N-heterocyclic inhibitors of TNF-alpha expression

Abstract

N-heterocyclic compounds that block cytokine production via inhibition of p38 kinase are disclosed. In one embodiment, compounds of the present invention are represented by Formula (I): Methods of production, pharmaceutical compositions and methods of treating conditions associated with inappropriate p38 kinase activity or TNF-α expression utilizing compounds of the present invention are also disclosed.

What is claimed is:  
     
         1 . A compound of Formula (I),  
       
         
           
           
               
               
           
         
       
       including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:  
 one or two of W, Y and X are ═N—;  
 one of W, Y and X is selected from ═C—CN, ═C—F, ═C—NO 2 , ═C—Br, ═C—NH 2 , ═C—NHC(O)CH 3  and ═C—Cl;  
 the remaining W, Y or X is ═CH—;  
 V is —NR 5 —;  
 Z is halogen or —N(R 1 )(R 2 );  
 R 1  and R 2  are the same or different and are selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl;  
 R 5  is hydrogen or alkyl;  
 R 6  is  
                     
 R 7  is hydrogen, alkyl, substituted alkyl, alkoxy, or halogen;  
 R 8  is hydrogen, alkyl, alkyloxy or cyano;  
 R 9  is —C(O)R 10  or unsubstituted or substituted heterocyclyl;  
 R 10  is —N(R 31 )(R 32 );  
 R 31  and R 32  are the same or different and are selected from hydrogen, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl;  
 R 11  is hydrogen, halogen, O—R 35  or —N(R 12 )(R 13 );  
 R 12  is hydrogen, alkyl, or substituted alkyl;  
 R 13  is —(CH 2 ) m R 14 ;  
 —N(R 12 )(R 13 ) taken together may form a heterocyclyl or substituted heterocyclyl;  
 m is 0, 1, 2 or 3;  
 R 14  is hydrogen, alkyl, substituted alkyl, —C(O)N(R 31 )(R 32 ), —N(R 33 )C(O)R 34 , aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl or  
                     
 R 15  is hydrogen, alkyl or substituted alkyl;  
 R 16  is hydrogen or alkyl; or  
 R 33  is hydrogen, alkyl, or substituted alkyl;  
 R 34  is alkyl, substituted alkyl, aryl or substituted aryl;  
 R 35  is hydrogen or -(lower alkyl)-R 36 ;  
 R 36  is N(R 37 )(R 38 );  
 R 37  is hydrogen, alkyl, or substituted alkyl;  
 R 38  is -(substituted alkyl)-R 14 ; and  
 N(R 37 )(R 38 ) taken together may form a heterocyclyl or substituted heterocyclyl.  
 
     
     
         2 . A compound of  claim 1 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    one or two of W, Y and X are ═N—;    one of W, Y and X is selected from ═C—CN, ═C—F, ═C—NO 2 , ═C—Br, ═C—NH 2 , ═C—NHC(O)CH 3  and ═C—Cl;    the remaining W, Y or X is ═CH—;    V is —NH—;    Z is —N(R 1 )(R 2 );    R 1  and R 2  are the same or different and are selected from hydrogen, alkyl or substituted alkyl wherein alkyl is of 1 to 8 carbons;    R 6  is                          R 7  is hydrogen, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, or halogen;    R 8  is hydrogen;    R 9  is —C(O)R 10  or unsubstituted or substituted heterocyclyl;    R 10  is —NH 2  or unsubstituted or substituted —NH-alkyl, —NH-alkoxy, —NH-heterocyclyl, —NH-phenyl, or —NH-CH 2 -phenyl wherein alkyl and alkoxy are of 1 to 6 carbons;    R 11  is hydrogen, halogen, O—R 35  or —N(R 12 )(R 13 ), wherein N(R 12 )(R 13 ) taken together may form a monocyclic heterocyclyl or substituted heterocyclyl of 5 to 7 atoms containing 1, 2, or 3 additional nitrogen atoms or wherein 
 R 12  is hydrogen;  
 R 13  is alkyl of 1 to 4 carbons or  
                     
 R 15  and R 16  are independently selected from hydrogen and methyl;  
 R 35  is hydrogen or -(lower alkyl)-R 36 ;  
 R 36  is N(R 37 )(R 38 );  
 R 37  is hydrogen, alkyl, or substituted alkyl;  
 R 38  is -(substituted alkyl)-R 14 ; and  
 N(R 37 )(R 38 ) taken together may form a heterocyclyl or substituted heterocyclyl.  
   
     
     
         3 . A compound of  claim 2 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    one or two of W, Y and X are ═N—;    one of W, Y and X is selected from ═C—CN, ═C—F, ═C—NO 2 , ═C—Br, ═C—NH 2 , ═C—NHC(O)CH 3  and ═C—Cl;    the remaining W, Y or X is ═CH—;    V is —NH—;    Z is —N(R 1 )(R 2 );    R 1  and R 2  are the same or different and are selected from hydrogen or alkyl of 1 to 8 carbons;    R 6  is                          R 7  is hydrogen, methyl, methoxy, Cl, Br, or F;    R 8  is hydrogen;    R 9  is —C(O)R 10  or unsubstituted or substituted heterocyclyl;    R 10  is —NH 2 , or unsubstituted or substituted —NH-alkyl, —NH-alkoxy, —NH-phenyl, or —NH—CH 2 -phenyl wherein alkyl and alkoxy are of 1 to 6 carbons; and    R 11  is hydrogen, halogen, O—R 35  or —N(R 12 )(R 13 ), wherein N(R 12 )(R 13 ) taken together form a monocyclic heterocyclyl or substituted heterocyclyl of 5 to 7 atoms containing 1, 2, or 3 additional nitrogen atoms.    
     
     
         4 . A compound of  claim 3 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    one of W, Y and X is ═N—;    one of W, Y and X is selected from ═C—CN, ═C—F, ═C—NO 2 , ═C—Br, ═C—NH 2 , ═C—NHC(O)CH 3  and ═C—Cl;    the remaining W, Y or X is ═CH—;    V is —NH—;    Z is —N(R 1 )(R 2 );    R 1  and R 2  are the same or different and are selected from hydrogen or alkyl of 1 to 8 carbons;    R 6  is                          R 7  is hydrogen, methyl, methoxy, Cl, Br, or F;    R 8  is hydrogen;    R 9  is —C(O)R 10  or unsubstituted or substituted heterocyclyl;    R 10  is —NH 2 , or unsubstituted or substituted —NH-alkyl, —NH-alkoxy, —NH-phenyl, or —NH—CH 2 -phenyl wherein alkyl and alkoxy are of 1 to 6 carbons;    R 11  is hydrogen, halogen, —O—R 35  or —N(R 12 )(R 13 ), wherein N(R 12 )(R 13 ) taken together form a monocyclic heterocyclyl or substituted heterocyclyl of 5 to 7 atoms containing 1, 2, or 3 additional nitrogen atoms; and    R 15  and R 16  are independently selected from hydrogen and methyl.    
     
     
         5 . A compound of  claim 4 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    R 10  is —NH 2 , unsubstituted or substituted —NH—CH 3 , —NH—C 2 H 5 , —NH—OCH 3 , or —NH—OC 2 H 5 .    
     
     
         6 . A compound of  claim 4 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    R 9  is unsubstituted or substituted triazole, thiazole, oxadiazole or imidazole.    
     
     
         7 . A compound of  claim 5 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    R 11  is hydrogen, halogen, —O-(substituted alkyl), —NH-(substituted alkyl) or                          
     
     
         8 . A compound of  claim 6 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    R 11  is hydrogen, halogen, —O-(substituted alkyl), —NH-(substituted alkyl) or                          
     
     
         9 . A compound of  claim 3 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    two of W, Y and X are ═N—;    the remaining W, Y or X is selected from ═C—CN, ═C—F, ═C—NO 2 , ═C—Br, ═C—NH 2 , ═C—NHC(O)CH 3 , and ═C—Cl;    V is —NH—;    Z is —N(R 1 )(R 2 );    R 1  and R 2  are the same or different and are selected from hydrogen or alkyl of 1 to 8 carbons;    R 6  is                          R 7  is hydrogen, methyl, methoxy, Cl, Br, or F;    R 8  is hydrogen;    R 9  is —C(O)R 10  or unsubstituted or substituted heterocyclyl;    R 10  is —NH 2 , or unsubstituted or substituted —NH-alkyl, —NH-alkoxy, —NH-phenyl, or —NH—CH 2 -phenyl wherein alkyl and alkoxy are of 1 to 6 carbons;    R 11  is hydrogen, halogen, —O—R 35  or —N(R 12 )(R 13 ), wherein N(R 12 )(R 13 ) taken together may form a monocyclic heterocyclyl or substituted heterocyclyl of 5 to 7 atoms containing 1, 2, or 3 additional nitrogen atoms; and    R 15  and R 16  are independently selected from hydrogen and methyl.    
     
     
         10 . A compound of  claim 9 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    R 10  is —NH 2 , unsubstituted or substituted —NH—CH 3 , —NH—C 2 H 5 , —NH—OCH 3 , or —NH—OC 2 H 5 .    
     
     
         11 . A compound of  claim 9 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    R 9  is unsubstituted or substituted triazole, thiazole, oxadiazole or imidazole.    
     
     
         12 . A compound of  claim 10 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    R 11  is hydrogen, halogen, —O-(substituted alkyl), —NH-(substituted alkyl) or                          
     
     
         13 . A compound of  claim 11 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, 
 wherein:    R 11  is hydrogen, halogen, —O-(substituted alkyl), —NH-(substituted alkyl) or                          
     
     
         14 . A pharmaceutical composition comprising as an active ingredient, a compound, or a prodrug or salt thereof, according to  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         15 . A pharmaceutical composition according to  claim 14 , further comprising one or more additional active ingredients.  
     
     
         16 . A pharmaceutical composition according to  claim 15 , wherein said additional active ingredient is an anti-inflammatory compound.  
     
     
         17 . A pharmaceutical composition according to  claim 16 , wherein said additional active ingredient is chosen from a steroid and an NSAID.  
     
     
         18 . A method of inhibiting TNF-α expression in a mammal, the method comprising administering to the mammal an effective amount of a composition according to  claim 14 .  
     
     
         19 . A method of treating TNF-α mediated disorder, the method comprising administering to a mammal in need of such treatment, an effective amount of a composition according to  claim 14 .  
     
     
         20 . The method according to  claim 19 , wherein the TNF-α mediated disorder is an inflammatory disorder.  
     
     
         21 . The method according to  claim 19 , wherein the TNF-α mediated disorder is chosen from bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease states, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Chron's disease, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure and cachexia.  
     
     
         22 . The method according to  claim 19 , wherein said composition according to  claim 16  is administered with one or more additional anti-inflammatory or immunosuppressive agents as a single dose form or as separate dosage forms.  
     
     
         23 . A method of treating a condition associated with TNF-α expression in a mammal, the method comprising administering to a mammal in need of such treatment, an effective amount of a composition according to  claim 14 .  
     
     
         24 . The method according to  claim 23 , wherein the condition associated with TNF-α expression is an inflammatory disorder.  
     
     
         25 . The method according to  claim 23 , wherein the condition associated with TNF-α expression is chosen from bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease states, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure and cachexia.  
     
     
         26 . The method according to  claim 23  wherein said composition according to  claim 16  is administered with one or more additional anti-inflammatory or immunosupressive agents as a single dose form or as separate dosage forms.  
     
     
         27 . A method of treating a condition associated with p38 kinase activity in a mammal, the method comprising administering to a mammal in need of such treatment, an effective amount of a composition according to  claim 14 .  
     
     
         28 . The method according to  claim 27 , wherein the condition associated with p38 kinase activity is an inflammatory disorder.  
     
     
         29 . The method according to  claim 27 , wherein the condition associated with p38 kinase activity is chosen from bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease states, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure and cachexia.  
     
     
         30 . The method according to  claim 27  wherein said composition according to  claim 14  is administered with one or more additional anti-inflammatory or immunosuppressive agents as a single dose form or as separate dosage forms.  
     
     
         31 . A compound of  claim 1 , including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein said compound is selected from: