1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists and methods and uses therefor

1. A compound having a structure according to formula I

wherein

each X 1 is independently N or CR 2 ;

X 2 is 0, CH 2 , NH, S, or N(C 1 -C 3 alkyl);

R 1 is H, CH 3 (CH 2 ) 1-3 , CH 3 (CH 2 ) 0-1 O(CH 2 ) 2-3 , CH 3 (CH 2 ) 0-3 C(═O), CH 3 (CH 2 ) 0-1 O(CH 2 ) 2-3 C(═O),

R 2 is H, O(C 1 -C 3 alkyl), C 1 -C 3 alkyl, Cl, F, or CN;

R 3 is H, halo, OH, CN, NH 2 , NH(C 1 -C 5 alkyl), N(C 1 -C 5 alkyl) 2 , NH(CH 2 ) 0-1 (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 the 5-membered heteroaromatic and the 6-membered heteroaromatic moiety comprises from 1 to 4 heteroatoms independently selected from N, O, or S;

wherein

the 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), (CH 2 ) 1-2 OH, (CH 2 ) 1-2 OMe; and

wherein a CH 2 group in the cycloalkyl, bicycloalkyl, spirocycloalkyl, or cyclic amine moiety is optionally replaced by O, S, NH, N(C 1 -C 3 alkyl), or N(Boc);

m is 0 or 1;

and

n is 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein the group R 1 is selected from the group consisting of

3. A compound according to claim 1 , wherein the group R 1 is

4. A compound according to claim 1 , wherein the moiety

is selected from the group consisting of

5. A compound according to claim 1 , wherein the moiety

6. A compound according to claim 1 , wherein the group R 3 is selected from the group consisting of Cl, H,

7. A compound according to claim 1 , wherein R 3 is a moiety

selected from the group consisting of

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

9. A compound according to claim 1 , having a structure according to formula Ia

10. A compound according to claim 9 , wherein R 1 is

11. A compound according to claim 1 , having a structure according to formula Ib

12. A compound according to claim 11 , wherein

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