Use of 2-substituted indazoles for the treatment and prophylaxis of autoimmune diseases

Abstract

The present application relates to substituted indazoles, to the use thereof alone or in combinations for treatment and/or prophylaxis of autoimmune disorders, and to the use thereof for production of medicaments for treatment and/or prophylaxis of autoimmune disorders, especially for treatment and/or prophylaxis of arthritides (especially psoriatic arthritis, rheumatoid arthritis, Bekhterev's disease, reactive arthritis, systematic juvenile idiopathic arthritis), systematic lupus erythematosus, multiple sclerosis, psoriasis, atopic dermatitis, allergic eczema and chronic-inflammatory bowel disorders (especially Crohn's disease and ulcerative colitis).

1 : A method for treatment or prophylaxis of an autoimmune disorder, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 1 -C 6 -alkyl, wherein the C 1 -C 6 -alkyl radical is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl, an unsubstituted or mono- or poly-halogen-substituted C 3 -C 6 -cycloalkyl, or an R 6 , R 7 SO 2 , R 7 SO or R 8 O radical,
 or a group selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         wherein * represents the bonding site of the group to the rest of the molecule; 
         R 2  and R 3  always have the same definition and are both either hydrogen or C 1 -C 6 -alkyl; 
         R 4  is halogen, cyano, an unsubstituted or a singly or multiply, identically or differently substituted C 1 -C 6 -alkyl or an unsubstituted or a singly or multiply, identically or differently substituted C 3 -C 6 -cycloalkyl, and the substituents are selected from the group consisting of halogen and hydroxyl; 
         R 5  is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C 1 -C 6 -alkyl; 
         R 6  is an unsubstituted or mono- or di-methyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms, which contains a heteroatom or a heterogroup selected from the group consisting of O, S, SO and SO 2 ; 
         R 7  is C 1 -C 6 -alkyl, wherein the C 1 -C 6 -alkyl radical is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C 3 -C 6 -cycloalkyl; or R 7  is C 3 -C 6 -cycloalkyl; and 
         R 8  is C 1 -C 6 -alkyl, wherein the C 1 -C 6 -alkyl radical is unsubstituted or mono- or polysubstituted identically or differently by halogen, 
         or a diastereomer, an enantiomer, a metabolite, a salt, a solvate, or a solvate of a salt thereof, and wherein the autoimmune disorder is mediated by IRAK4. 
       
     
     
         2 : The method of  claim 1 , wherein:
 R 1  is C 1 -C 6 -alkyl, wherein the C 1 -C 6 -alkyl radical is unsubstituted or mono- or polysubstituted identically or differently by fluorine, hydroxyl, or an R 6 , R 7 SO 2 , R 7 SO or R 8 O radical;   R 2  and R 3  always have the same definition and are both either hydrogen or C 1 -C 3 -alkyl;   R 4  is halogen, cyano, or C 1 -C 3 -alkyl, wherein the C 1 -C 3 -alkyl radical is unsubstituted or mono- or polysubstituted identically or differently by halogen or hydroxyl;   R 5  is hydrogen, fluorine, chlorine, or C 1 -C 3 -alkyl;   R 6  is oxetanyl or tetrahydrofuranyl;   R 7  is C 1 -C 4 -alkyl, wherein the C 1 -C 4 -alkyl radical is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms, and   R 8  is an unsubstituted C 1 -C 4 -alkyl radical or a tri-fluorine-substituted C 1 -C 4 -alkyl radical.   
     
     
         3 : The method of  claim 1 , wherein R 4  is difluoromethyl, trifluoromethyl or methyl. 
     
     
         4 : The method of  claim 1 , wherein R 5  is hydrogen or fluorine. 
     
     
         5 : The method of  claim 1 , wherein R 2  and R 3  are both either hydrogen or methyl. 
     
     
         6 : The method of  claim 2 , wherein:
 R 1  is C 2 -C 6 -alkyl, wherein the C 2 -C 6 -alkyl radical is unsubstituted, or
 the C 2 -C 6 -alkyl radical is mono-, di- or tri-fluorine-substituted or 
 the C 2 -C 6 -alkyl radical is monosubstituted by hydroxyl, R 6 , R 7 SO 2 , or R 8 O, or 
   R 1  is an oxetanyl-substituted C 1 -C 3 -alkyl radical;   R 2  and R 3  always have the same definition and are both either hydrogen or methyl;   R 4  is an unsubstituted or mono- or poly-halogen-substituted C 1 -C 3 -alkyl radical or a C 1 -C 3 -alkyl radical substituted by one hydroxyl group or a C 1 -C 3 -alkyl radical substituted by one hydroxyl group and three fluorine atoms;   R 5  is hydrogen, fluorine, or C 1 -C 3 -alkyl;   R 7  is C 1 -C 3 -alkyl, and   R 8  is C 1 -C 4 -alkyl, wherein the C 1 -C 4 -alkyl radical is unsubstituted or mono-, di- or tri-fluorine-substituted.   
     
     
         7 : The method of  claim 6 , wherein:
 R 1  is a C 2 -C 5 -alkyl radical substituted by hydroxyl or C 1 -C 3 -alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy or trifluoromethyl, or   R 1  is a methyl-SO 2 -substituted C 2 -C 4 -alkyl radical, or   R 1  is an oxetan-3-yl-substituted C 1 -C 2 -alkyl radical;   R 2  and R 3  always have the same definition and are both hydrogen or methyl;   R 4  is methyl, ethyl, trifluoro-C 1 -C 3 -alkyl, difluoro-C 1 -C 3 -alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, or 2,2,2-trifluoro-1-hydroxyethyl, and   R 5  is hydrogen, fluorine, or methyl.   
     
     
         8 : The method of  claim 7 , wherein:
 R 1  is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulphonyl)ethyl, or 3-(methylsulphonyl)propyl;   R 2  and R 3  are both methyl or hydrogen;   R 4  is difluoromethyl, trifluoromethyl, or methyl, and   R 5  is hydrogen or fluorine.   
     
     
         9 : The method of  claim 8 , wherein:
 R 1  is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulphonyl)propyl, or 2-(methylsulphonyl)ethyl;   R 2  and R 3  are both methyl;   R 4  is difluoromethyl or trifluoromethyl, and   R 5  is hydrogen.   
     
     
         10 : The method of  claim 8 , wherein:
 R 1  is 3-hydroxy-3-methylbutyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-(methylsulphonyl)propyl, or 2-(methylsulphonyl)ethyl;   R 2  and R 3  are both methyl;   R 4  is methyl, and   R 5  is fluorine, wherein R 5  is in the ortho position to R 4 .   
     
     
         11 : The method of  claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
 1) N-[6-(2-Hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;   2) N-[6-(Hydroxymethyl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide,   3) N-[6-(2-Hydroxypropan-2-yl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide,   4) N-[6-(Hydroxymethyl)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide,   5) N-[2-(2-Hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide,   6) N-[6-(2-Hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide,   7) N-[2-(2-Hydroxyethyl)-6-(hydroxymethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;   8) N-[6-(2-Hydroxypropan-2-yl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide,   9) N-[6-(Hydroxymethyl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;   10) N-{6-(2-Hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;   11) N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;   12) N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;   13) 6-(Difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]pyridine-2-carboxamide;   14) 6-(Difluoromethyl)-N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}pyridine-2-carboxamide,   15) 6-(Difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]pyridine-2-carboxamide;   16) N-[6-(2-Hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;   17) N-{6-(2-Hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;   18) N-{6-(2-Hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;   19) 5-Fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide;   20) N-[2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide,   21) 6-(2-Hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]pyridine-2-carboxamide, and   22) N-{2-[2-(1-Hydroxycyclopropyl)ethyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide.   
     
     
         12 : The method of  claim 1 , wherein the autoimmune disorder is selected from the group consisting of multiple sclerosis, systemic lupus erythematosus, psoriasis, arthritis, chronic-inflammatory bowel disorder, atopic dermatitis and allergic eczema. 
     
     
         13 : A method for treatment or prophylaxis of pain, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 1 -C 6 -alkyl, wherein the C 1 -C 6 -alkyl radical is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl, an unsubstituted or mono- or poly-halogen-substituted C 3 -C 6 -cycloalkyl, or an R 6 , R 7 SO 2 , R 7 SO or R 8 O radical,
 or a group selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         wherein * represents the bonding site of the group to the rest of the molecule; 
         R 2  and R 3  always have the same definition and are both either hydrogen or C 1 -C 6 -alkyl; 
         R 4  is halogen, cyano, an unsubstituted or a singly or multiply, identically or differently substituted C 1 -C 6 -alkyl or an unsubstituted or a singly or multiply, identically or differently substituted C 3 -C 6 -cycloalkyl, and the substituents are selected from the group consisting of halogen and hydroxyl; 
         R 5  is hydrogen, halogen or an unsubstituted or mono- or poly-halogen-substituted C 1 -C 6 -alkyl; 
         R 6  is an unsubstituted or mono- or di-methyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms, which contains a heteroatom or a heterogroup selected from the group consisting of O, S, SO and SO 2 ; 
         R 7  is C 1 -C 6 -alkyl, wherein the C 1 -C 6 -alkyl radical is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C 3 -C 6 -cycloalkyl; or R 7  is C 3 -C 6 -cycloalkyl; and 
         R 8  is C 1 -C 6 -alkyl, wherein the C 1 -C 6 -alkyl radical is unsubstituted or mono- or polysubstituted identically or differently by halogen, 
         or a diastereomer, an enantiomer, a metabolite, a salt, a solvate, or a solvate of a salt thereof. 
       
     
     
         14 - 16 . (canceled) 
     
     
         17 : A method for treatment or prophylaxis of an autoimmune disorder, comprising administering to a patient in need thereof an effective amount of a compound of formula (III) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is 4,4,4-trifluorobutyl, 3-hydroxy-3-methylbutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 3-hydroxy-2-methylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl, 2-hydroxyethyl, 2-(methylsulphonyl)ethyl, 3-(methylsulphonyl)propyl, or 2-(1-hydroxycyclopropyl)ethyl; 
         R 4  is difluoromethyl, trifluoromethyl or methyl; and 
         R 5  is hydrogen or fluorine, 
         or a diastereomer, an enantiomer, a metabolite, a salt, a solvate, or a solvate of a salt thereof, and wherein the autoimmune disorder is mediated by IRAK4. 
       
     
     
         18 . The method of  claim 17 , wherein the compound of formula (III) is selected from the group consisting of:
 methyl 5-{[(5-fluoro-6-methylpyridin-2-yl)carbonyl]amino}-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate, and   methyl 2-(3-hydroxy-3-methylbutyl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate.   
     
     
         19 : The method of  claim 12 , wherein the arthritis is psoriatic arthritis, Bekhterev's disease, rheumatoid arthritis, reactive arthritis, or systemic juvenile idiopathic arthritis. 
     
     
         20 : The method of  claim 12 , wherein the chronic-inflammatory bowel disorder is Crohn's disease or ulcerative colitis. 
     
     
         21 : The method of  claim 13 , wherein the pain is selected from the group consisting of acute pain, chronic pain, inflammatory pain, and neuropathic pain. 
     
     
         22 : The method of  claim 13 , wherein the pain is selected from the group consisting of hyperalgesia, allodynia, pain from arthritis, post-operative pain, pain caused by spinal cord injuries, inflammation-induced pain, lower back pain, neuropathic pain and chronic pain. 
     
     
         23 : The method of  claim 13 , wherein the pain is pain from arthritis and the arthritis is selected from the group consisting of osteoarthritis, rheumatoid arthritis, psoriatic arthritis, Bekhterev's disease, reactive arthritis, and systemic juvenile idiopathic arthritis.