Adenosine receptor antagonists and uses thereof

Abstract

Disclosed herein are compounds, compositions, formulations, and methods for modulating the A2B adenosine receptor.

1 . A compound represented by Formula (A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein: 
         R 1  and R 2  are each independently selected from hydrogen, and substituted or unsubstituted alkyl; 
         R 3  is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl, wherein if R 3  is substituted then R 3  is substituted with one or more groups selected from halogen, —CN, —OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, and substituted or unsubstituted C 1 -C 4 heteroalkyl; 
         R 4  is substituted or unsubstituted alkyl; 
         R 6  is hydrogen or substituted or unsubstituted alkyl; 
         or R 4  and R 6  are taken together with the carbon atom to which they are attached to form a ring that is a substituted or unsubstituted C 3 -C 10 cycloalkyl, or substituted or unsubstituted C 2 -C 10 heterocycloalkyl, wherein if the ring is substituted then it is substituted with one or more R 15 ;
 R 15  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), —C(═O)R 16 , —C(═O)—OR 16 , —C(═O)N(R 16 ) 2 ; 
 each R 16  is independently selected from hydrogen and substituted or unsubstituted alkyl; 
 
         R 15  is hydrogen, R 7 , —C(═O)R 7 , —C(═O)—OR 7 , —C(═O)N(R 7 )(R), —C(═O)—SR 7 , or —P(═O)(OR) 2 ; 
         or R 4  and R 5  are taken together with the atoms to which they are attached to form a substituted or unsubstituted C 2 -C 10 heterocycloalkyl; 
         R 7  is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), —(C(R 10 ) 2 O) m —R 1 , —(CH 2 CH 2 O) n —R 11 , or —(C(R 10 ) 2 ) p —OR 11 ; 
         R 8  is hydrogen or alkyl; 
         or R 7  and R 8  are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C 2 -C 10 heterocycloalkyl; 
         each R 9  is independently selected from hydrogen and alkyl; 
         each R 10  is independently selected from hydrogen and alkyl; 
         R 11  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C(═O)R 12 , —C(═O)—OR 12 , —C(═O)N(R 12 )(R), —C(═O)—SR 12 , or —P(═O)(OR 9 ) 2 ; 
         R 12  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), or -alkyl-(substituted or unsubstituted heteroaryl); 
         m is 1, 2, 3, 4, 5, or 6; 
         n is 1, 2, 3, 4, 5, or 6; 
         p is 1, 2, 3, 4, 5, or 6; 
         wherein substituted means that the referenced group is substituted with one or more additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C(═O)NH 2 , —C(═O)NH(alkyl), —C(═O)N(alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(alkyl), —S(═O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 4  is C 1 -C 6 alkyl;   R 6  is selected from hydrogen, and C 1 -C 6 alkyl.   
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl;   R 3  is selected from substituted or unsubstituted phenyl.   
     
     
         6 . (canceled) 
     
     
         7 . The compound of  claim 5 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  is ethyl;   R 2  is n-propyl; and   R 3  is 3-(trifluoromethyl)phenyl.   
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         14 . The compound of  claim 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl;   R 3  is selected from substituted or unsubstituted phenyl.   
     
     
         15 . (canceled) 
     
     
         16 . The compound of  claim 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         17 . The compound of  claim 16 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 4  is methyl or ethyl;   R 5  is hydrogen, R′, —C(═O)R 7 , —C(═O)—OR 7 , —C(═O)N(R 7 )(R 8 ), —C(═O)—SR 7 , or —P(═O)(OR 9 ) 2 ;   R 7  is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, —CH 2 -(substituted or unsubstituted phenyl), —CH 2 -(substituted or unsubstituted heteroaryl), —CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl), —CH(R 10 )O—R 11 , —(CH 2 CH 2 O) n —R 11 , or —(C(R 11 ) 2 ) p —OR 11 ;   each R 10  is independently selected from hydrogen and methyl;   R 11  is hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C(═O)R 12 , —C(═O)—OR 2 , —C(═O)N(R 12 )(R 8 ), —C(═O)—SR 12 , or —P(═O)(OR 9 ) 2 .   
     
     
         18 . The compound of  claim 16 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 5  is R 7 , —C(═O)R 7 , —C(═O)—OR 7 , —C(═O)N(R 7 )(R 8 ), —C(═O)—SR 7 , or —P(═O)(OH) 2 ;   R 7  is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substituted or unsubstituted bicyclo[4.3.0]nonanyl, or substituted or unsubstituted decalinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, —CH 2 -(substituted or unsubstituted phenyl), —CH 2 -(substituted or unsubstituted heteroaryl), —CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl), —CH(R 10 )O—R 1 , —(CH 2 CH 2 O) n —R 1 , or —(C(R 10 ) 2 ) p —OR 11 ;   each R 10  is independently selected from hydrogen and methyl;   R 11  is hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C(═O)R 12 , —C(═O)—OR 2 , —C(═O)N(R 12 )(R 8 ), —C(═O)—SR 12 , or —P(═O)(OR 9 ) 2 .   
     
     
         19 . The compound of  claim 16 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         20 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure of Formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         Y is selected from —CH 2 —, O, S, —NR 15 —, and —S(O) 2 —; 
         Z is O or S; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         21 . The compound of  claim 20 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl;   R 3  is selected from substituted or unsubstituted phenyl.   
     
     
         22 . (canceled) 
     
     
         23 . The compound of  claim 20 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         24 . The compound of  claim 23 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         25 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure of Formula (IIa): 
       
         
           
           
               
               
           
         
         wherein: 
         Y is selected from —CH 2 —, O, S, —NR 15 —, and —S(O) 2 —; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         26 . The compound of  claim 25 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl;   R 3  is selected from substituted or unsubstituted phenyl.   
     
     
         27 . (canceled) 
     
     
         28 . The compound of  claim 25 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         29 . A compound represented by Formula (B): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein: 
         R 1  and R 2  are each independently selected from hydrogen, and substituted or unsubstituted alkyl; 
         R 3  is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl, wherein if R 3  is substituted then R 3  is substituted with one or more groups selected from halogen, —CN, —OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, and substituted or unsubstituted C 1 -C 4 heteroalkyl; 
         R 4  is hydrogen or substituted or unsubstituted alkyl; 
         R 6  is hydrogen or substituted or unsubstituted alkyl; 
         or R 4  and R 6  are taken together with the carbon atom to which they are attached to form a ring that is a substituted or unsubstituted C 3 -C 10 cycloalkyl, or substituted or unsubstituted C 2 -C 10 heterocycloalkyl, wherein if the ring is substituted then it is substituted with one or more R 15 ;
 R 15  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), —C(═O)R 16 , —C(═O)—OR 16 , —C(═O)N(R 16 ) 2 ; 
 each R 16  is independently selected from hydrogen and substituted or unsubstituted alkyl; 
 
         R 5  is substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), —(C(R 10 ) 2 O) m —R 11 , —C(═O)—(C(R 10 ) 2 O) m —R 11 , —C(═O)—(CH 2 CH 2 O) n —R 11 , —C(═O)—R a  or —C(═O)—OR 7 ; 
         R a  is substituted or unsubstituted bicyclic cycloalkyl, substituted or unsubstituted bicyclic heterocycloalkyl, substituted or unsubstituted bicyclic heteroaryl, (substituted or unsubstituted heterocycloalkyl containing at least one O atom in the ring), substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted azapenyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-4-yl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl; 
         or R 4  and R 5  are taken together with the atoms to which they are attached to form a substituted or unsubstituted C 2 -C 10 heterocycloalkyl; 
         R 7  is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), —(C(R 10 ) 2 O) m —R 1 , —(CH 2 CH 2 O) n —R 11 , or —(C(R 11 ) 2 ) p —OR 11 ; 
         each R 9  is independently selected from hydrogen and alkyl; 
         each R 10  is independently selected from hydrogen and alkyl; 
         R 11  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C(═O)R 12 , —C(═O)—OR 1 , —C(═O)N(R 12 )(R), —C(═O)—SR 12 , or —P(═O)(OR 9 ) 2 ; 
         R 12  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), or -alkyl-(substituted or unsubstituted heteroaryl); 
         m is 1, 2, 3, 4, 5, or 6; 
         n is 1, 2, 3, 4, 5, or 6. 
         p is 1, 2, 3, 4, 5, or 6; 
         wherein substituted means that the referenced group is substituted with one or more additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C(═O)NH 2 , —C(═O)NH(alkyl), —C(═O)N(alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(alkyl), —S(═O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. 
       
     
     
         30 . The compound of  claim 29 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 4  is hydrogen;   R 6  is hydrogen;   R 5  is substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), —(C(R 10 ) 2 O) m —R 11 , —C(═O)—(C(R 10 ) 2 O) m —R 11 , —C(═O)—(CH 2 CH 2 O) n —R 11 , —C(═O)—R a  or —C(═O)—OR 7 .   
     
     
         31 . The compound of  claim 29 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl;   R 3  is selected from substituted or unsubstituted phenyl.   
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . The compound of  claim 29 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         35 . The compound of  claim 34 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 11  is hydrogen, substituted or unsubstituted alkyl, —C(═O)R 12 , —C(═O)—OR 2 , —C(═O)N(R 12 )(R 8 ), or —P(═O)(OR 9 ) 2 .   
     
     
         36 . The compound of  claim 35 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         37 . The compound of  claim 35 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         38 . The compound of  claim 29  or  claim 30 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 5  is —C(═O)—(C(R 10 ) 2 O) m —R 11 , —C(═O)—(CH 2 CH 2 O) n —R 11 , —C(═O)—R a  or —C(═O)—OR 7 . 
 
     
     
         39 . The compound of  claim 38 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         40 . The compound of  claim 39 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R a  is substituted or unsubstituted bicyclic cycloalkyl that is a fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro bicyclic cycloalkyl;   or R a  is substituted or unsubstituted bicyclic heterocycloalkyl that is a fused bicyclic heterocycloalkyl, bridged bicyclic heterocycloalkyl, or spiro bicyclic heterocycloalkyl;   or R a  is substituted or unsubstituted bicyclic heteroaryl.   
     
     
         41 . (canceled) 
     
     
         42 . The compound of  claim 40 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         43 . The compound of  claim 39 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R a  is substituted or unsubstituted heterocycloalkyl containing at least one O atom in the ring, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted azapenyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-4-yl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl.   
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . The compound of  claim 43 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         47 . The compound of  claim 29 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  is ethyl;   R 2  is n-propyl;   R 3  is 3-(trifluoromethyl)phenyl;   R 5  is —C(═O)—(C(R 10 ) 2 O) m —R 11 , —C(═O)—(CH 2 CH 2 O) n —R 11 , or —C(═O)—OR 7 .   
     
     
         48 . The compound of  claim 47 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         49 . The compound of  claim 29 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  is ethyl;   R 2  is n-propyl;   R 3  is 3-(trifluoromethyl)phenyl;   R 5  is substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl).   
     
     
         50 . The compound of  claim 49 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         51 . A pharmaceutical formulation, comprising a compound of  claim 1 , or any pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . A method of modulating the A 2B  adenosine receptor in a mammal comprising administering to the mammal a compound of  claim 1 , or any pharmaceutically acceptable salt or solvate thereof. 
     
     
         55 . (canceled) 
     
     
         56 . (canceled) 
     
     
         57 . (canceled)