Bicyclic heteroaryl cycloalkyldiamine derivatives as inhibitors of spleen tyrosine kinases (syk)

Abstract

The present invention relates to bicyclic heteroaryl cycloalkyldiamine derivatives, to processes for their production, to their use as SYK inhibitors and to pharmaceutical compositions comprising them. Formula (I)

1 - 11 . (canceled) 
     
     
         12 . A medicament comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein X1 is CR1; 
         X2 is CH; 
         Y is CH 2  or O; 
         A is bicyclic heteroaryl having from 8 to 10 ring atoms, wherein 1-3 of said ring atoms are heteroatoms selected from N, O and S and wherein said heteroaryl may be unsubstituted or substituted at a carbon atom by a R2 or at a nitrogen atom by a R3; 
         R1 is H, Hal or C 1-4  alkyl; R2 is H, C 1-4  alkyl, C 3-5  cycloalkyl, CN or Hal; and R3 is H or alkyl. 
       
     
     
         13 . The medicament of  claim 12 , said compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X1 is CH; X2 is CH; Y is CH 2 ; A is bicyclic heteroaryl having from 8 to 10 ring atoms, wherein 1-2 of said ring atoms are heteroatoms selected from N, O and S and wherein said heteroaryl may be unsubstituted or substituted at a carbon atom by a R2 and at a nitrogen atom by a R3; R2 is H, C 1-4  alkyl, C 3-5  cycloalkyl, CN or Hal; and R3 is H or alkyl. 
     
     
         14 . The medicament of  claim 12 , said compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X1 is CH; X2 is CH; Y is CH 2 ; A is an unsubstituted or substituted indole moiety, wherein the substituent is R2 and is attached to a carbon atom of the indole moiety; and wherein R2 is C 1-4  alkyl. 
     
     
         15 . The medicament of  claim 12 , consisting of a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
         Y is CH 2  or O; and R2 is H, C 1-4  alkyl or Hal. 
       
     
     
         16 . The medicament of  claim 15 , said compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein Y is CH 2 ; and R2 is H, or C 1-4  alkyl or Hal. 
     
     
         17 . The medicament of  claim 12 , comprising a compound selected from the group consisting of:
 7-((1R,2S)-2-Amino-cyclohexylamino)-8-fluoro-5-(5-fluoro-3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-8-fluoro-5-(quinolin-5-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(1-methyl-1H-indol-4-ylamino)-3H-pyrido [3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-5-(2-methyl-2H-indazol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(5-fluoro-3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinolin-6-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(benzofuran-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(benzo[b]thiophen-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-5-(2-methyl-quinolin-5-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2- Amino-cyclohexylamino)-5-(1H-indol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(1H-indazol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinolin-3-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(8-methyl-quinolin-5-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-4-oxo-3,4-dihydro-pyrido [3,4-d]pyridazin-5-ylamino)-1H-indole-3-carbonitrile,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(7-methyl-1H-indol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinolin-5-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(2-methyl-1H-indol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinoxalin-6-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinolin-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinolin-8-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((3R,4R)-3-Amino-tetrahydro-pyran-4-ylamino)-5-(3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((3R,4R)-3-Amino-tetrahydro-pyran-4-ylamino)-5-(benzo[b]thiophen-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((3R,4R)-3-Amino-tetrahydro-pyran-4-ylamino)-5-(5-fluoro-3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, and   7-((3R,4R)-3-Amino-tetrahydro-pyran-4-ylamino)-5-(1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one.   
     
     
         18 . Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder which is mediated by or is susceptible to SYK activity, 
       
         
           
           
               
               
           
         
         wherein X1 is CR1; 
         X2 is CH; 
         Y is CH2 or O; 
         A is bicyclic heteroaryl having from 8 to 10 ring atoms, wherein 1-3 of said ring atoms are heteroatoms selected from N, O and S and wherein said heteroaryl may be unsubstituted or substituted at a carbon atom by a R2 or at a nitrogen atom by a R3; 
         R1 is H, Hal or C 1-4  alkyl; R2 is H, C 1-4  alkyl, C 3-5  cycloalkyl, CN or Hal; and R3 is H or alkyl. 
       
     
     
         19 . The use of a compound of  claim 18 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder which is mediated by or is susceptible to SYK activity, wherein X1 is CH; X2 is CH; Y is CH 2 ; A is bicyclic heteroaryl having from 8 to 10 ring atoms, wherein 1-2 of said ring atoms are heteroatoms selected from N, O and S and wherein said heteroaryl may be unsubstituted or substituted at a carbon atom by a R2 and at a nitrogen atom by a R3; R2 is H, C 1-4  alkyl, C 3-5  cycloalkyl, CN or Hal; and R3 is H or alkyl. 
     
     
         20 . The use of a compound of  claim 18 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder which is mediated by or is susceptible to SYK activity, wherein X1 is CH; X2 is CH; Y is CH 2 ; A is an unsubstituted or substituted indole moiety, wherein the substituent is R2 and is attached to a carbon atom of the indole moiety; and wherein R2 is C 1-4  alkyl. 
     
     
         21 . The use of a compound of  claim 18 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder which is mediated by or is susceptible to SYK activity, wherein said compound consists of a compound of formula (II), or a pharmaceutically acceptable salt thereof, and wherein 
       
         
           
           
               
               
           
         
         Y is CH2 or O; and R2 is H, C 1-4  alkyl or Hal. 
       
     
     
         22 . The use of a compound of  claim 21 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder which is mediated by or is susceptible to SYK activity, wherein Y is CH 2 ; and R2 is H, or C 1-4  alkyl or Hal. 
     
     
         23 . The use of a compound of  claim 18 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder which is mediated by or is susceptible to SYK activity, wherein said compound is selected from the group consisting of:
 7-((1R,2S)-2-Amino-cyclohexylamino)-8-fluoro-5-(5-fluoro-3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-8-fluoro-5-(quinolin-5-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(1-methyl-1H-indol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-5-(2-methyl-2H-indazol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(5-fluoro-3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinolin-6-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(benzofuran-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(benzo[b]thiophen-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-5-(2-methyl-quinolin-5-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-5-(1H-indol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(1H-indazol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinolin-3-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(8-methyl-quinolin-5-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyridazin-5-ylamino)-1H-indole-3-carbonitrile,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(7-methyl-1H-indol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinolin-5-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(2-methyl-1H-indol-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, 7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinoxalin-6-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinolin-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((1R,2S)-2-Amino-cyclohexylamino)-5-(quinolin-8-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((3R,4R)-3-Amino-tetrahydro-pyran-4-ylamino)-5-(3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((3R,4R)-3-Amino-tetrahydro-pyran-4-ylamino)-5-(benzo[b]thiophen-4-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one,   7-((3R,4R)-3-Amino-tetrahydro-pyran-4-ylamino)-5-(5-fluoro-3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one, and   7-((3R,4R)-3-Amino-tetrahydro-pyran-4-ylamino)-5-(1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one.