2'-Methyl-5'-(1,3,4-Oxadiazol-2-yl)-1,1'-Biphenyl-4-Carboxamide Derivatives and Their Use 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 - 9 . (canceled)  
   
   
       10 . A process for preparing a compound of formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 when m is 0 to 4, R 1  is selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, —SO 2 NR 4 R 5 , —CONR 4 R 5  and —COOR 4 ;  
 and when m is 2 to 4, R 1  is additionally selected from C 1-6 alkoxy, hydroxy, NR 4 R 5 , —NR 4 SO 2 R 5 , —NR 4 SOR 5 , —NR 4 COR 5 , and —NR 4 CONR 4 R 5 ;  
 R 2  is selected from hydrogen, C 1-6 alkyl and —(CH 2 ) n —C 3-7 cycloalkyl;  
 R 4  and R 5  are independently selected from hydrogen, C 1-6 alkyl, heterocyclyl optionally substituted by C 1-4 alkyl; and phenyl wherein the phenyl is optionally substituted by up to two groups independently selected from C 1-6 alkoxy, C 1-6 alkyl and halogen; or R 4  and R 5 , together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic or heteroaryl ring optionally containing one additional heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring may be substituted by up to two C 1-6 alkyl groups;  
 R 6  is selected from hydrogen and C 1-4 alkyl;  
 U is selected from methyl and halogen;  
 X and Y are each selected independently from hydrogen, methyl and halogen;  
 m is selected from 0, 1, 2, 3 and 4 wherein each carbon atom of the resulting carbon chain may be optionally substituted with one or two groups selected independently from C 1-6 alkyl;  
 n is selected from 0, 1, 2 and 3;  
 r is selected from 0, 1 and 2;  
 or a pharmaceutically acceptable salt or solvate thereof  
 which comprises:  
 (a) reacting a compound of formula (XII)  
                     
 wherein R 3 , U, X, Y and r are as defined in formula (I),  
 with a compound of formula (XIII)  
   R 1 (CH 2 ) m NR 2 H  (XIII)  
 wherein R 1 , R 2  and m are as defined in formula (I),  
 under amide forming conditions;  
 b) reacting a compound of formula (XIV)  
                     
 wherein R 3 , X and Y are as defined in formula (I),  
 with a compound of formula (XV)  
                     
 wherein R 1 , R 2 , U, m and r are as defined in formula (I) and hal is halogen, in the presence of a catalyst.  
                     
 
   
   
       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 a compound according to formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 when m is 0 to 4, R 1  is selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, —SO 2 NR 4 R 5 , —CONR 4 R 5  and —COOR 4 ;  
 and when m is 2 to 4, R 1  is additionally selected from C 1-6 alkoxy, hydroxy, NR 4 R 5 , —NR 4 SO 2 R 5 , —NR 4 SOR 5 , —NR 4 COR 5 , and —NR 4 CONR 4 R 5 ;  
 R 2  is selected from hydrogen, C 1-6 alkyl and —(CH 2 ) n —C 3-7 cycloalkyl;  
 R 4  and R 5  are independently selected from hydrogen, C 1-6 alkyl, heterocyclyl optionally substituted by C 1-4 alkyl; and phenyl wherein the phenyl is optionally substituted by up to two groups independently selected from C 1-6 alkoxy, C 1-6 alkyl and halogen; or R 4  and R 5 , together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic or heteroaryl ring optionally containing one additional heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring may be substituted by up to two C 1-6 alkyl groups;  
 R 6  is selected from hydrogen and C 1-4 alkyl;  
 U is selected from methyl and halogen;  
 X and Y are each selected independently from hydrogen, methyl and halogen;  
 m is selected from 0, 1, 2, 3 and 4 wherein each carbon atom of the resulting carbon chain may be optionally substituted with one or two groups selected independently from C 1-6 alkyl;  
 n is selected from 0, 1, 2 and 3;  
 r is selected from 0, 1 and 2;  
 or a pharmaceutically acceptable salt or solvate thereof.  
 
   
   
       13 . (canceled)  
   
   
       14 . (canceled)  
   
   
       15 . The method according to  claim 12  wherein the p38 mediated disease state is rheumatoid arthritis, psoriasis, osteoarthritis, inflammatory bowel disease, toxic shock syndrome, asthma, chronic pulmonary inflammation, chronic obstructive pulmonary disease (COPD), and osteoporosis.  
   
   
       16 . A method of treating inflammation in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 when m is 0 to 4, R 1  is selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, —SO 2 NR 4 R 5 , —CONR 4 R 5  and —COOR 4 ;  
 and when m is 2 to 4, R 1  is additionally selected from C 1-6 alkoxy, hydroxy, NR 4 R 5 , —NR 4 SO 2 R 5 , —NR 4 SOR 5 , —NR 4 COR 5 , and —NR 4 CONR 4 R 5 ;  
 R 2  is selected from hydrogen, C 1-6 alkyl and —(CH 2 ) n —C 3-7 cycloalkyl;  
 R 4  and R 5  are independently selected from hydrogen, C 1-6 alkyl, heterocyclyl optionally substituted by C 1-4 alkyl; and phenyl wherein the phenyl is optionally substituted by up to two groups independently selected from C 1-6 alkoxy, C 1-6 alkyl and halogen; or R 4  and R 5 , together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic or heteroaryl ring optionally containing one additional heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring may be substituted by up to two C 1-6 alkyl groups;  
 R 6  is selected from hydrogen and C 1-4 alkyl;  
 U is selected from methyl and halogen;  
 X and Y are each selected independently from hydrogen, methyl and halogen;  
 m is selected from 0, 1, 2, 3 and 4 wherein each carbon atom of the resulting carbon chain may be optionally substituted with one or two groups selected independently from C 1-6 alkyl;  
 n is selected from 0, 1, 2 and 3;  
 r is selected from 0, 1 and 2;  
 or a pharmaceutically acceptable salt or solvate thereof.  
 
   
   
       17 . The process according to  claim 10  wherein R 1  is selected from C 1-4 alkyl, C 3-6 cycloalkyl, —CONHCH 3 , —SO 2 NH 2 , —SO 2 N(CH 3 ) 2 , methoxy, —NHSO 2 CH 3  and —NHCOCH 3 .  
   
   
       18 . The process according to  claim 10  wherein R 1  is selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, —CONR 4 R 5 , hydroxy and NR 4 R 5 .  
   
   
       19 . The process according to  claim 10  wherein R 2  is selected from hydrogen, C 1-4 alkyl and —CH 2 -cyclopropyl.  
   
   
       20 . The process according to  claim 19  wherein R 2  is hydrogen.  
   
   
       21 . The process according to  claim 10  wherein R 6  is C 1-4 alkyl.  
   
   
       22 . The process according to  claim 10  wherein m is selected from 0, 1 and 2.  
   
   
       23 . A compound according to  claim 21  wherein R 6  is methyl.  
   
   
       24 . The process according to  claim 10  wherein R 6  is methyl; R 2  is hydrogen or methyl, X and Y are hydrogen, and r is 0.  
   
   
       25 . The process according to  claim 10  wherein R 1  is hydroxy, cyclopropyl, dimethylamine, diethylamine, or CONR 4 R 5 .  
   
   
       26 . The process according to  claim 19  wherein R 1  is hydroxy, cyclopropyl, dimethylamine, diethylamine, or CONR 4 R 5 .  
   
   
       27 . The process according to  claim 10  which is: 
 N-(3-Hydroxypropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(Cyclopropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-[(Dimethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(Cyclopropylmethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-[3-(Diethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(Cyclopropylmethyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(3-Hydroxypropyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-Cyclohexyl-N-ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-Dicyclopropylmethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-pentyl-1,1′-biphenyl-4-carboxamide;    N-(Cyclopropylmethyl)-5′-(5-ethyl-1,3,4-oxadiazol-2-yl)-2′-methyl-1,1′-biphenyl-4-carboxamide;    N-(Cyclopropylmethyl)-2′-methyl-5′-(5-n-propyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-[2-(3,4-Dimethoxyphenylamino)-2-oxoethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(3,3-Dimethylbutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(2,3-Dimethylcyclohexyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(Isobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-[2,2-Dimethyl-1-(methylaminocarbonyl)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    2′-Methyl-N-(3-methylcyclohexyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-Cyclohexyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-Cyclopropyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    (1,2-Dimethylpropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(1,3-Dimethylpentyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(2-Cyclohexylethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    2′-Methyl-N-(2-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(Cyclobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(1-Cyclopropylethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    N-(2,4-Dimethyl-3-pentyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    2′-Methyl-N-(1-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide;    2′-Methyl-N-(2-methylallyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide; or    a pharmaceutically acceptable salt or solvate thereof.