Heterocyclic compounds as adenosine antagonists

Abstract

5,6-disubstituted 2-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 stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
 A is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         
           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 —OR 2a , —NHR 2b , —C(O)NHR 2b , or C 1 -C 6  alkyl, wherein the C 1 -C 6  alkyl of R 2  is substituted by —OR 2c , —NHR 2c , or —C(O)NHR 2c ;
 each R 2a  and R 2b  is independently cyclohexane, 6-membered heterocyclyl, —(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), 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 ; 
 R 2c  is 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is further substituted by C 1 -C 6  alkyl optionally substituted by halogen, —OH or oxo; 
 
           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(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 , C 3 -C 6  cycloalkyl, 3- to 6-membered heterocyclyl, —(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)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl), wherein each R 3  is independently optionally substituted by halogen, oxo, —CN, —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 8 R 9 , —NR 8 S(O) 2 R 9 , 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 or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, oxo, —CN, —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 8 R 9 , —NR 8 S(O) 2 R 9 , or C 1 -C 6  alkyl optionally substituted by oxo, —OH or halogen; 
           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 or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, oxo, —CN, —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 8 R 9 , —NR 8 S(O) 2 R 9 , or C 1 -C 6  alkyl optionally substituted by oxo, —OH or halogen; 
           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, —CN, —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 8 R 9 , —NR 8 S(O) 2 R 9  or C 1 -C 6  alkyl optionally substituted by oxo, —OH or halogen; 
           R 8  and R 9  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, OH, oxo or NH 2 ; 
           or R 8  and R 9  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, OH, oxo or NH 2 . 
         
       
     
     
         2 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
 B is a phenyl optionally substituted by R 3 , or a 5- or 6-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, —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , or —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 and 3- to 6-membered heterocyclyl of R 1  are independently optionally substituted by R 4 ;   each R 1a  is independently hydrogen, C 1 -C 6  alkyl, or C 3 -C 6  cycloalkyl;   each R 1b  and R 1c  is independently hydrogen, C 1 -C 6  alkyl, or C 3 -C 6  cycloalkyl;
 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. 
   
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1  is hydrogen. 
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is —OR 2a . 
     
     
         7 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is —NHR 2b . 
     
     
         8 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is —C(O)NHR 2b . 
     
     
         9 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is C 1 -C 6  alkyl substituted by —OR 2c , —NHR 2c , or —C(O)NHR 2c . 
     
     
         10 - 12 . (canceled) 
     
     
         13 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4  is R 3  and each R 3  is independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —NR 6 R 7 , —NO 2 , —C(O)R 5 , —C(O)OR 5 , —C(O)NR 6 R 7 , —C(O)NR 5 S(O) 2 R 6 , —OC(O)R 5 , —OC(O)NR 6 R 7 , —NR 5 C(O)R 6 , —NR 5 C(O)NR 6 R 7 , —S(O)R 5 , —S(O) 2 R 5 , C 3 -C 6  cycloalkyl and C 1 -C 6  alkyl optionally substituted by halogen. 
     
     
         14 . The compound of  claim 13 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R 3  is independently selected from the group consisting of halogen, —OR 5  and C 1 -C 6  alkyl optionally substituted by halogen. 
     
     
         15 . (canceled) 
     
     
         16 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is a phenyl optionally substituted by R 3 . 
     
     
         17 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is a 5- to 6-membered heteroaryl optionally substituted by R 4 . 
     
     
         18 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is a 6-membered heteroaryl selected from the group consisting of pyridyl and pyrimidinyl, which is optionally substituted by R 4 . 
     
     
         19 - 20 . (canceled) 
     
     
         21 . The compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         22 - 29 . (canceled) 
     
     
         30 . A compound of Table 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         31 . A pharmaceutical composition comprising a compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. 
     
     
         32 . A method of treating a disease mediated by an adenosine signaling pathway in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         33 . A method of treating cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         34 . A method of inhibiting an adenosine receptor of subtype A 2A , A 2B  or A 3  in a cell, comprising administering a compound of  claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to the cell. 
     
     
         35 . The method of  claim 34 , wherein the adenosine receptor is of subtype A 2A . 
     
     
         36 - 37 . (canceled)