Toll-like receptor 7 (TLR7) agonists having a benzotriazole moiety, conjugates thereof, and methods and uses therefor
Compounds having a structure according to formula (I) where R 1 , R 2 , and R 3 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 (I)
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;
R 2 is, independently for each occurrence thereof, H, C 1 -C 3 alkyl, halo, O(C 1 -C 3 alkyl), CN, or NO 2 ;
R 3 is H, Me, or (CH 2 ) x R 4 , where the subscript x is 2, 3, or 4; and
R 4 is H, halo, OH, CN, NH 2 , NH(C 1 -C 5 alkyl), N(C 1 -C 5 alkyl) 2 , NH(C 3 -C 6 cycloalkyl), NH(C 4 -C 8 bicycloalkyl), NH(C 6 -C 10 spirocycloalkyl), N(C 3 -C 6 cycloalkyl) 2 , NH(CH 2 ) 1-3 (aryl), N((CH 2 ) 1-3 (aryl)) 2 , a cyclic amine moiety having the structure
a 6-membered aromatic or heteroaromatic moiety or a 5-membered heteroaromatic moiety;
wherein
an alkyl, cycloalkyl, bicycloalkyl, spriocycloalkyl, cyclic amine, 6-membered aromatic or heteroaromatic, or 5-membered heteroaromatic moiety is optionally substituted with one or more substituents selected from OH, halo, CN, (C 1 -C 3 alkyl), O(C 1 -C 3 alkyl), C(═O)(Me), SO 2 (C 1 -C 3 alkyl), C(═O)(Et), NH 2 , NH(Me), N(Me) 2 , NH(Et), N(Et) 2 , and N(C 1 -C 3 alkyl) 2 ; and
a cycloalkyl, bicycloalkyl, sprioalkyl, or cyclic amine moiety may have a CH 2 group replaced by O, S, NH, N(C 1 -C 3 alkyl), or N(t-butyoxycarbonyl).
2. A compound according to claim 1 , wherein R 1 is n-BuO or MeOCH 2 CH 2 O and R 4 is OH, Cl,
3. A compound according to claim 1 , having a structure represented by formula (Ia)
4. A compound according to claim 3 , wherein R 1 is n-BuO or MeOCH 2 CH 2 O and R 4 is OH, Cl,
5. A compound according to claim 4 , wherein R 1 is n-BuO.
6. A compound according to claim 1 , selected from the group consisting of