COMPOUNDS AND COMPOSITIONS AS TLR ACTIVITY MODULATORS
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 C 1 -C 4 alkyl, —C(R 5 ) 2 OH, -L 1 R 5 or -L 1 R 6 ;
L 1 is —C(O)— or —O—;
L 2 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, arylene, heteroarylene 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;
L 4 is arylene or heteroarylene;
R 2 is C 1 -C 4 alkyl;
R 3 is selected from -L 3 R 5 , -L 1 R 5 , -L 3 R 7 , -L 3 L 4 L 3 R 7 , -L 3 L 4 R 5 , -L 3 L 4 L 3 R 5 , —OL 3 R 7 , —OL 3 L 4 R 7 , —OL 3 L 4 L 3 R 7 , —OR 8 , —OL 3 L 4 R 5 and —OL 3 L 4 L 3 R 5 ;
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;
R 8 is H or C 1 -C 4 alkyl;
each p is independently selected from 1, 2, 3, 4, 5 and 6, and
q is 1, 2, 3 or 4.
2 . The compound of claim 1 , wherein:
R 1 is C 1 -C 4 alkyl;
R 2 is C 1 -C 4 alkyl;
R 3 is —OL 3 R 7 ;
R 7 is —CF 2 P(O)(OH) 2 ;
L 3 is C 1 -C 6 alkylene or —((CR 4 R 4 ) p O) q (CH 2 ) p —;
p is 2, and
q is 1, 2, 3 or 4.
3 . The compound of claim 1 , wherein:
R 1 is -L 1 R 6 or -L 1 R 5 ;
R 2 is C 1 -C 4 alkyl;
R 3 is —OR 8
R 5 is —P(O)(OH) 2 ;
R 6 is —CF 2 P(O)(OH) 2 , and
L 1 is —C(O)—.
4 . The compound of claim 1 , wherein:
R 1 is C 1 -C 4 alkyl;
R 2 is C 1 -C 4 alkyl;
R 3 is —OL 3 L 4 R 5 —OL 3 L 4 L 3 R 5 , or —OL 3 L 4 L 3 R 7 ;
R 5 is —P(O)(OH) 2 ;
R 7 is CF 2 P(O)(OH) 2 ;
each L 3 is independently a C 1 -C 6 alkylene, and
L 4 is phenylene.
5 . The compound of claim 1 , wherein:
R 1 is C 1 -C 6 alkyl;
R 2 is C 1 -C 6 alkyl;
R 3 is -L 1 R 5 ;
R 5 is —P(O)(OH) 2 , and
L 1 is —C(O)— or —O—.
6 . The compound of claim 1 , wherein R 8 is methyl.
7 . The compound of claim 1 , wherein R 1 is methyl.
8 . The compound of claim 1 , wherein R 2 is methyl.
9 . The compound of claim 1 , wherein the compound is selected from:
4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutylphosphonic acid;
4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dihydrogen phosphate;
5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic acid;
3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)-1,1-difluoropropylphosphonic acid;
2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1-difluoroethylphosphonic acid;
2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonic acid;
3-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenylphosphonic acid;
5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonylphosphonic acid;
6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexylphosphonic acid;
4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)benzylphosphonic acid, and
3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)-1,1-difluoropropylphosphonic acid.
10 . A compound of Formula (I), or pharmaceutically acceptable salt thereof:
wherein:
R 1 is L 2 R 5 ;
L 1 is —C(O)— or —O—;
L 2 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, arylene, heteroarylene 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;
L 4 is arylene or heteroarylene;
R 2 is C 1 -C 4 alkyl;
R 3 is selected from -L 1 R 5 , -L 3 L 4 L 3 R 7 , -L 3 L 4 R 5 , -L 3 L 4 L 3 R 5 , —OL 3 L 4 R 7 , —OL 3 L 4 L 3 R 7 , —OR 8 , —OL 3 L 4 R 5 and —OL 3 L 4 L 3 R 5 ;
each R 4 is independently selected from H and fluoro;
R 5 is —P(O)(OH) 2 ,
R 7 is —CF 2 P(O)(OH) 2 or —C(O)OH;
R 8 is H or C 1 -C 4 alkyl;
each p is independently selected from 1, 2, 3, 4, 5 and 6, and
q is 1, 2, 3 or 4.
11 . The compound of claim 13 , wherein the compound is selected from:
(E)-2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinylphosphonic acid;
2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonic acid, and
(E)-2-(5-Amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonic acid.
12 . A compound selected from:
(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methylphosphonic acid;
3-(5-amino-2-(2-methyl-4-(3-phosphonopropoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
3-(5-amino-2-(2-methyl-4-(2-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethylphosphonic acid;
6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexylphosphonic acid;
2-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)ethylphosphonic acid;
5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentylphosphonic acid, and
4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)butylphosphonic acid.
13 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
14 . The use of a compound of claim 1 in the manufacture of a medicament for treating a disease or disorder in a patient where modulation of a TLR7 receptor is implicated.
15 . The use of claim 14 , wherein the disease or condition is an infectious disease, an inflammatory disease, a respiratory disease, a dermatological disease or an autoimmune disease.
16 . The use of claim 14 , wherein the disease or condition is asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, dermatitis, actinic keratosis, basal cell carcinoma, allergic rhinitis, psoriasis, scleroderma , urticaria, rheumatoid arthritis, multiple sclerosis, cancer, breast cancer, HIV or lupus
17 . A method for treating a disease or disorder where modulation of TLR7 receptor is implicated, wherein the method comprises administering to a system or subject in need of such treatment an effective amount of a compound of Formula (I) of claim 1 , wherein the compound of Formula (I) is a TLR7 receptor agonist.
18 . The method of claim 17 , wherein the disease or condition is an infectious disease, an inflammatory disease, a respiratory disease, a dermatological disease or an autoimmune disease.
19 . The method of claim 17 , wherein the disease or condition is asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, dermatitis, actinic keratosis, basal cell carcinoma, allergic rhinitis, psoriasis, scleroderma , urticaria, rheumatoid arthritis, multiple sclerosis, cancer, breast cancer, HIV or lupus.