Phenyl-substituted pyrimidine compounds useful as kinase inhibitors

Abstract

Compounds having the formula (I), and pharmaceutically acceptable salts, and solvates thereof, are useful as kinase inhibitors, wherein: two of X 1 , X 2 , and X 3 are N, and the remaining one of X 1 , X 2 , and X 3 is —CR 1 ; R 1 is hydrogen or —CN; and N, G, Z, R 2 , R 3 , R 4 , R 5 , and R 6 are described in the specification. Also disclosed are pharmaceutical compositions containing compounds of formula (I), and methods of treating conditions associated with the activity of p38 kinase and/or conditions associated with the activity of LIM kinase.

1 . A compound of formula (I  
     
       
         
         
             
             
         
       
     
     enantiomers, diastereomers, pharmaceutically-acceptable salts, and solvates thereof, wherein: 
 two of X 1 , X 2 , and X 3  are N, and the remaining one of X 1 , X 2 , and X 3  is CR 1 ;  
 R 1  is hydrogen or —CN;  
 n is zero, 1, 2, or 3;  
 each R 2  is independently C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —OR 4 , —SR 4 , —CO 2 R 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —S(═O)R 6 , —SO 2 R 6 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —NR 4 SO 2 R 6 , —NR 4 C(═O)R 5 , —NR 4 CO 2 R 5 , —NR 4 C(═O)NR 5 R 6 , halogen, cyano, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 G is a monocyclic five- or six-membered heteroaryl, which is optionally substituted with one to three R 3 ;  
 each R 3  is independently hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —OR 4 , —SR 4 , —CO 2 R 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —S(═O)R 6 , —SO 2 R 6 , —NR 4 SO 2 NR 5 R 6 , —NR 4 SO 2 R 6 , —NR 4 C(═O)R 5 , —NR 4 CO 2 R 5 , —NR 4 C(═O)NR 5 R 6 , halogen, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 each R 4  is independently hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 each R 5  is independently hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, and/or substituted cycloalkyl;  
 wherein when R 4  and R 5  are alkyl and/or substituted alkyl and are bonded to the same atom, R 4  and R 5  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo;  
 each R 6  is independently C 1-8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 wherein when R 5  and R 6  are alkyl and/or substituted alkyl and are bonded to the same atom, R 5  and R 6  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo;  
 Z is hydrogen, C 1 -C 8  alkyl, C 1 -C 8  substituted alkyl, cycloalkyl, substituted cycloalkyl, —OR 7 , —SR 7 , —CO 2 R 7 , —C(═O)NR 7 R 8 , —NR 7 R 8 , —S(═O)R 9 , —SO 2 R 8 , —SO 2 NR 7 R 8 , —NR 7 SO 2 NR 8 R 9 , —NR 7 SO 2 R 9 , —NR 7 C(═O)R 8 , —NR 7 CO 2 R 8 , —NR 7 C(═O)NR 8 R 9 , halogen, cyano, aryl, substituted aryl, heterocyclo, or substituted heterocyclo;  
 R 7  is hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo;  
 R 8  is hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, or substituted cycloalkyl;  
 wherein when R 7  and R 8  are alkyl and/or substituted alkyl and are bonded to the same atom, R 7  and R 8  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo;  
 R 9  is C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo; and  
 wherein when R 8  and R 9  are alkyl and are bonded to the same atom, R 8  and R 9  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo; with the provisos that:  
 (a) G is not thiazolyl with 4-methyl substitution or oxazolyl with 4-methyl substitution;  
 (b) G is not 2-pyridyl, substituted 2-pyridyl, or dichlorothienyl when Z is hydrogen;  
 (c) G is not substituted 2-pyridyl when Z is —OR 7  or chlorine;  
 (d) G is not  
                     
  wherein X is hydrogen or alkali, when Z is hydrogen and R 1  is hydrogen;  
 (e) G is not unsubstituted pyrazolyl or 4-pyridyl when n is zero and Z is hydrogen;  
 (f) G is not isoxazolyl substituted with phenyl or isoxazolyl substituted with substituted phenyl when n is 1, R 2  is chlorine, and Z is hydrogen;  
 (g) G is not 3-pyridyl or dichloro-4-pyridyl when Z is hydrogen, R 1  is hydrogen, and at least one R 2  is —C(═O)OX, wherein X is hydrogen or alkali;  
 (h) n is 1, 2, or 3 when R 1  is —CN;  
 (i) R 2  is not optionally substituted phenoxy attached to para-position of the phenyl ring;  
 (j) R 7  is not pyrazolyl, substituted pyrazolyl, alkyl substituted triazolyl, indazolyl, or substituted indazolyl when Z is —NR 7 R 8 ;  
 (k) Z is not NR 7 R 8  when R 1  is —CN; and  
 (l) n is 1, 2, or 3 when Z is unsubstituted phenyl.  
 
   
   
       2 . The compound according to  claim 1  wherein X 2  and X 3  are N, and X 1  is —CR 1 .  
   
   
       3 . The compound according to  claim 1  wherein G is thiazolyl, thiadiazolyl, oxadiazolyl, oxazolyl, imidazolyl, triazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, which is optionally substituted with one to three R 3 .  
   
   
       4 . The compound according to  claim 1  wherein Z is —NR 7 R 8 , —NR 7 SO 2 NR 8 R 9 , pyridyl, or substituted pyridyl.  
   
   
       5 . A compound of formula (I)  
     
       
         
         
             
             
         
       
     
     wherein: 
 two of X 1 , X 2 , and X 3  are N, and the remaining one of X 1 , X 2 , and X 3  is —CR 1 ;  
 R 1  is hydrogen or —CN;  
 n is zero, 1, 2, or 3;  
 each R 2  is independently C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —OR 4 , —SR 4 , —CO 2 R 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —S(—O)R 6 , —SO 2 R 6 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —NR 4 SO 2 R 6 , —NR 4 C(═O)R 5 , —NR 4 CO 2 R 5 , —NR 4 C(═O)NR 5 R 6 , halogen, cyano, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 G is —C(═O)NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —NR 4 SO 2 R 6 , —NR 4 C(═O)R 5 , —NR 4 C(═O)NR 5 R 6 , or a monocyclic five- or six-membered heteroaryl optionally substituted with one to three R 3 ;  
 each R 3  is independently hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —OR 4 , —SR 4 , —CO 2 R 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —S(═O)R 6 , —SO 2 R 6 , —NR 4 SO 2 NR 5 R 6 , —NR 4 SO 2 R 6 , —NR 4 C(═O)R 5 , —NR 4 CO 2 R 5 , —NR 4 C(═O)NR 5 R 6 , halogen, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 each R 4  is independently hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 each R 5  is independently hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, and/or cycloalkyl;  
 wherein when R 4  and R 5  are alkyl and/or substituted alkyl and are bonded to the same atom, R 4  and R 5  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo;  
 each R 6  is independently C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 wherein when R 5  and R 6  are alkyl and/or substituted alkyl and are bonded to the same atom, R 5  and R 6  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo;  
 Z is —NR 7 R 8  or pyridyl, pyridazinyl, or pyrazinyl optionally substituted with one to three R 10 ;  
 R 7  is independently hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo;  
 R 8  is independently hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, or substituted cycloalkyl;  
 wherein when R 7  and R 8  are alkyl and/or substituted alkyl and are bonded to the same atom, R 7  and R 8  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo; and  
 each R 10  is independently halogen, cyano, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, and/or substituted alkynyl;  
 with the provisos that:  
 (a) G is not thiazolyl with 4-methyl substitution or oxazolyl with 4-methyl substitution;  
 (b) n is 1, 2, or 3 when R 1  is —CN;  
 (c) R 7  is not pyrazolyl, substituted pyrazolyl, indazolyl, substituted indazolyl, or alkyl substituted triazolyl when Z is —NR 7 R 8 ; and  
 (d) Z is not —NR 7 R 8  when R 1  is —CN.  
 
   
   
       6 . The compound according to  claim 5  wherein X 2  and X 3  are N, and X 1  is —CR 1 .  
   
   
       7 . The compound according to  claim 5  wherein G is selected from thiazolyl, thiadiazolyl, oxadiazolyl, oxazolyl, imidazolyl, triazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl, which is optionally substituted with one to three R 3 .  
   
   
       8 . The compound according to  claim 5  wherein G is —C(═O)NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —NR 4 SO 2 R 6 , —NR 4 C(═O)R 5 , or —NR 4 C(═O)NR 5 R 6 .  
   
   
       9 . The compound according to  claim 5  wherein Z is —NR 7 R 8 , pyridyl, or substituted pyridyl.  
   
   
       10 . A compound of formula  
     
       
         
         
             
             
         
       
     
     wherein: 
 two of X 1 , X 2 , and X 3  are N, and the remaining one of X 1 , X 2 , and X 3  is —CR 1 ;  
 R 1  is hydrogen or —CN;  
 n is zero, 1, 2, or 3;  
 each R 2  is independently C 1 -C 8  alkyl, C 1 -C 8  substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —OR 4 , —SR 4 , —CO 2 R 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —S(═O)R 6 , —SO 2 R 6 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —NR 4 SO 2 R 6 , —NR 4 C(═O)R 5 , —NR 4 CO 2 R 5 , —NR 4 C(═O)NR 5 R 6 , halogen, cyano, aryl, substituted aryl, heterocyclo, substituted heterocyclo;  
 each R 4  is independently hydrogen, C 1 -C 8  alkyl, C 1 -C 8  substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 each R 5  is independently hydrogen, C 1 -C 8  alkyl, and/or C 1 -C 8  substituted alkyl;  
 wherein when R 4  and R 5  are alkyl and/or substituted alkyl and are bonded to the same atom, R 4  and R 5  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo; and  
 each R 6  is independently C 1 -C 8  alkyl, C 1 -C 8  substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 wherein when R 5  and R 6  are alkyl and/or substituted alkyl and are bonded to the same atom, R 5  and R 6  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo;  
 G is —C(═O)NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —NR 4 SO 2 R 6 , —NR 4 C(═O)R 5 , or —NR 4 C(═O)NR 5 R 6 ;  
 Z is hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, —OR 7 , —SR 7 , —CO 2 R 7 , —C(═O)NR 7 R 8 , —NR 7 R 8 , —S(═O)R 9 , —SO 2 R 9 , —SO 2 NR 7 R 8 , —NR 7 SO 2 NR 8 R 9 , —NR 7 SO 2 R 9 , —NR 7 C(═O)R 8 , —NR 7 CO 2 R 8 , —NR 7 C(═O)NR 8 R 9 , halogen, cyano, aryl, substituted aryl, heterocyclo, and/or substituted heterocyclo;  
 R 7  is hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo;  
 R 8  is hydrogen, C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, or substituted cycloalkyl;  
 wherein when R 7  and R 8  are alkyl or substituted alkyl and are bonded to the same atom, R 7  and R 8  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo;  
 R 9  is C 1 -C 8  alkyl, substituted C 1 -C 8  alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo; and  
 wherein when R 8  and R 9  are alkyl or substituted alkyl and are bonded to the same atom, R 8  and R 9  can be optionally linked together to form a four-, five-, or six-membered ring heterocyclo or substituted heterocyclo; with the provisos that:  
 (a) when R 1  is —CN and G is —NR 4 C(═O)R 5 , then R 5  is hydrogen;  
 (b) R 2  is not optionally substituted phenoxy attached to para-position of the phenyl; and  
 (c) n is 1, 2, or 3 when Z is unsubstituted phenyl.  
 
   
   
       11 . The compound according to  claim 10  wherein X 2  and X 3  are N, and X 1  is —CR 1 .  
   
   
       12 . A pharmaceutical composition comprising at least one compound according to  claim 1  and a pharmaceutically-acceptable carrier or diluent.  
   
   
       13 . A pharmaceutical composition comprising at least one compound according to  claim 5  and a pharmaceutically-acceptable carrier or diluent.  
   
   
       14 . A pharmaceutical composition comprising at least one compound according to  claim 10  and a pharmaceutically-acceptable carrier or diluent.  
   
   
       15 . A method of treating an inflammatory disorder and/or cancer comprising administering to a patient in need of such treatment a pharmaceutical composition according to  claim 12 .  
   
   
       16 . A method of inhibiting p38 kinase, LIM kinase 1, and/or LIM kinase 2 in a mammal comprising administering to the mammal in need of such treatment at least one compound according to  claim 1 .  
   
   
       17 . A method of treating an inflammatory disorder and/or cancer comprising administering to a patient in need of such treatment a pharmaceutical composition according to  claim 13 .  
   
   
       18 . A method of inhibiting p38 kinase, LIM kinase 1, and/or LIM kinase 2 in a mammal comprising administering to the mammal in need of such treatment at least one compound according to  claim 5 .  
   
   
       19 . A method of treating an inflammatory disorder and/or cancer comprising administering to a patient in need of such treatment a pharmaceutical composition according to  claim 14 .  
   
   
       20 . A method of inhibiting p38 kinase, LIM kinase 1, and/or LIM kinase 2 in a mammal comprising administering to the mammal in need of such treatment at least one compound according to  claim 10.