C-pyrazole A2A receptor agonists
View Patent ↗2-adenosine C-pyrazole compositions having the following formula: and methods for using the compositions as A 2A receptor agonists to stimulate mammalian coronary vasodilatation for therapeutic purposes and for purposes of imaging the heart.
1. A compound having the formula:
wherein R 1 is —CH 2 OH, —C(═O)NR 5 R 6 ;
R 2 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, NO 2 , heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , N(R 20 ) 2 NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2 and wherein each optional heteroaryl, aryl, and heterocyclyl substituent is optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, mono- or di-alkylamino, alkyl or aryl or heteroaryl amide, NCOR 22 , NR 20 SO 2 R 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , OC(O)R 20 , OC(O)N(R 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, and OR 20 ;
R 3 and R 4 are each individually selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, heterocyclyl, aryl, heteroaryl, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , N(R 20 ) 2 NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2 wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, NO 2 , heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , N(R 20 ) 2 NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20, CON(R 20 ) 2 , CONR 20 SO 2 R 22, NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2 and wherein each optional heteroaryl, aryl, and heterocyclyl substituent is optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, NCOR 22 , NR 20 SO 2 R 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , OC(O)R 20 , OC(O)N(R 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, and OR 20 ;
R 5 and R 6 are each individually selected from H, and C 1-8 alkyl having from 1 to 2 substituents independently selected from the group consisting of halo, NO 2 , heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , N(R 20 ) 2 NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2 , and wherein each option heteroaryl, aryl, and heterocyclyl substituent is optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, NCOR 22 , NR 20 SO 2 R 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , OC(O)R 20 , OC(O)N(R 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, and OR 20 ;
R 20 is selected from the group consisting of H, C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, —O—C 1-6 alkyl, CF 3 , aryl, and heteroaryl; and
R 22 is selected from the group consisting of C 1-15 alkyl,C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, —O—C 1-6 alkyl, CF 3 , and heteroaryl wherein, when R 1 is CH 2 OH, and R 3 is H and R 4 is H, and the pyrazole ring is attached through C 4 , then R 2 is not H.