Toll-like receptor 7 (TLR7) agonists having a pyridine or pyrazine moiety, conjugates thereof, and methods and uses therefor
Compounds having a structure according to formula (I) where R 1 and Ar are as defined herein, are agonists for the Toll-like receptor 7 (TLR7) and can be used as adjuvants for stimulating the immune system. Some such compounds can be used in conjugates for targeted delivery to the organ or tissue of intended action.
1. A compound having a structure according to formula (Ia)
wherein
R 1 is (C 1 -C 5 alkyl)O, (C 1 -C 2 alkyl)O(CH 2 ) 2-3 O, (C 1 -C 5 alkyl)C(═O)O, (C 1 -C 5 alkyl)NH, (C 1 -C 2 alkyl)O(CH 2 ) 2-3 NH, or (C 1 -C 5 alkyl)C(═O)NH; and
R 3 and R 4 are independently H; C 1 -C 6 alkyl; (CH 2 ) 2-4 OH; (CH 2 ) 2-4 O(C 1 -C 3 alkyl); (CH 2 ) 2-4 NH 2 ; (CH 2 ) 2-4 NH(C 1 -C 3 alkyl); (CH 2 ) 2-4 N(C 1 -C 3 alkyl) 2 ; (CH 2 ) 1-3 (aryl); (CH 2 ) 1-3 (heteroaryl); (CH 2 ) 2-4 (OCH 2 CH 2 ) 2-8 (CH 2 ) 2-4 NHBoc;
wherein a CH 2 group in the cycloaliphatic ring may be replaced by O, S, NH, or N(C 1 -C 3 alkyl) and the cycloaliphatic ring may be substituted with C 1 -C 3 alkyl, OH, O(C 1 -C 3 alkyl), halo, (CH 2 ) 0-3 NH 2 , or (CH 2 ) 0-3 NH(C 1 -C 3 alkyl);
or R 3 and R 4 combine with the nitrogen to which they are bonded to form a cyclic amine of the structure
wherein a CH 2 group in the cycloaliphatic ring that is separated from the amine nitrogen by at least two CH 2 groups may be replaced by O, S, NH, or N(C 1 -C 3 alkyl) and the cyclic amine may be substituted with C 1 -C 3 alkyl, OH, O(C 1 -C 3 alkyl), halo, (CH 2 ) 0-3 NH 2 , or (CH 2 ) 0-3 NH(C 1 -C 3 alkyl).
2. A compound according to claim 1 , wherein —N(R 3 )(R 4 ) is
3. A compound according to claim 1 , wherein, in formula (Ia), R 1 is n-BuO.
4. A compound according to claim 1 , wherein R 4 is H and R 3 is other than H.
5. A compound according to claim 1 , wherein R 1 is n-BuO or MeOCH 2 CH 2 O.
6. A compound according to claim 1 , selected from the group consisting of compounds (Ia-01) through (Ia-11):