2‐Amino[1,2,4]triazolo[1,5‐c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure–Activity Relationships of Potent Adenosine Receptor Antagonists

2‐Amino1,2,4]triazolo1,5‐c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A₃AR antagonists were discovered, including 3,5‐diphenyl1,2,4]triazolo4,3‐c]quinazoline ( 17 , K_i human A₃AR 1.16 nm ) and 5′‐phenyl‐1,2‐dihydro‐3′H‐spiroindole‐3,2′‐1,2,4]triazolo1,5‐c]quinazolin]‐2‐one ( 20 , K_i human A₃AR 6.94 nm ). In addition, multitarget antagonists were obtained, such as the dual A₁/A₃ antagonist 2,5‐diphenyl1,2,4]triazolo1,5‐c]quinazoline ( 13 b , K_i human A₁AR 51.6 nm , human A₃AR 11.1 nm ), and the balanced pan‐AR antagonists 5‐(2‐thienyl)1,2,4]triazolo1,5‐c]quinazolin‐2‐amine ( 11 c , K_i human A₁AR 131 nm , A_2AAR 32.7 nm , A_2BAR 150 nm , A₃AR 47.5 nm ) and 9‐bromo‐5‐phenyl1,2,4]triazolo1,5‐c]quinazolin‐2‐amine ( 11 q , K_i human A₁AR 67.7 nm , A_2AAR 13.6 nm , A_2BAR 75.0 nm , A₃AR 703 nm ). In many cases, significantly different affinities for human and rat receptors were observed, which emphasizes the need for caution in extrapolating conclusions between different species.