Compounds and compositions as TLR activity modulators
View Patent ↗The invention provides a novel class of compounds, immunogenic compositions and pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with Toll-Like Receptors 7. In one aspect, the compounds are useful as adjuvants for enhancing the effectiveness of a vaccine.
1. A compound of Formula (I), or pharmaceutically acceptable salt thereof:
wherein:
R 1 is -L 2 R 5 , -L 2 R 6 , —OL 2 R 5 , or —OL 2 R 6
L 2 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene and C 2 -C 6 alkenylene of L 2 are optionally substituted with 1 to 4 fluoro groups;
each L 3 is independently selected from C 1 -C 6 alkylene and —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 3 is optionally substituted with 1 to 4 fluoro groups;
R 2 is H or C 1 -C 4 alkyl;
R 3 is selected from -L 3 R 5 , -L 3 R 7 , —OL 3 R 7 ;
each R 4 is independently selected from H and fluoro;
R 5 is —P(O)(OH) 2 ,
R 6 is —CF 2 P(O)(OH) 2 or —C(O)OH;
R 7 is —CF 2 P(O)(OH) 2 or —C(O)OH;
each p is independently selected from 1, 2, 3, 4, 5 and 6, and
q is 1, 2, 3 or 4.
2. A compound of Formula (I), or pharmaceutically acceptable salt thereof:
wherein:
R 1 is -L 2 R 6 ;
R 2 is C i -C 6 alkyl;
R 3 is —OL 3 R 5 or —OL 3 R 7 ;
R 5 is —P(O)(OH) 2 ;
R 6 is —C(O)OH;
R 7 is —CF 2 P(O)(OH) 2 ;
L 2 is C 1 -C 6 alkylene, and
L 3 is C 1 -C 6 alkylene substituted with 1 to 4 fluoro groups.
3. The compound of claim 1 , wherein:
R 1 is -L 2 R 6 ;
R 2 is C 1 -C 6 alkyl;
R 3 is —OL 3 R 5 or —OL 3 R 7 ;
R 5 is —P(O)(OH) 2 ;
R 6 is —C(O)OH;
R 7 is —CF 2 P(O)(OH) 2 ;
L 2 is C i -C 6 alkylene;
L 3 is —((CR 4 R 4 ) p O) q (CH 2 ) p —;
R 4 is H;
q is 1 or 2, and
p is 2.
4. The compound of claim 1 , wherein R 2 is methyl.
5. The compound of claim 1 , wherein the compound is selected from:
3-(5-amino-2-(4-(4,4-difluoro-4-phosphonobutoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
3-(5-amino-2-(2-methyl-4-(3-phosphonopropoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid; and
3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid.
6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
7. A method for activating a TLR7 receptor, wherein the method comprises administering to a system or a subject a therapeutically effective amount of a compound of Formula (I) of claim 1 .