1,8-naphthyridinone compounds and uses thereof

Abstract

1,8-naphthyridinone 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.

What is claimed is: 
     
         1 . A compound of the Formula (I): 
       
         
           
           
               
               
           
         
       
       or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
 R 2  and R 4  are each independently H, R b  or oxo; 
 R 3  is independently H or R c ; 
 each R b  and R c  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C═NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —C(O)NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 9 , —P(O)(OR 9 )(OR 10 ), 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 8 , —(C 1 -C 3  alkylene)SR 8 , —(C 1 -C 3  alkylene)NR 9 R 10 , —(C 1 -C 3  alkylene)CF 3 , —(C 1 -C 3  alkylene)NO 2 , —C═NH(OR 8 ), —(C 1 -C 3  alkylene)C(O)R 8 , —(C 1 -C 3  alkylene)OC(O)R 8 , —(C 1 -C 3  alkylene)C(O)OR 8 , —(C 1 -C 3  alkylene)C(O)NR 9 R 10 , —(C 1 -C 3  alkylene)OC(O)NR 9 R 10 , —(C 1 -C 3  alkylene)NR 8 C(O)R 9 , —(C 1 -C 3  alkylene)NR 8 C(O)OR 9 , —(C 1 -C 3  alkylene)NR 8 C(O)NR 9 R 10 , —(C 1 -C 3  alkylene)S(O)R 8 , —(C 1 -C 3  alkylene)S(O) 2 R 8 , —(C 1 -C 3  alkylene)NR 8 S(O)R 9 , —C(O)(C 1 -C 3  alkylene)NR 8 S(O)R 9 , —(C 1 -C 3  alkylene)NR 8 S(O) 2 R 9 , —(C 1 -C 3  alkylene)C(O)NR 8 S(O) 2 R 9 , —(C 1 -C 3  alkylene)S(O)NR 9 R 10 , —(C 1 -C 3  alkylene)S(O) 2 NR 9 R 10 , —(C 1 -C 3  alkylene)P(O)(OR 9 )(OR 10 ), —(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 b  and R c  is independently optionally substituted by halogen, oxo, —CN, —OR 11 , —NR 11 R 12 , —C(O)R 11 , —OC(O)R 11 , —C(O)OR 11 , —C(O)NR 11 R 12 , —OC(O)NR 11 R 12 , —NR 11 C(O)R 12 , —NR 11 C(O)OR 12 , —S(O)R 11 , —S(O) 2 R 11 , —NR 11 S(O)R 12 , —C(O)NR 11 S(O)R 12 , —NR 11 S(O) 2 R 12 , —C(O)NR 11 S(O) 2 R 12 , —S(O)NR 11 R 12 , —S(O) 2 NR 11 R 12 , —(C 1 -C 3  alkylene)OR 11 , —(C 1 -C 3  alkylene)NR 11 R 12 , —(C 1 -C 3  alkylene)C(O)R 11 , —(C 1 -C 3  alkylene)S(O)R 11 , —(C 1 -C 3  alkylene)S(O) 2 R 11 , —(C 1 -C 3  alkylene)C(O)NR 11 R 12 , —(C 1 -C 3  alkylene)NR 11 C(O)R 12 , —(C 1 -C 3  alkylene)NR 11 S(O) 2 R 12 , —(C 1 -C 3  alkylene)S(O) 2 NR 11 R 12 , 3-6-membered heterocyclyl optionally substituted by oxo, —OH, NH 2  or halogen, C 3 -C 8  cycloalkyl optionally substituted by oxo, —OH, NH 2  or halogen, —(C 1 -C 3  alkylene)3-6-membered heterocyclyl optionally substituted by oxo, —OH, NH 2  or halogen, —(C 1 -C 3  alkylene)C 3 -C 8  cycloalkyl optionally substituted by oxo, —OH, NH 2  or halogen, or C 1 -C 6  alkyl optionally substituted by oxo, —OH, NH 2  or halogen; 
    is a single bond or a double bond, wherein when   is a double bond, R 2  is oxo; 
    is a single bond or a double bond, wherein when   is a double bond, R 4  is oxo; 
 one of   and   is a double bond and the other is a single bond; 
 A is 
 
       
         
           
           
               
               
           
         
       
       wherein
    is a single bond or a double bond; 
 X 1  is N or CR′, wherein R′ is —NR 8 S(O) 2 R 9  or oxo; 
 X 2  is N, NR″ or CR″, wherein R″ is R 7 ,
 or R′ and R″ are taken together with the atoms to which they attach to form a 5- or 6-membered heteroaryl ring containing one, two, three, or four N atoms; 
 
 B is phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, or 9- to 10-membered heteroaryl, wherein the phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl of B is optionally further substituted with R 7 ,
 provided that when A is optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted quinazolinyl, or optionally substituted benzimidazolyl, then B is substituted with 1, 2, 3, or 4 R 7  and at least one R 7  is —CN, and 
 when X 1  is N and X 2  is CR″, then B is substituted with 1, 2, 3, or 4 R 7  and at least one R 7  is —CN; 
 
 R 6  is H or R 7 ; 
 each R 7  is independently oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C═NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —C(O)NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , —P(O)(OR 9 )(OR 10 ), 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 8 , —(C 1 -C 3  alkylene)SR 8 , —(C 1 -C 3  alkylene)NR 9 R 10 , —(C 1 -C 3  alkylene)CF 3 , —(C 1 -C 3  alkylene)NO 2 , —(C 1 -C 3  alkylene)C(O)R 8 , —(C 1 -C 3  alkylene)OC(O)R 8 , —(C 1 -C 3  alkylene)C(O)OR 8 , —(C 1 -C 3  alkylene)C(O)NR 9 R 10 , —(C 1 -C 3  alkylene)OC(O)NR 9 R 10 , —(C 1 -C 3  alkylene)NR 8 C(O)R 9 , —(C 1 -C 3  alkylene)NR 8 C(O)OR 9 , —(C 1 -C 3  alkylene)NR 8 C(O)NR 9 R 10 , —(C 1 -C 3  alkylene)S(O)R 8 , —(C 1 -C 3  alkylene)S(O) 2 R 8 , —(C 1 -C 3  alkylene)NR 8 S(O)R 9 , —C(O)(C 1 -C 3  alkylene)NR 8 S(O)R 9 , —(C 1 -C 3  alkylene)NR 8 S(O) 2 R 9 , —(C 1 -C 3  alkylene)C(O)NR 8 S(O) 2 R 9 , —(C 1 -C 3  alkylene)S(O)NR 9 R 10 , —(C 1 -C 3  alkylene)S(O) 2 NR 9 R 10 , —(C 1 -C 3  alkylene)P(O)(OR 9 )(OR 10 ), —(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 6  and R 7  is independently optionally substituted by halogen, oxo, —OR 11 , —NR 11 R 12 , —C(O)R 11 , —CN, —S(O)R 11 , —S(O) 2 R 11 , —P(O)(OR 11 )(OR 12 ), —(C 1 -C 3  alkylene)OR 11 , —(C 1 -C 3  alkylene)NR 11 R 12 , —(C 1 -C 3  alkylene)C(O)R 11 , —(C 1 -C 3  alkylene)S(O)R 11 , —(C 1 -C 3  alkylene)S(O) 2 R 11 , —(C 1 -C 3  alkylene)P(O)(OR 11 )(OR 12 ), C 3 -C 8  cycloalkyl, or C 1 -C 6  alkyl optionally substituted by oxo, —OH or halogen; 
 each R 8  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, 3-6-membered heterocyclyl, —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(C 6 -C 14  aryl), —(C 1 -C 3  alkylene)(5-6-membered heteroaryl), or —(C 1 -C 3  alkylene)(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, 3-6-membered heterocyclyl, —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(C 6 -C 14  aryl), —(C 1 -C 3  alkylene)(5-6-membered heteroaryl), and —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl) of R 8  are independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14 , —P(O)(OR 13 )(OR 14 ), phenyl optionally substituted by halogen, or C 1 -C 6  alkyl optionally substituted by halogen, —OH or oxo; 
 R 9  and R 10  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, 3-6 membered heterocyclyl, —(C 1 -C 3  alkylene)NR 11 R 12 , —(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 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, 3-6 membered heterocyclyl, —(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 9  and R 10  are independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14  or C 1 -C 6  alkyl optionally substituted by halogen, —OH or oxo;
 or R 9  and R 10  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 13 , —NR 3 R 14  or C 1 -C 6  alkyl optionally substituted by halogen, oxo or —OH; 
 
 R 11  and R 12  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 11  and R 12  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 13  and R 14  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 13  and R 14  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 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is H, oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , —C(O)OR 8 , —(C 1 -C 3  alkylene)NR 9 R 10 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6  cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14  aryl. 
     
     
         3 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is H, oxo, halogen, —OR 8 , —C(O)NR 9 R 10 , —C(O)OR 8 , or —(C 1 -C 3  alkylene)NR 9 R 10 . 
     
     
         4 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is selected from the group consisting of: H, oxo, bromo, methoxy, 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is H. 
     
     
         6 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4  is H, oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6  cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14  aryl. 
     
     
         8 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4  is H. 
     
     
         9 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —C(O)NR 9 R 10 , —(C 1 -C 3  alkylene)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6  cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14  aryl. 
     
     
         11 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3  is H, —CN, —C(O)NR 9 R 10 , or —(C 1 -C 3  alkylene)NR 9 R 10 . 
     
     
         12 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3  is selected from the group consisting of: H, —CN, 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1  is CR. 
     
     
         14 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1  is N. 
     
     
         15 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2  is N. 
     
     
         16 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2  is NR″. 
     
     
         17 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2  is CR″. 
     
     
         18 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1  is CR and X 2  is CR″, and R and R″ are taken together with the atoms to which they attach to form a 5- or 6-membered heteroaryl ring containing one, two, three, or four N atoms. 
     
     
         19 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of any of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is phenyl, optionally substituted with R 7 . 
     
     
         21 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is 5- to 6-membered heteroaryl optionally further substituted with R 7 . 
     
     
         22 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each optionally substituted with R 7 . 
     
     
         23 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is furanyl, pyridinyl, oxazoyl, or oxadiazoyl, each optionally substituted with R 7 . 
     
     
         24 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is a 9- to 10-membered heteroaryl optionally further substituted with R 7 . 
     
     
         25 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzoimidazoyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzoisoxazolyl, benzoxadiazolyl, benzothiophenyl, benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, triazolopyridinyl, furopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl, thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl and imidazothiazolyl, each optionally substituted with R 7 . 
     
     
         26 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       each of which is optionally substituted with R 7 . 
     
     
         27 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 7  is independently halogen, —CN, or C 1 -C 6  alkyl optionally substituted by halogen. 
     
     
         28 . The compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         29 . A compound selected from the compounds of Table 1, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         30 . A pharmaceutical composition comprising a compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. 
     
     
         31 . A method of treating 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 isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         32 . 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 isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         33 . A method of inhibiting adenosine receptors of subtypes A 2a , A 2b , or A 3  in a cell, comprising administering a compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to the cells. 
     
     
         34 . The method of  claim 33 , wherein the adenosine receptors are of subtype A 2a . 
     
     
         35 . Use of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treatment of a disease mediated by an adenosine signaling pathway. 
     
     
         36 . A kit comprising a compound of  claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.