Toll-like receptor 7 (TLR7) agonists having a heterobiaryl moiety, conjugates thereof, and methods and uses therefor

1. A compound having a structure according to formula (I) or (II)

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 ;

X is, independently for each occurrence thereof, CR 2 or N; and

Ar is a 5-membered heteroaromatic moiety selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,3,4-oxatiazolyl, and 1,2,3,4-thiatriazolyl.

2. A compound according to claim 1 , having a structure represented by formula (I′)

wherein each X′ is independently CH or N and Ar and R 1 are as defined in claim 1 .

3. A compound according to claim 1 , having a structure represented by formula (II′)

wherein each X′ is independently CH or N and Ar and R 1 are as defined in claim 1 .

4. A compound having a structure represented by formula (Ia), (Ib), or (Ic)

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, each X′ is independently CH or N, and R 4 is H, C 1 -C 3 alkyl, C 3 -C 3 cycloalkyl (CH 2 ) 1-3 R 3 , (CH 2 ) 1-3 C(═O)(CH 2 ) 0-3 R 3 , where R 3 is 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, spirocycloalkyl, 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, spirocycloalkyl, or cyclic amine moiety may have a CH 2 group replaced by O, S, NH, N(C 1 -C 3 alkyl), or N(t-butoxycarbonyl).

5. A compound according to claim 4 , having a structure represented by formula (Ia):

6. A compound according to claim 4 , having a structure represented by formula (Ib):

7. A compound according to claim 4 , having a structure represented by formula (Ic):

8. A compound according to claim 4 , wherein R 4 is

9. A compound according to claim 1 , conjugated to an antibody against mesothelin, prostate specific membrane antigen, CD19, CD22, CD30, CD70, B7H3, B7H4, protein tyrosine kinase 7, glypican-3, RG1, fucosyl-GM1, CTLA-4, or CD44.

10. A compound according to claim 1 , which is covalently bonded to a poly(ethylene glycol) moiety between 2 kDa and 40 kDa in size.

11. A compound according to claim 4 , conjugated to an antibody against mesothelin, prostate specific membrane antigen, CD19, CD22, CD30, CD70, B7H3, B7H4, protein tyrosine kinase 7, glypican-3, RG1, fucosyl-GM1, CTLA-4, or CD44.

12. A compound according to claim 4 , which is covalently bonded to a poly(ethylene glycol) moiety between 2 kDa and 40 kDa in size.

13. A compound according to claim 5 , selected from the group consisting of

14. A compound according to claim 6 , selected from the group consisting of

15. A compound according to claim 7 , which is