Pyrazine derivatives useful as adenosine receptor antagonists

Abstract

The present invention provides a compound of formula (I) wherein: A represents an optionally substituted monocyclic or polycyclic aryl or heteroaryl group B represents an optionally substituted monocyclic nitrogen-containing heteroaryl group; and either a) R 1 and R 2 represent hydrogen or specified substituents, or b) R 2 , R 1 and the —NH— group to which R 1 is attached, form a moiety selected from the moiety of formulae (IIa) and (IIb): (IIa) These compounds are useful as antagonists of the A2B receptor, for instance in the treatment of asthma.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a monocyclic, polycyclic aryl or heteroaryl group optionally substituted by one or more substituents each independently chosen from halogen atoms, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, C 1-4 alkoxy, aryl-C 1-4 alkoxy, C 1-4 alkylthio, mono or di-C 1-4 alkylamino, trifluoromethyl, hydroxy and cyano groups; 
 B is a monocyclic nitrogen-containing heteroaryl group optionally substituted by one or more substituents each independently chosen from halogen atoms, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, C 1-4 alkylthio, mono or di-C 1-4 alkylamino, trifluoromethyl and cyano groups; and
 R 2 , R 1  and the —NH— group to which R 1  is attached, form a moiety chosen from the moiety of formulae (IIa) and (IIb): 
 
 
       
         
           
           
               
               
           
         
         
           wherein: 
           each instance of R a  is independently chosen from a hydrogen atom, halogen atoms, —OH, —NH 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, saturated heterocyclic rings, C 1-4 alkoxy, and C 1-4 alkylthio groups; wherein the aryl or heteroaryl groups are each independently unsubstituted or substituted with at least one group chosen from halogen atoms, C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxy, mono or di-C 1-4 alkylamino, cyano, trifluoromethyl, trifluoromethoxy, carbamoyl and carboxy groups; and 
           R b  is chosen from a hydrogen atom, halogen atoms, C 1-4 alkyl, C 1-4 alkylamino, aryl-C 1-4 alkylamino and —NH 2  groups; 
         
         or a pharmaceutically acceptable salt thereof, or a N-oxide thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein A is an optionally substituted monocyclic five or six-membered heteroaryl ring or an optionally substituted phenyl ring. 
     
     
         3 . The compound according to  claim 1 , wherein A is an optionally substituted pyridine, oxazole, furan, pyrazole, pyrazine or phenyl group. 
     
     
         4 . The compound according to  claim 1 , wherein A is an optionally substituted pyridine, oxazol, furan or pyrazol group. 
     
     
         5 . The compound according to  claim 4  wherein A is a pyridine ring unsubstituted or substituted with alkoxy groups or halogen atoms. 
     
     
         6 . The compound according to  claim 1 , wherein A is a pyridine ring either unsubstituted or substituted with one or two halogen atoms. 
     
     
         7 . The compound according to  claim 6 , wherein A is a pyridine ring either unsubstituted or substituted with one halogen atom. 
     
     
         8 . The compound according to  claim 1 , wherein B is an optionally substituted monocyclic, five or six-membered heteroaryl ring having one or two nitrogen atoms. 
     
     
         9 . The compound according to  claim 8 , wherein B is an optionally substituted pyridine or pyrimidine group. 
     
     
         10 . The compound according to  claim 1 , wherein B is a pyridine ring either unsubstituted or substituted with one or two halogen atoms. 
     
     
         11 . The compound according to  claim 10  wherein B is a pyridine ring either unsubstituted or substituted with one halogen atom. 
     
     
         12 - 17 . (canceled) 
     
     
         18 . The compound according to  claim 1 , wherein R 2 , R 1  and the —NH— group to which R 1  is attached form a moiety of formula (IIa) or (IIb): 
       
         
           
           
               
               
           
         
         wherein: 
         each instance of R a  is chosen from C 3-8 cycloalkyl groups, saturated heterocyclic rings, and aryl and heteroaryl groups; wherein the aryl and heteroaryl groups are each independently unsubstituted or substituted with one or more halogen atom; and 
         R b  is a hydrogen atom. 
       
     
     
         19 . The compound according to  claim 18 , wherein R 2 , R 1  and the —NH— group to which R 1  is attached form a moiety of formula (IIb): 
       
         
           
           
               
               
           
         
         wherein: 
         R a  is chosen from C 3-8 cycloalkyl, saturated heterocyclic rings, aryl and heteroaryl groups; wherein the aryl and heteroaryl groups are each independently unsubstituted or substituted with one or more halogen atoms. 
       
     
     
         20 . The compound according to  claim 1  chosen from:
 6-(3-Fluorophenyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;   6-(3-Fluorophenyl)-2-methyl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;   5-(3-Fluorophenyl)-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one;   6-(3-Fluorophenyl)-5-pyridin-4-yl-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazine;   6-(2-Fluorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine;   6-(3-Chlorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine;   6-(3-Fluorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine;   6-(2-Furyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;   2-Cyclopentyl-6-(2-furyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;   2,6-Di-2-furyl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;   6-(2-Furyl)-2-pyridin-3-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;   6-(2-Furyl)-2,5-dipyridin-4-yl-1H-imidazo[4,5-b]pyrazine;   6-(2-Furyl)-2-pyridin-2-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;   6-(2-Furyl)-2-pyrazin-2-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;   5-Pyridn-3-yl-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one;   2-(4-Fluorophenyl)-6-pyridin-3-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;   6-(2-Furyl)-5-pyrimidin-4-yl-1H-imidazo[4,5-b]pyrazine;   5-(2-Furyl)-6-pyrimidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one;   6-(2-Furyl)-2-pyridin-3-yl-5-pyrimidin-4-yl-1H-imidazo[4,5-b]pyrazine;   6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine;   5-[2-(Methylthio)pyrimidin-4-yl]-6-(2-thienyl)-1H-imidazo[4,5-b]pyrazine;   3-(2-Furyl)-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine;   3-(2-Furyl)-6-phenyl-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine;   6-Cyclohexyl-3-(2-furyl)-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine;   6-(4-Fluorophenyl)-2-(3-fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine;   2-(3-Fluoropyridin-4-yl)-6-pyridin-2-yl-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine;   2-(3-Fluoropyridin-4-yl)-3,6-dipyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine;   4-[2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin-6-yl]benzonitril;   4-[2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin-6-yl]benzamid;   2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin;   2-(4-Fluorophenyl)-5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazin;   5-(3-Fluoropyridin-4-yl)-6-pyridin-3-yl-2-[4-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyrazin;   2-[1-(4-Chlorophenyl)ethyl]-5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazin;   5(3-Fluoropyridin-4-yl)-2-(methylthio)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazin; and   5-(3-Fluoropyridin-4-yl)-2-morpholin-4-yl-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazin.   
     
     
         21 . (canceled) 
     
     
         22 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable diluent or carrier. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . A method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by antagonism of the A 2B  adenosine receptor, which comprises administering to said subject an effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a monocyclic, polycyclic aryl or heteroaryl group optionally substituted by one or more substituents each independently chosen from halogen atoms, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, C 1-4 alkoxy, aryl-C 1-4 alkoxy, C 1-4 alkylthio, mono or di-C 1-4 alkylamino, trifluoromethyl, hydroxy and cyano groups; 
 B is a monocyclic nitrogen-containing heteroaryl group optionally substituted by one or more substituents each independently chosen from halogen atoms, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, C 1-4 alkylthio, mono or di-C 1-4 alkylamino, trifluoromethyl and cyano groups; 
 and either
 a) R 1  is a group of formula:
   -L-(CR′R″) n -G 
 wherein L is a direct bond or a linking group chosen from —(CO)—, —(CO)O—, —(CO)NR′—, —SO 2 — and —SO 2 NR′—; 
 R′ and R″ are each independently chosen from a hydrogen atom and C 1-4 alkyl groups; 
 n is an integer from 0 to 6; and 
 G is chosen from a hydrogen atom and C 1-4 alkyl, aryl, heteroaryl, C 3-8 cycloalkyl and saturated or unsaturated heterocyclic groups, wherein the C 1-4 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl groups are each independently unsubstituted or substituted with one or more substituents chosen from halogen atoms, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, mono or di-C 1-4 alkylamino, trifluoromethyl, trifluoromethoxy, carbamoyl, carboxy and cyano groups; 
 and R 2  is chosen from a hydrogen atom, halogen atoms and C 1-4 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, mono or di-C 1-4 alkylamino, C 1-4 alkoxy-(CO)—, —NH 2 , mono or di-C 1-4 alkylamino-(CO)— and cyano groups, wherein the C 1-4 alkyl, C 2-5 alkenyl and C 2-5 alkynyl groups may be each independently unsubstituted or substituted by one aryl or heteroaryl group; 
 
 
 or
 b) R 2 , R 1  and the —NH— group to which R 1  is attached, form a moiety chosen from the moiety of formulae (IIa) and (IIb): 
 
 
       
         
           
           
               
               
           
         
         
           wherein: 
           each instance of R a  is independently chosen from a hydrogen atom, halogen atoms, —OH, —NH 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, saturated heterocyclic rings, C 1-4 alkoxy, and C 1-4 alkylthio groups; wherein the aryl or heteroaryl groups are each independently unsubstituted or substituted with at least one group chosen from halogen atoms, C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxy, mono or di-C 1-4 alkylamino, cyano, trifluoromethyl, trifluoromethoxy, carbamoyl and carboxy groups; and 
           R b  is chosen from a hydrogen atom, halogen atoms C 1-4 alkyl, C 1-4 alkylamino, aryl-C 1-4 alkylamino and —NH, groups; 
         
         or a pharmaceutically acceptable salt thereof, or a N-oxide thereof; with the proviso that the compound is not chosen from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-benzamide and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-formamide. 
       
     
     
         26 . The method according to  claim 25 , wherein the pathological condition or disease is chosen from asthma, bronchoconstriction, allergic diseases, hypertension, atherosclerosis, reperfusion injury, myocardial ischemia, retinopathy, inflammation, gastrointestinal tract disorders, cell proliferation disorders, diabetes mellitus, and autoimmune diseases. 
     
     
         27 . A composition comprising:
 (i) a compound of formula (I)   
       
         
           
           
               
               
           
         
       
       wherein:
 A is a monocyclic, polycyclic aryl or heteroaryl group optionally substituted by one or more substituents each independently chosen from halogen atoms, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, C 1-4 alkoxy, aryl-C 1-4 alkoxy, C 1-4 alkylthio, mono or di-C 1-4 alkylamino, trifluoromethyl, hydroxy and cyano groups; 
 B is a monocyclic nitrogen-containing heteroaryl group optionally substituted by one or more substituents each independently chosen from halogen atoms, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, C 1-4 alkylthio, mono or di-C 1-4 alkylamino, trifluoromethyl and cyano groups; 
 and either
 a) R 1  is a group of formula;
   -L-(CR′R″) n -G 
 wherein L is a direct bond or a linking group chosen from —(CO)—, —(CO)O—, —(CO)NR′—, —SO 2 — and —SO 2 NR′—; 
 R′ and R″ are each independently chosen from a hydrogen atom and C 1-4 alkyl groups; 
 n is an integer from 0 to 6; and 
 G is chosen from a hydrogen atom and C 1-4 alkyl, aryl, heteroaryl, C 3-8 cycloalkyl and saturated or unsaturated heterocyclic groups, wherein the C 1-4 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl groups are each independently unsubstituted or substituted with one or more substituents chosen from halogen atoms, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, mono or di-C 1-4 alkylamino, trifluoromethyl, trifluoromethoxy, carbamoyl, carboxy and cyano groups; 
 and R 2  is chosen from a hydrogen atom, halogen atoms and C 1-4 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, mono or di-C 1-4 alkylamino, C 1-4 alkoxy-(CO)—, —NH 2 , mono or di-C 1-4 alkylamino-(CO)— and cyano groups, wherein the C 1-4 alkyl, C 2-5 alkenyl and C 2-5 alkynyl groups may be each independently unsubstituted or substituted by one aryl or heteroaryl group; 
 
 
 or
 b) R 2 , R 1  and the —NH— group to which R 1  is attached, form a moiety chosen from the moiety of formulae (IIa) and (IIb): 
 
 
       
         
           
           
               
               
           
         
         
           wherein: 
           each instance of R a  is independently chosen from a hydrogen atom, halogen atoms, —OH, —NH 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, saturated heterocyclic rings, C 1-4 alkoxy, and C 1-4 alkylthio groups; wherein the aryl or heteroaryl groups are each independently unsubstituted or substituted with at least one group chosen from halogen atoms, C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxy, mono or di-C 1-4 alkylamino, cyano, trifluoromethyl, trifluoromethoxy, carbamoyl and carboxy groups; and 
           R b  is chosen from a hydrogen atom, halogen atoms C 1-4 alkyl, C 1-4 alkylamino, aryl-C 1-4 alkylamino and —NH 2  groups; 
         
         or a pharmaceutically acceptable salt thereof, or a N-oxide thereof; with the proviso that the compound is not chosen from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-benzamide and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-formamide; and
 (ii) at least one compound chosen from (1) antagonists of M3 muscarinic receptors, (2) β2-agonists, (3) PDE4 inhibitors, (4) corticocosteroids, (5) leukotriene D4 antagonists, (6) inhibitors of egfr-kinase, (7) p38 kinase inhibitors, (8) NK1 receptor agonists, (9) CRTh2 antagonists, (10) syk kinase inhibitors, (11) CCR3 antagonists and (12) VLA-4 antagonists, for simultaneous, separate or sequential administration.