogen, or unsubstituted or mono- or poly-halogen substituted C １ -C ６ is alkyl, R ６ However, O, S, SO and SO ２ is an unsubstituted or monomethyl- or dimethyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms containing a heteroatom or hetero group from the group R ７ But C １ -C ６ -alkyl, and said C １ -C ６ - the alkyl group is halogen, hydroxyl, or C ３ -C ６ -cycloalkyl, which may be identically or differently unsubstituted, monosubstituted or polysubstituted, or R ７ is C ３ -C ６ -cycloalkyl, R ８ But C １ -C ６ -alkyl, and said C １ -C ６ - alkyl groups which are identically or differently unsubstituted, mono- or polysubstituted by halogens), and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof.

63. R １ But C １ -C ６ -alkyl, and said C １ -C ６ - the alkyl group is fluorine, hydroxyl, or R ６ , R ７ SO ２ , R ７ SO, or R ８ are identically or differently unsubstituted, mono- or polysubstituted by O groups, R ２ and R ３ always have the same definition and both are hydrogen or C １ -C ３ alkyl, R ４ is halogen, cyano, or C １ -C ３ -alkyl, and said C １ -C ３ the alkyl groups are identically or differently unsubstituted, mono- or polysubstituted by halogen or hydroxyl, R ５ is hydrogen, fluorine, chlorine, or C １ -C ３ - alkyl, R ６ is oxetanyl or tetrahydrofuranyl, R ７ But C １ -C ４ -alkyl, and said C １ -C ４ the alkyl group is unsubstituted, monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms, R ８ is unsubstituted C １ -C ４ -Alkyl group or tri-fluorine substituted C １ -C ４ The method of claim 62, wherein the - is an alkyl group.

64. R ４ 64. The method of claim 62 or 63, wherein is difluoromethyl, trifluoromethyl, or methyl.

65. R ５ 65. The method of any one of claims 62 to 64, wherein is hydrogen or fluorine.

66. R ２ and R ３ The method of any one of claims 62 to 65, wherein both are either hydrogen or methyl.

67. R １ But C ２ -C ６ -alkyl, and said C ２ -C ６ - the alkyl group is unsubstituted or C ２ -C ６ the alkyl group is mono-, di- or trifluorine substituted, or C ２ -C ６ - the alkyl group is hydroxyl, R ６ , R ７ SO ２ , or R ８ monosubstituted by O or R １ is an oxetanyl-substituted C １ -C ３ - is an alkyl group, R ２ and R ３ always have the same definition and are both either hydrogen or methyl, R ４ is unsubstituted or mono- or poly-halogen-substituted C １ -C ３ - alkyl group or C substituted with one hydroxyl group １ -C ３ - alkyl group or C substituted with one hydroxyl group and three fluorine atoms １ -C ３ - is an alkyl group, R ５ is hydrogen, fluorine, or C １ -C ３ - alkyl, R ７ But C １ -C ３ - alkyl, R ８ But C １ -C ４ -alkyl, and said C １ -C ４ 64. The method of claim 63, wherein the alkyl group is unsubstituted, mono-, di-, or tri-fluorine substituted.

68. R １ is hydroxyl or C １ -C ３ -C substituted by alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl ２ -C ５ - alkyl group or methyl -SO ２ - Substitution C ２ -C ４ -alkyl group or oxetan-3-yl substituted C １ -C ２ - is an alkyl group, R ２ and R ３ always have the same definition and are both hydrogen or methyl, R ４ However, methyl, ethyl, trifluoro-C １ -C ３ -Alkyl, difluoro-C １ -C ３ -alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl; R ５ 68. The method of claim 67, wherein is hydrogen, fluorine, or methyl.

69. R １ is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulfonyl)ethyl, or 3-(methylsulfonyl)propyl; R ２ and R ３ are both methyl or hydrogen, R ４ is difluoromethyl, trifluoromethyl, or methyl; R ５ 69. The method of claim 68, wherein is hydrogen or fluorine.

70. R １ is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl; R ２ and R ３ But both are methyl, R ４ is difluoromethyl or trifluoromethyl, R ５ 70. The method of claim 69, wherein is hydrogen.

71. R １ is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl; R ２ and R ３ But both are methyl, R ４ is methyl, R ５ is fluorine, and R ５ is R ４ 70. The method of claim 69, wherein the carboxyl group is in the ortho position relative to

72. 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-(methylsulfonyl)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-(methylsulfonyl)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-(methylsulfonyl)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 72. The method of any one of claims 62 to 71, wherein the compound is N-{2-[2-(1-hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide.

73. 63. The method of claim 62, wherein the IRAK4 inhibitor is compound 1. 【Chemistry 9】

74. 63. The method of claim 62, wherein the inflammation is associated with osteoarthritis.

75. 63. The method of claim 62, wherein the inflammation is associated with degenerative joint disease (DJD).

76. 63. The method of claim 62, wherein the inflammation is associated with inflammatory bowel disease (IBD), diabetes mellitus, kidney disease, disc disease, and allergic inflammation, or a combination thereof.

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

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

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

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

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

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

84. 82. The method of any one of claims 62-81, wherein the composition is administered once, twice, three times, four times, or five times daily.

85. 85. The method of any one of claims 62 to 84, wherein the composition is administered once daily.

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

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

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

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

91. 91. The method of any one of claims 62 to 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.

93. 1. 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 said IRAK4 inhibitor is a compound of general formula (I): 【Chemistry 10】 (In the formula, R １ But C １ -C ６ -alkyl, and said C １ -C ６ - alkyl group is halogen, hydroxyl, unsubstituted or mono- or poly-halogen substituted C ３ -C ６ -cycloalkyl, or R ６ , R ７ SO ２ , R ７ SO or R ８ O group or is unsubstituted, mono- or polysubstituted by groups selected from the following, which may be the same or different: 【Chemistry 11】 where * represents the point of attachment of the group to the rest of the molecule; R ２ and R ３ always have the same definition and both are hydrogen or C １ -C ６ alkyl, R ４ is halogen, cyano, unsubstituted or single or multiple, identical or different substituted C １ -C ６ - alkyl, or unsubstituted or singly or multiply, identically or differently substituted C ３ -C ６ -cycloalkyl, said substituents being selected from the group of halogen and hydroxyl, R ５ is hydrogen, halogen, or unsubstituted or mono- or poly-halogen substituted C １ -C ６ is alkyl, R ６ However, O, S, SO and SO ２ is an unsubstituted or monomethyl- or dimethyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms containing a heteroatom or hetero group from the group R ７ But C １ -C ６ -alkyl, and said C １ -C ６ - the alkyl group is halogen, hydroxyl, or C ３ -C ６ -cycloalkyl, which may be identically or differently unsubstituted, monosubstituted or polysubstituted, or R ７ is C ３ -C ６ -cycloalkyl, R ８ But C １ -C ６ -alkyl, and said C １ -C ６ - alkyl groups which are identically or differently unsubstituted, mono- or polysubstituted by halogens), and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of salts thereof.

94. R １ But C １ -C ６ -alkyl, and said C １ -C ６ - the alkyl group is fluorine, hydroxyl, or R ６ , R ７ SO ２ , R ７ SO, or R ８ unsubstituted, mono- or polysubstituted by identical or different O groups, R ２ and R ３ always have the same definition and both are hydrogen or C １ -C ３ alkyl, R ４ is halogen, cyano, or C １ -C ３ -alkyl, and said C １ -C ３ the alkyl groups are unsubstituted, mono- or polysubstituted, identically or differently, by halogen or hydroxyl, R ５ is hydrogen, fluorine, chlorine, or C １ -C ３ - alkyl, R ６ is oxetanyl or tetrahydrofuranyl, R ７ But C １ -C ４ -alkyl, and said C １ -C ４ the alkyl group is unsubstituted, monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms, R ８ is unsubstituted C １ -C ４ -Alkyl group or tri-fluorine substituted C １ -C ４ - alkyl group.

95. R ４ 95. The method of claim 93 or 94, wherein is difluoromethyl, trifluoromethyl, or methyl.

96. R ５ The method of any one of claims 93 to 95, wherein is hydrogen or fluorine.

97. R ２ and R ３ The method of any one of claims 93 to 96, wherein both are either hydrogen or methyl.

98. R １ But C ２ -C ６ -alkyl, wherein C ２ -C ６ - the alkyl group is unsubstituted or C ２ -C ６ the alkyl group is mono-, di- or trifluorine substituted, or C ２ -C ６ - the alkyl group is hydroxyl, R ６ , R ７ SO ２ , or R ８ monosubstituted by O or R １ is an oxetanyl-substituted C １ -C ３ - is an alkyl group, R ２ and R ３ always have the same definition and are both either hydrogen or methyl, R ４ is unsubstituted or mono- or poly-halogen-substituted C １ -C ３ - alkyl group or C substituted with one hydroxyl group １ -C ３ - alkyl group or C substituted with one hydroxyl group and three fluorine atoms １ -C ３ - is an alkyl group, R ５ is hydrogen, fluorine, or C １ -C ３ - alkyl, R ７ But C １ -C ３ - alkyl, R ８ But C １ -C ４ -alkyl, and said C １ -C ４ 95. The method of claim 94, wherein the alkyl group is unsubstituted, mono-, di-, or tri-fluorine substituted.

99. R １ is hydroxyl or C １ -C ３ -C substituted by alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl ２ -C ５ - alkyl group or methyl -SO ２ - Substitution C ２ -C ４ -alkyl group or oxetan-3-yl substituted C １ -C ２ - is an alkyl group, R ２ and R ３ always have the same definition and are both hydrogen or methyl, R ４ However, methyl, ethyl, trifluoro-C １ -C ３ -Alkyl, difluoro-C １ -C ３ -alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, and 2,2,2-trifluoro-1-hydroxyethyl; R ５ 98. The method of claim 97, wherein is hydrogen, fluorine, or methyl.

100. R １ is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulfonyl)ethyl, or 3-(methylsulfonyl)propyl; R ２ and R ３ are both methyl or hydrogen, R ４ is difluoromethyl, trifluoromethyl, or methyl; R ５ 100. The method of claim 99, wherein is hydrogen or fluorine.

101. R １ is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl; R ２ and R ３ But both are methyl, R ４ is difluoromethyl or trifluoromethyl, R ５ is hydrogen.

102. R １ is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulfonyl)propyl, or 2-(methylsulfonyl)ethyl; R ２ and R ３ But both are methyl, R ４ is methyl, R ５ is fluorine, and R ５ is R ４ The method of claim 100, wherein the compound is in the ortho position relative to

103. 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-(methylsulfonyl)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-(methylsulfonyl)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-(methylsulfonyl)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 The method according to any one of claims 92 to 102, wherein the compound is N-{2-[2-(1-hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide.

104. 94. The method of claim 93, wherein the IRAK4 inhibitor is compound 1. 【Chemistry 12】

105. 105. The method of any one of claims 92 to 104, wherein the mammal is a dog, cat, horse, pig, cow, sheep, or goat.

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

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

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

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

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

112. 112. The method of any one of claims 92-111, wherein the composition is administered once, twice, three times, four times, or five times daily.

113. 113. The method of any one of claims 92 to 112, wherein the composition is administered once daily.

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

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

116. 116. The method of claim 115, wherein the carrier is an excipient, lubricant, antioxidant, emulsifier, stabilizer, solvent, diluent, buffer, vehicle, or a combination thereof.

117. 117. The method of any one of claims 92 to 116, wherein the composition is in the form of a tablet, optionally a chewable tablet.

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

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

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