Amino-pyridine-containing spleen tyrosine kinase (syk) inhibitors

Abstract

The invention provides certain amino-pyridine-containing compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and n are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk) kinase.

1 . A compound of the Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is selected from the group consisting of:
 (i) —C 1 -C 3  alkyl; 
 (ii) fluoroalkyl; 
 (iii) —CH 2 OR 1a ,
 wherein R 1a  is selected from the group consisting of H and C 1 -C 6  alkyl; 
 
 (iv) —N(R 1b ) 2 ,
 wherein each occurrence of R 1b  is selected from the group consisting of H and C 1 -C 3  alkyl, or two R 1b  together with the N atom to which they are attached form a group of the formula 
 
 
       
       
         
           
           
               
               
           
         
         
           
              wherein r is 1, 2, 3, or 4; 
           
           (v) —O—(C 1 -C 3  alkyl); 
           (vi) N(H)C(O)—(C 1 -C 3  alkyl); 
           (vii) halo; 
           (viii) H; and 
           (ix) morpholinyl; 
         
         R 2  is —OH, —O—(C 1 -C 3  alkyl), —N(R 2a ) 2 , —N(R 2a )C(O)—R 2b ; or —F;
 wherein each occurrence of R 2a  is selected from the group consisting of H and C 1 -C 3  alkyl; and 
 R 2b  is C 1 -C 6  alkyl; 
 
         R 3  is CO 2 R 3a , —CH 2 CO 2 R 3a , —CH 2 CH 2 CO 2 R 3a , tetrazole, —C(O)N(R 3b ) 2 , —CH 2 OH, H, halo, —OH C 1 -C 6  alkyl, —O—(C 1 -C 3  alkyl), —N(R 3b ) 2 , —CN, —C(O)N(H)S(O) 2 R 3c , —C(O)—N(H)(R 3d ), —C(O)N(H)C(O)R 3a , —P(O)(OR 3b ) 2 , or —B(OH) 2 ;
 wherein R 3a  is selected from the group consisting of H and C 1 -C 6  alkyl; 
 wherein each R 3b  is independently selected from the group consisting of H and C 1 -C 3  alkyl; 
 wherein R 3c  is selected from the group consisting of C 1 -C 3  alkyl, C 1 -C 3  fluoroalkyl, C 3 -C 6  cycloalkyl, and phenyl, wherein said phenyl is unsubstituted or substituted with one or two C 1 -C 3  alkyl; 
 wherein R 3d  is selected from the group consisting of —CN, —O—(C 1 -C 3  alkyl), and tetrazole; 
 
         R 4  is —CO 2 R 4a , —CH 2 CO 2 R 4a , —CH 2 CH 2 CO 2 R 4a , tetrazole, —C(O)N(R 4b ) 2 , —CH 2 OH, H, halo, —OH, C 1 -C 6  alkyl, —O—(C 1 -C 3  alkyl), —N(R 4b ) 2 , —CN, —C(O)N(H)S(O) 2 R 4c , —C(O)—N(H)(R 4d ), —C(O)N(H)C(O)R 4a , —P(O)(OR 4b ) 2 , or —B(OH) 2 ;
 wherein R 4a  is selected from the group consisting of H and C 1 -C 6  alkyl; 
 wherein each R 4b  is independently selected from the group consisting of H and C 1 -C 3  alkyl; 
 wherein R 4c  is selected from the group consisting of C 1 -C 3  alkyl, C 1 -C 3  fluoroalkyl, C 3 -C 6  cycloalkyl, and phenyl, wherein said phenyl is unsubstituted or substituted with one or two C 1 -C 3  alkyl; 
 wherein R 4d  is selected from the group consisting of —CN, —O—(C 1 -C 3  alkyl), and tetrazole; 
 
         R 5  is —CO 2 R 5a , —CH 2 CO 2 R 5a , —CH 2 CH 2 CO 2 R 5a , tetrazole, —C(O)N(R 5b ) 2 , —CH 2 OH, H, halo, —OH, C 1 -C 6  alkyl, —O—(C 1 -C 3  alkyl), —N(R 5b ) 2 , —CN, —C(O)N(H)S(O) 2 R 5c , —C(O)—N(H)(R 5d ), —C(O)N(H)C(O)R 5a , —P(O)(OR 5b ) 2 , or —B(OH) 2 ;
 wherein R 5a  is selected from the group consisting of H and C 1 -C 6  alkyl; 
 wherein each R 5b  is independently selected from the group consisting of H and C 1 -C 3  alkyl; 
 wherein R 5c  is selected from the group consisting of C 1 -C 3  alkyl, C 1 -C 3  fluoroalkyl, C 3 -C 6  cycloalkyl, and phenyl, wherein said phenyl is unsubstituted or substituted with one or two C 1 -C 3  alkyl; 
 wherein R 5d  is selected from the group consisting of —CN, —O—(C 1 -C 3  alkyl), and tetrazole; 
 
         R 6  is selected from the group consisting of:
 (i) C 1 -C 6  alkyl; 
 (ii) C 1 -C 3  fluoroalkyl; 
 (iii) —O—(C 1 -C 6  alkyl); 
 (iv) —O—(C 1 -C 3  fluoroalkyl); 
 (v) —R 6a , wherein R 6a  is selected from the group consisting of:
 (a) C 3 -C 6  cycloalkyl; 
 (b) a group of the formula 
 
 
       
       
         
           
           
               
               
           
         
         
           
              wherein m is 1, 2, 3, or 4; 
             (c) a group of the formula 
           
         
       
       
         
           
           
               
               
           
         
         
           
              where R 6a1  is H, C 1 -C 3  alkyl, or —CH 2 CH 2 NH 2 ; and 
             (d) a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S; 
             wherein R 6a  is unsubstituted or substituted with 1 to 3 R 6a2  moieties selected from the group consisting of halo and C 1 -C 3  alkyl; 
           
           (vi) —O—R 6b ,
 wherein R 6b  is selected from the group consisting of: 
 (a) C 3 -C 6  cycloalkyl; and 
 (b) a group of the formula 
 
         
       
       
         
           
           
               
               
           
         
         
           
              wherein p is 0, 1, or 2, and q is 1, 2, or 3; 
             wherein R 6b  is unsubstituted or substituted with 1 to 2 R 6b1  moieties selected from the group consisting of fluoro and C 1 -C 3  alkyl; 
           
           (vii) —N(R 6c ) 2 , wherein each occurrence of R 6c  is selected from the group consisting of H and C 1 -C 3  alkyl; 
           (viii) —N(H)C(O)—(C 1 -C 3  alkyl); 
           (ix) —N(H)C(O)O—(C 1 -C 3  alkyl); 
           (x) —NHC(O)—N(R 6d ) 2 , wherein each R 6d  is H or C 1 -C 3  alkyl; 
           (xi) halo; and 
           (xii) H; 
         
         R 7  is H or halo; 
         R 8  is H or halo; 
         R 9  is H or halo; and 
         n is 0, 1, or 2. 
       
     
     
         2 - 12 . (canceled) 
     
     
         13 . A method of treating a disease or condition mediated by Spleen tyrosine kinase (Syk) comprising administering a therapeutically effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         14 - 16 . (canceled)