Alkyl chain modified imidazoquinoline TLR7/8 agonist compounds and uses thereof
Disclosed are alkyl chain modified 1H-imidazoquinoline compounds, derivatives and analogs thereof, as Toll-like receptor-7 and -8 agonists for enhancing immune responses. Also provided are methods of making pharmaceutical compositions containing these compounds. The present disclosure also describes methods of use for the alkyl chain modified 1H-imidazoquinoline compounds, derivatives and analogs thereof, and pharmaceutical compositions containing these compounds for the treatment of disease in a subject.
1. A method of treating cancer in a mammalian subject in need thereof, comprising administering to the mammalian subject a pharmaceutical composition in an amount sufficient to treat cancer in the mammalian subject, the composition comprising (i) a compound of formula (J), or a salt thereof, and (ii) a pharmaceutically acceptable excipient, wherein the compound of formula (J) has the following structure:
wherein:
R 0 is —(CH 2 ) z (C(CH 3 ) 2 )R A or —(CH 2 ) m R A ;
m is 0, 1, 2, or 3;
z is 1 or 2;
R A is C 3 -C 8 cycloalkyl optionally substituted by 1 to 4 groups independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkylene, and halogen;
X is —NH—;
R 1 is C 3 -C 6 alkyl, —(CH 2 ) p OR 1a , —(CH 2 ) p NHR 1b or —(CH 2 ) p R 1c ; where R 1a and R 1b are independently C 1 -C 3 alkyl; R 1c is C 3 -C 4 cycloalkyl; and p is 1 or 2;
R 2 is NHR 2a ; where R 2a is H, OH, NH 2 , or methyl;
each R 3 is independently halogen, C 1 -C 8 alkyl, —(C 1 -C 7 alkylene)—NH 2 , or —CH 2 -phenylene-CH 2 NH 2 ;
q is 0, 1, 2, 3, or 4; and
R 4a and R 4b are independently H or C 1 -C 8 alkyl.
2. The method of claim 1 , wherein the pharmaceutical composition is administered by intratumoral injection.
3. The method of claim 1 , further comprising administering an effective amount of a second therapeutic agent to the subject.
4. The method of claim 3 , wherein the second therapeutic agent is a chemotherapeutic agent.
5. The method of claim 3 , wherein the second therapeutic agent is an antagonist of an inhibitory immune checkpoint molecule.
6. The method of claim 3 , wherein the second therapeutic agent is an epigenetic modulator.
7. The method of claim 3 , wherein the second therapeutic agent is an inducer of immunogenic cell death.
8. The method of claim 5 , wherein the inhibitory immune checkpoint molecule is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4 (CD152), LAG-3, TIM-3, TIGIT, IL-10, and TGF-beta.
9. The method of claim 1 , wherein R 0 is —(CH 2 ) m R A .
10. The method of claim 9 , wherein m is 2.
11. The method of claim 1 , wherein R 0 is —(CH 2 ) z (C(CH 3 ) 2 )R A .
12. The method of claim 11 , wherein z is 1.
13. The method of claim 9 , wherein R A is cyclopropyl, cyclobutyl, or cyclopentyl.
14. The method of claim 9 , wherein R A is C 3 -C 6 cycloalkyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl, methylene, and halogen.
15. The method of claim 1 , wherein m is 1 or 2.
16. The method of claim 15 , wherein R A is C 3 -C 8 cycloalkyl.
17. The method of claim 15 , wherein R A is cyclopropyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl and methylene.
18. The method of claim 1 , wherein m is 0 and R A is cyclohexyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl and methylene.
19. The method of claim 1 , wherein R 0 is selected from the group consisting of:
20. The method of claim 1 , wherein the compound of formula (J) is Compound No. 63-33, 63-35, 63-36, or 63-38 to 63-49:
Compound No.
Formula
63-33
63-35
63-36
63-38
63-39
63-40
63-41
63-42
63-43
63-44
63-45
63-46
63-47
63-48
63-49
or a salt thereof.
21. The method of claim 20 , wherein the pharmaceutical composition further comprises an antigen.