Heterocyclic compounds as adenosine antagonists

Abstract

Aminopyrazine compounds as modulators of an adenosine receptor are provided. The compounds may find use as therapeutic agents for the treatment of diseases mediated through a G-protein-coupled receptor signaling pathway and may find particular use in oncology.

1 : A compound of the formula (I): 
       
         
           
           
               
               
           
         
       
       or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
 A is 4-hydroxyphenyl optionally further substituted by R 3 , 4-hydroxy-2-pyridyl optionally further substituted by R 4 , a naphthyl substituted by R 4 , a 9- or 10-membered bicylic heterocylyl optionally substituted by R 4 , or a 9- or 10-membered bicyclic heteroaryl optionally substituted by R 4 ; 
 B is a phenyl optionally substituted by R 3 , C 3 -C 6  cycloalkyl optionally substituted by R 4 , 3- to 6-membered heterocyclyl optionally substituted by R 4  or a 5- to 10-membered heteroaryl optionally substituted by R 4 ; 
 R 1  is a hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3  alkylene)(5-6-membered heteroaryl), —(C 1 -C 3  alkylene)(C 6  aryl), —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —NR 1b R 1c , —S(O) 2 R 1a , —(C 1 -C 3  alkylene)C(O)NR 1b R 1c , —(C 1 -C 3  alkylene)C(O)R 1a  or —(C 1 -C 3  alkylene)NR 1b R 1c , wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3  alkylene)(5-6-membered heteroaryl), and —(C 1 -C 3  alkylene)(C 6  aryl) of R 1  are independently optionally substituted by R 4 ; 
 each R 1a  is independently hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, 3-6-membered heterocyclyl, C 6  aryl, 5-6-membered heteroaryl, —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3  alkylene)(C 6  aryl) or —(C 1 -C 3  alkylene)(5-6-membered heteroaryl), wherein each of which is optionally substituted by methyl, ethyl, halogen, oxo, —CF 3 , —OH, —OCH 3 , —CN, —C(O)OCH 3 , —C(O)OC 2 H 5 , —NH 2  or —NHCH 3 ; 
 each R 1b  and R 1c  is independently hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, 3-6-membered heterocyclyl, C 6  aryl, 5-6-membered heteroaryl, —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3  alkylene)(C 6  aryl) or —(C 1 -C 3  alkylene)(5-6-membered heteroaryl), wherein each of which is optionally substituted by methyl, ethyl, halogen, oxo, —CF 3 , —OH, —OCH 3 , —CN, —C(O)OCH 3 , —C(O)OC 2 H 5 , —NH 2  or —NHCH 3 ;
 or R 1b  and R 1c  are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocyclyl; 
 
 R 2  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 14  aryl, C 5 -C 14  heteroaryl, C 3 -C 6  cycloalkyl, 3- to 6-membered heterocyclyl, —CN, halogen, —OR 2a , —SR 2a , —NR 2b R 2c , —C(O)R 2a , —NR 2b C(O)R 2c , —NR 2a C(O)NR 2b R 2c , —C(O)OR 2a , —C(O)ONR 2b R 2c  or —C(O)NR 2b R 2c , wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 14  aryl, C 3 -C 6  cycloalkyl and 3- to 6-membered heterocyclyl of R 2  are independently optionally substituted by R 4 ; 
 each R 2a  is independently hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -aryl, 5- to 6-membered heteroaryl, —(C 1 -C 3  alkylene)N(C 2 H 5 ) 2 , —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3  alkylene)(5-6-membered heteroaryl) or —(C 1 -C 3  alkylene)(C 6  aryl), wherein each of which is optionally substituted by methyl, ethyl, halogen, oxo, —CF 3 , —OH, —OCH 3 , —CN, —C(O)OCH 3 , —C(O)OC 2 H 5 , —NH 2  or —NHCH 3 ; 
 each R 2b  and R 2c  is independently hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -aryl, 5- to 6-membered heteroaryl, —(C 1 -C 3  alkylene)N(C 2 H 5 ) 2 , —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3  alkylene)(C 6  aryl) or —(C 1 -C 3  alkylene)(5-6-membered heteroaryl), wherein each of which is optionally substituted by methyl, ethyl, halogen, oxo, —CF 3 , —OH, —OCH 3 , —CN, —C(O)OCH 3 , —C(O)OC 2 H 5 , —NH 2  or —NHCH 3 ;
 or R 2b  and R 2c  are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocyclyl; 
 
 each R 3  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —CN, —OR 5 , —SR 5 , —NR 6 R 7 , —NO 2 , —C═NH(OR 5 ), —C(O)R 5 , —OC(O)R 5 , —C(O)OR 5 , —C(O)NR 6 R 7 , —OC(O)NR 6 R 7 , —NR 5 C(O)R 6 , —NR 5 C(O)OR 6 , —NR 5 C(O)NR 6 R 7 , —S(O)R 5 , —S(O) 2 R 5 , —NR 5 S(O)R 6 , —C(O)NR 5 S(O)R 6 , —NR 5 S(O) 2 R 6 , —C(O)NR 5 S(O) 2 R 6 , —S(O)NR 6 R 7 , —S(O) 2 NR 6 R 7 , —P(O)(OR 6 ) (OR 7 ), C 3 -C 6  cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, —(C 1 -C 3  alkylene)CN, —(C 1 -C 3  alkylene)OR 5 , —(C 1 -C 3  alkylene)SR 5 , —(C 1 -C 3  alkylene)NR 6 R 7 , —(C 1 -C 3  alkylene)CF 3 , —(C 1 -C 3  alkylene)NO 2 , —C═NH(OR 5 ), —(C 1 -C 3  alkylene)C(O)R 5 , —(C 1 -C 3  alkylene)OC(O)R 5 , —(C 1 -C 3  alkylene)C(O)OR 5 , —(C 1 -C 3 alkylene)C(O)NR 6 R 7 , —(C 1 -C 3  alkylene)OC(O)NR 6 R 7 , —(C 1 -C 3  alkylene)NR 5 C(O)R 6 , —(C 1 -C 3 alkylene)NR 5 C(O)OR 6 , —(C 1 -C 3  alkylene)NR 5 C(O)NR 6 R 7 , —(C 1 -C 3  alkylene)S(O)R 5 , —(C 1 -C 3  alkylene)S(O) 2 R 5 , —(C 1 -C 3  alkylene)NR 5 S(O)R 6 , —C(O)(C 1 -C 3  alkylene)NR 5 S(O)R 6 , —(C 1 -C 3 alkylene)NR 5 S(O) 2 R 6 , —(C 1 -C 3  alkylene)C(O)NR 5 S(O) 2 R 6 , —(C 1 -C 3  alkylene)S(O)NR 6 R 7 , —(C 1 -C 3  alkylene)S(O) 2 NR 6 R 7 , —(C 1 -C 3  alkylene)P(O)(OR 6 )(OR 7 ), —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-12-membered heterocyclyl), —(C 1 -C 3  alkylene)(5-10-membered heteroaryl) or —(C 1 -C 3  alkylene)(C 6 -C 14  aryl), wherein each R 3  is independently optionally substituted by halogen, oxo, —OR 8 , —NR 8 R 9 , —C(O)R 8 , —CN, —S(O)R 8 , —S(O) 2 R 8 , —P(O)(OR 8 )(OR 9 ), —(C 1 -C 3  alkylene)OR 8 , —(C 1 -C 3  alkylene)NR 8 R 9 , —(C 1 -C 3  alkylene)C(O)R 8 , —(C 1 -C 3  alkylene)S(O)R 8 , —(C 1 -C 3  alkylene)S(O) 2 R 8 , —(C 1 -C 3  alkylene)P(O)(OR 8 )(OR 9 ), C 3 -C 8  cycloalkyl, or C 1 -C 6  alkyl optionally substituted by oxo, —OH or halogen; 
 each R 4  is independently oxo or R 3 ; 
 R 5  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5-6-membered heteroaryl or 3-6-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5-6-membered heteroaryl and 3-6-membered heterocyclyl of R 5  are independently optionally substituted by halogen, oxo, —CN, —OR 9 , —NR 9 R 10 , —P(O)(OR 9 )(OR 10 ), phenyl optionally substituted by halogen, or C 1 -C 6  alkyl optionally substituted by halogen, —OH or oxo; 
 R 6  and R 7  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5-6-membered heteroaryl, —(C 1 -C 3  alkylene)(C 6  aryl) or 3-6 membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5-6-membered heteroaryl, —(C 1 -C 3  alkylene)(C 6  aryl) and 3-6 membered heterocyclyl of R 6  and R 7  are independently optionally substituted by halogen, oxo, —CN, —OR 9 , —NR 9 R 10  or C 1 -C 6  alkyl optionally substituted by halogen, —OH or oxo;
 or R 6  and R 7  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 9 , —NR 9 R 10  or C 1 -C 6  alkyl optionally substituted by halogen, oxo or —OH; 
 
 R 8  and R 9  in R 3  are each independently hydrogen, C 1 -C 6  alkyl optionally substituted by halogen or oxo, C 2 -C 6  alkenyl optionally substituted by halogen or oxo, or C 2 -C 6  alkynyl optionally substituted by halogen or oxo;
 or R 8  and R 9  in R 3  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6  alkyl optionally substituted by halogen or oxo; and 
 
 R 9  and R 10  in R 5 , R 6  and R 7  are each independently hydrogen, C 1 -C 6  alkyl optionally substituted by halogen or oxo, C 2 -C 6  alkenyl optionally substituted by halogen or oxo, or C 2 -C 6  alkynyl optionally substituted by halogen or oxo;
 or R 9  and R 10  in R 5 , R 6  and R 7  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6  alkyl optionally substituted by oxo or halogen. 
 
 
     
     
         2 - 46 . (canceled)