Imidazopyrazine syk inhibitors

Abstract

Certain imidazopyrazines and pharmaceutical compositions thereof are provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of Syk activity, which comprises administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are provided. Also provided are methods for determining the presence or absence of Syk kinase in a sample.

1 - 10 . (canceled) 
     
     
         11 : At least one chemical entity chosen from compounds of Formula I: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein
 R 1  is phenyl substituted with one or two groups chosen from
 halo, 
 hydroxy, 
 carboxy, 
 cyano, 
 cycloalkyl optionally substituted with one or two groups chosen from hydroxy, lower alkoxy, and lower alkyl, 
 cycloalkyloxy optionally substituted with one or two groups chosen from hydroxy, lower alkoxy, and lower alkyl, 
 heterocycloalkyl optionally substituted with one or two groups chosen from acyl, halo, optionally substituted amino, hydroxy, lower alkoxy, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with one, two, or three halo groups, optionally substituted amino, optionally substituted heterocycloalkyl, and oxo, 
 heterocycloalkyloxy optionally substituted with one or two groups chosen from halo, optionally substituted amino, hydroxy, lower alkoxy, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with one, two, or three halo groups, optionally substituted amino, optionally substituted heterocycloalkyl, and oxo, 
 heteroaryl, 
 amino optionally substituted with one or two groups chosen from lower alkyl, lower alkyl substituted with halo, lower alkyl substituted with hydroxy, and lower alkyl substituted with lower alkoxy, 
 —C(O)NR 6 R 7  wherein R 6  and R 7  are independently selected from hydrogen, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with optionally substituted amino, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, or R 6  and R 7  together with the nitrogen to which they are bound form a 3- to 7-membered heterocycloalkyl ring optionally substituted with one or two groups chosen from hydroxy, lower alkyl, and lower alkyl substituted with hydroxy, 
 —S(O) 2 NR 6 R 7  wherein R 6  and R 7  are independently selected from hydrogen, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted optionally substituted amino, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, or R 6  and R 7  together with the nitrogen to which they are bound form a 3- to 7-membered heterocycloalkyl ring optionally substituted with one or two groups chosen from hydroxy, lower alkyl, and lower alkyl substituted with hydroxy, provided that at least one of R 6  and R 7  is not hydrogen, 
 lower alkoxy optionally substituted with one or two groups chosen from hydroxy, lower alkoxy, optionally substituted aminocarbonyl, optionally substituted amino, carboxy, aminocarbonyl, and heterocycloalkyl, 
 heteroaryloxy, and 
 lower alkyl optionally substituted with one or two groups chosen from hydroxy, lower alkoxy, halo, trifluoromethyl, optionally substituted amino, and heterocycloalkyl optionally substituted with lower alkyl; or 
 R 1  is 
 
 
       
         
           
           
               
               
           
         
         
            wherein A is chosen from aryl, cycloalkyl and heterocycloalkyl groups, each of which groups having from 5 to 7 ring atoms including the atoms shared with the 6 membered aromatic ring and each of which groups being optionally substituted; 
           R 2  is chosen from optionally substituted aryl and optionally substituted heteroaryl; 
           R 3  is chosen from hydrogen, lower alkyl, and halo; 
           R 4  is chosen from hydrogen and lower alkyl; and 
           R 5  is hydrogen, 
           provided that 
           if R 3  and R 4  are hydrogen and R 1  is 3-methoxy-4-(morpholin-4-ylcarbonyl)phenyl, 4-(morpholin-4-yl)phenyl, 3,4-diethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-(4-ethylpiperazin-1-1)phenyl, 4-(3-oxopiperazin-1-yl)phenyl, 4-(morpholin-4-yl)phenyl, 3-methoxy-4-(morpholin-4-yl)phenyl, 3-methoxy-4-methylphenyl, 4-methoxy-3-methylphenyl, 2-(dimethylamino)ethoxy-3-methoxyphenyl, 3-ethoxy-4-methoxyphenyl, or 4-ethoxy-3-methoxyphenyl, then R 2  is not phenyl substituted with —(CO)NHR 6  where R 6  is optionally substituted aryl; 
           if R 3  and R 4  are hydrogen and R 1  is 3,4-dimethoxyphenyl, then R 2  is not phenyl substituted with
 —(CO)NR 8 R 9  where R 8  and R 9  taken together form an heterocycloalkyl or optionally substituted heteroaryl or where R 8  is hydrogen, methyl or ethyl and R 9  is hydrogen, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkyl, or optionally substituted heteroaryl wherein said phenyl is further optionally substituted with a group chosen from methyl, methoxy, and halo, or 
 —(SO 2 )NHR 10  where R 10  is optionally substituted phenyl; 
 
           if R 3  and R 4  are hydrogen and R 1  is 4-(morpholin-4-yl)phenyl, then R 2  is not pyridinyl, 2-fluorophenyl, benzo[d][1,3]dioxolyl, 2-methoxyphenyl, 2,6-dimethoxyphenyl, 3-acetamidophenyl, 3-carboxyphenyl, 2-(hydroxymethyl)phenyl, furanyl, or 3-(hydroxyethylcarbamoyl)phenyl; 
           if R 3  and R 4  are hydrogen and R 1  is chlorophenyl, then R 2  is not phenyl substituted with piperidin-1-yl-carbonyl or NH(CO)NHR 12  where R 12  is phenyl substituted with trifluoromethyl or one or more halogens; 
           if R 3  and R 4  are hydrogen and R 1  is phenyl substituted with optionally substituted piperazinyl then R 2  is not 3-aminophenyl; 
           if R 3  and R 4  are hydrogen and R 1  is 4-chlorophenyl, then R 2  is not 4-carboxyphenyl, 3-(2-(dimethylamino)ethylcarbamoyl)phenyl, or 4-(2-(dimethylamino)ethylcarbamoyl)phenyl; and 
           if R 3  and R 4  are hydrogen and R 1  is 4-(2-hydroxy-ethyl)phenyl or 4-(hydroxyethyl)phenyl, then R 2  is not 2-methoxyphenyl or 2-fluorophenyl; 
           if R 3  and R 4  are hydrogen and R 1  is 4-[(4-ethylpiperazin-1-yl)methyl]phenyl or 4-(2-hydroxypropan-2-yl)phenyl, then R 2  is not phenyl substituted with —(CO)NR 8 R 9  where R 8  is hydrogen and R 9  is hydrogen, methyl or optionally substituted aryl wherein said phenyl is optionally further substituted with a group chosen from methyl; 
           if R 3  and R 4  are hydrogen and R 2  is 4-carbamoylphenyl, then R 1  is not 4-(hydroxymethyl)phenyl, 3-(1-hydroxyethyl)phenyl, 4-(1H-imidazol-2-yl)-3-methylphenyl, 3-methoxy-4-(piperidin-4-yloxy)phenyl, 3-methoxy-4-(2-methoxyethoxy)phenyl, 4[2-(dimethylamino)ethoxy]-3-methoxyphenyl, 4-(2-hydroxyethoxy)-3-methoxyphenyl, 3-methoxy-4-(propan-2-yloxy)phenyl, 3-methoxy-4-propoxyphenyl, 4-(propylcarbamoyl)phenyl, 4-ethoxy-3-methoxyphenyl, 4-(1H-imidazol-2-yl)phenyl, 3-methoxy-4-(1H-pyrazol-5-yl)phenyl, 
           if R 3  and R 4  are hydrogen and R 2  is pyridin-3-yl substituted with carbamoyl, then R 1  is not 3,4-dimethoxyphenyl, 
           if R 3  and R 4  are hydrogen and R 1  is 4-ethoxy-3-methoxyphenyl, then R 2  is not phenyl substituted with methyl and further substituted with —(CO)NR 8 R 9  where R 8  is hydrogen and R 9  is 4-(methylcarbamoyl)phenyl, and 
           further provided that R 2  is not phenyl substituted with —NHC(O)R 11  where R 11  is optionally substituted aryl. 
         
       
     
     
         12 : A pharmaceutical composition comprising at least one chemical entity of claim  1 , together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients. 
     
     
         13 : A method for treating a patient having a disease responsive to the inhibition of Syk activity, comprising administering to the patient an effective amount of at least one chemical entity according to claim  1 .