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 compound of the following formula:
or a salt thereof, 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 compound of claim 1 , or a salt thereof, wherein R 0 is —(CH 2 ) m R A .
3. The compound of claim 2 , or a salt thereof, wherein m is 2.
4. The compound of claim 1 , or a salt thereof, wherein R 0 is —(CH 2 ) z (C(CH 3 ) 2 )R A .
5. The compound of claim 4 , or a salt thereof, wherein z is 1.
6. The compound of claim 2 , or a salt thereof, wherein R A is cyclopropyl, cyclobutyl, or cyclopentyl.
7. The compound of claim 2 , or a salt thereof, 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.
8. The compound of claim 1 , or a salt thereof, wherein m is 1 or 2.
9. The compound of claim 8 , or a salt thereof, wherein R A is C 3 -C 8 cycloalkyl.
10. The compound of claim 8 , or a salt thereof, wherein R A is cyclopropyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl and methylene.
11. The compound of claim 1 , or a salt thereof, 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.
12. The compound of claim 1 , or a salt thereof, wherein R 0 is selected from the group consisting of:
13. The compound of claim 1 , which 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.
14. A pharmaceutical composition comprising (i) the compound according to claim 1 , or a salt thereof and (ii) a pharmaceutically acceptable excipient.
15. The pharmaceutical composition of claim 14 , further comprising an antigen.