Biphenyl-Derivatives as p38 Kinase Inhibitors

Abstract

Compounds of formula (I): or pharmaceutically acceptable salts or solvates thereof, and their use as pharmaceuticals, particularly as p38 kinase inhibitors.

1 - 11 . (canceled)  
   
   
       12 . A method for treating a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38 kinase comprising administering to a patient in need thereof an effective amount of a compound according to the formula (I),  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is a phenyl group which may be optionally substituted;  
 R 2  is selected from hydrogen, C 1-6 alkyl and —(CH 2 ) q —C 3-7 cycloalkyl;  
 R 3 is the group —NH—CO—R 4 ;  
 R 4  is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —(CH 2 ) q —C 3-7 cycloalkyl, trifluoromethyl, —(CH 2 ) r phenyl optionally substituted by R 5  and/or R 6 , —(CH 2 ) r heteroaryl optionally substituted by R 5  and/or R 6 , —(CH 2 ) r heterocyclyl optionally substituted by R 5  and/or R 6  and —(CH 2 ) r fused bicyclyl optionally substituted by R 5 and/or R 6 ;  
 R 5  is selected from C 1-6 alkyl, C 1-6 alkoxy, —(CH 2 ) q —C 3-7 cycloalkyl, —CONR 7 R 8 , —NHCOR 8 , —SO 2 NHR 7 , —NHSO 2 R 8 , halogen, —(CH 2 ) s NR 9 R 10 , oxy, trifluoromethyl, phenyl optionally substituted by one or more R 6  groups and heteroaryl wherein the heteroaryl may be optionally substituted by one or more R 6  groups  
 R 6  is selected from C 1-6 alkyl, C 1-6 alkoxy, halogen trifluoromethyl and —NR 9 R 10 ;  
 or R 5  and R 6  together with the carbon atoms to which they are bound, form a five- or six-membered saturated or unsaturated ring to give a fused bicyclic ring system wherein the ring that is formed by R 5  and R 6  may optionally contain one or two heteroatoms selected from oxygen, nitrogen and sulfur;  
 R 7  is selected from hydrogen, C 1-6 alkyl and phenyl wherein the phenyl group may be optionally substituted by one or more R 6  groups;  
 R 8  is selected from hydrogen and C 1-6 alkyl;  
 or R 7  and R 8 , together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen sulfur and N—R x , wherein the ring may be substituted by up to two C 1-6 alkyl groups;  
 R x  is selected from hydrogen and methyl;  
 R 9  is selected from hydrogen, C 1-6 alkyl and —(CH 2 ) q —C 3-7 cycloalkyl optionally substituted by C 1-6 alkyl;  
 R 10  is selected from hydrogen and C 1-6 alkyl;  
 or R 9  and R 10  together with the nitrogen atom to which they are bound, form a three- to seven-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen sulfur and N—R x , wherein the ring may contain up to one double bond and the ring may be substituted by one or more R 11  groups  
 R 11  is selected from C 1-6 alkyl, oxy —CH 2 OC 1-6 alkyl, trichloromethyl and —N(C 1-6 alkyl) 2 ;  
 U is selected from methyl and halogen;  
 W is selected from methyl and chloro;  
 X and Y are each selected independently from hydrogen methyl and halogen; m is selected from 0, 1, 2, 3 and 4, and may be optionally substituted with up to two groups selected independently from C 1-6 alkyl;  
 n is selected from 0, 1 and 2;  
 q is selected from 0, 1 and 2;  
 r is selected from 0 and 1;  
 s is selected from 0, 1, 2 and 3;  
 or a pharmaceutically acceptable salt or solvate thereof.  
 
   
   
       13 . (canceled)  
   
   
       14 . (canceled)  
   
   
       15 . The method according to  claim 12  wherein the disease or condition mediated by p38 kinase activity or by cytokines produced by the activity of p38 kinase are selected from osteoarthritis, asthma, eczema, allergic rhinitis, allergic conjunctivitis, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, silicosis, endotoxemia, toxic shock syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, aneurism, stroke, irritable bowel syndrome, muscle degeneration, bone resorption diseases, osteoporosis, diabetes, reperfusion injury, graft vs. host reaction, allograft rejections, sepsis, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), malaria, leprosy, infectious arthritis, leishmaniasis, Lyme disease, glomerulonephritis, gout, psoriatic arthritis, Reiter's syndrome, traumatic arthritis, rubella arthritis, Crohn's disease, ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, non-articular inflammatory conditions, pain, osteoporosis, restenosis, thrombosis, and angiogenesis.  
   
   
       16 . The method according to  claim 12  wherein R 1  is substituted by one or two substituents selected from halogen, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy, benzyloxy, hydroxy, cyano, —CH 2 CH 2 OH, —(CH 2 ) p —NHCH 3 , —(CH 2 ) p —N(CH 3 ) 2 , —(CH 2 ) p CONR 5 R 6 , —(CH 2 ) p CO 2 R 5 , —(CH 2 ) p NR 5 COR 6 , —(CH 2 ) p OCOR 5 , —(CH 2 ) p OCONR 5 R 6 , —(CH 2 ) p NR 5 COOR 6 , —(CH 2 ) p COR 5 , —(CH 2 ) p SO 2 NR 5 R 6 , —(CH 2 ) p NR 5 SO 2 R 6 , —SO 2 R 5 , —(CH 2 ) p NR 5 R 6 , —(CH 2 ) p NR 5 CONR 5 R 6  and —(CH 2 ) p CONR 5 SO 2 R 6 ; 
 wherein p is selected from 0, 1 and 2; and    R 5  and R 6  are independently selected from hydrogen, C 1-4 alkyl and phenyl.    
   
   
       17 . The method according to  claim 12  wherein group R 1  is substituted by one or two substituents selected from C 1-4 alkoxy, hydroxy, —(CH 2 ) p NR 10 SO 2 R 11  and —(CH 2 ) p NR 10 R 11 ; and wherein p is selected from 0, 1 and 2.  
   
   
       18 . The method according to  claim 12  wherein R 2  is selected from hydrogen, C 1-4 alkyl and —CH 2 -cyclopropyl.  
   
   
       19 . The method according to  claim 18  wherein R 2  is hydrogen.  
   
   
       20 . The method according to  claim 12  wherein m is selected from 0, 1 and 2.  
   
   
       21 . The method according to  claim 12  wherein R 4  is selected from —(CH 2 ) r phenyl optionally substituted by R 5  and/or R 6  and —(CH 2 ) r heteroaryl optionally substituted by R 5  and/or R 6 .  
   
   
       22 . The method according to  claim 21  wherein R 4  is —(CH 2 ) r heteroaryl optionally substituted by R 5  and/or R 6 .  
   
   
       23 . The method according to  claim 12  wherein the compound of formula (I) is: 
 N-(4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-pyrrolidin-1-ylisonicotinamide;    N-{4′-[(4-Methoxyanilino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide;    N-(4′-{[(2-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;    N-(4′-{[(4-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;    N-(4′-{[(3-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;    N-(4′-{[(3,5-Dihydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;    N-(4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isoxazole-5-carboxamide;    N-{6-Methyl-4′-[({4-[(methylsulfonyl)amino]phenyl}amino)-carbonyl]-1,1′-biphenyl-3-yl}isoxazole-5-carboxamide;    N-(6-Methyl-4′-{[(4-{[(methylsulfonyl)amino]methyl}phenyl)-amino]carbonyl}-1,1′-biphenyl-3-yl)isoxazole-5-carboxamide;    N-(4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;    N-{6-Methyl-4′-[({4-[(methylsulfonyl)amino]phenyl}amino)carbonyl]-1,1′-biphenyl-3-yl}thiophene-3-carboxamide;    N-{4′-[({3-[(Dimethylamino)methyl]benzyl}amino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}thiophene-3-carboxamide;    N-(4′-{[(3,5-Dihydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide;    N-(4′-{[(2-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide;    N-(4′-{[(3-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide;    N-(6-Methyl-4′-{[(4-{[(methylsulfonyl)amino]methyl}phenyl)amino]-carbonyl}-1,1′-biphenyl-3-yl)-3-furamide;    N-{6-Methyl-4′-[( {4-[(methylsulfonyl)amino]phenyl}amino)carbonyl]-1,1′-biphenyl-3-yl}-3-furamide; or a pharmaceutically acceptable salt of solvate thereof.