2-amino-quinoline derivatives
Described herein are 2-amino-quinoline derivatives that are agonists of toll-like receptors 7 and 8 (TLR7/8), pharmaceutical compositions, and methods of use of the compounds and compositions to treat various diseases, such as viral, cancer, and allergic diseases, in need thereof by administering a therapeutically effective amount of a 2-amino-quinoline derivative.
1. A compound represented by a formula:
or a salt thereof;
wherein a dashed line represents the presence or absence of a bond;
A 1 is CR 1 , NR 1A , or N;
A 2 is NR 2 A;
B 1 is CR 5 or N;
B 2 is CR 6 or N;
B 3 is CR 7 or N;
R 1 is F, Cl, Br, I, NO 2 , CN, R a , —OR a , —NR a R b , —NHCOR a , —NHSO 2 R a , —OCOR a , or —SO 2 R a ;
X is a bond, O, NR a , —CO—, —SO—, or —SO 2 —, —CONR a , hydrocarbyl, and R 3 is H or C 1-30 organyl; or X—R 3 is F or Cl;
R 1A , R 2A , R 4 , R a , and R b are independently H or C 1-30 organyl;
R 5 , R 6 , and R 7 are independently F, Cl, Br, I, NO 2 , CN, R a , —OR a , —NR a R b , —NHCOR a , —NHSO 2 R a , —OR a , —SO 2 R a , —SO 2 NHR a , or —X 1 —(C m H 2m O 0−1 )—Z—(C n H 2n+1 ), —(C m H 2m O 0−1 )—Z—(C n H 2n+1 ), wherein R 5 and R 6 or R 6 and R 7 can be optionally linked to form a ring;
wherein X 1 is a bond, 0, NR a , —CO—, —SO—, or —SO 2 —;
Z is a bond, O, NHSO 2 , or NHCO;
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23,
wherein C 1-30 organyl, is an optionally substituted organic substituent group having a free valence at a carbon, selected from the group consisting of alkyl, C 1-30 alkyl, C 1-12 alkyl, C 1-6 alkyl, C 1-3 alkyl, methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 13 alkyl, C 14 alkyl, C 15 alkyl, C 16 alkyl, C 17 alkyl, C 18 alkyl, C 19 alkyl, C 20 alkyl, C 21 alkyl, C 22 alkyl, C 23 alkyl, C 24 alkyl, C 25 alkyl, C 26 alkyl, C 27 alkyl, C 28 alkyl, C 29 alkyl, C 30 alkyl, C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl, C 9 cycloalkyl, C 10 cycloalkyl, C 11 cycloalkyl, C 12 cycloalkyl, alkenyl, C 2-12 alkenyl, C 2-6 alkenyl, ethenyl, C 3 alkenyl, C 4 alkenyl, C 5 alkenyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 4 cycloalkenyl, C 5 cycloalkenyl, C 6 cycloalkenyl, C 7 cycloalkenyl, C 8 cycloalkenyl, C 9 cycloalkenyl, C 10 cycloalkenyl, C 11 cycloalkenyl, C 12 cycloalkenyl; alkynyl, C 2-12 alkynyl, C 2-6 alkynyl, ethynyl, C 3 alkynyl, C 4 alkynyl, C 5 alkynyl, C 6 alkynyl, C 7 alkynyl, C 8 alkynyl, C 9 alkynyl, C 10 alkynyl, C 11 alkynyl, C 12 alkynyl, C 5 cycloalkynyl, C 6 cycloalkynyl, C 7 cycloalkynyl, C 8 cycloalkynyl, C 9 cycloalkynyl, C 10 cycloalkynyl, C 11 cycloalkynyl, C 12 cycloalkynyl, aryl, phenyl, naphthyl; heterocyclyl, heteroary, CN, —C(O)R a , —C(O)OR a , —C(O)NHR a , —C(O)NR a R b , —C(O)—Z-organyl, wherein Z is a bond, O, S, or NR a R b , —C(R a R b )—OR a , —C(R a R b )— and NR a R b ; wherein R a and R b are each independently H or C 1-30 alkyl, alkenyl, alkynyl, or phenyl; wherein the optional substitution comprises halogen, hydroxyl, amine, alkoxyl, aryl, heteroaryl, sulfone, sulfonamide, carboxylic acid, amide, reversed amide, ester, cycloalkyl, heterocycloalkyl, carbonyl, alkyl, alkenyl, alkynyl, phosphonamidic acid, phosphinic amide, or phosphine oxide.
2. The compound of claim 1 , represented by a formula:
or a salt thereof, wherein R 3 is C 1-30 organyl.
3. The compound of claim 1 , wherein R 1 or R 1A is C 1-12 optionally substituted alkyl.
4. The compound of claim 3 , wherein R 1 or R 1A is —C r H 2r+1 O, or an ester thereof, wherein r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
5. The compound of claim 4 , wherein R 1 or R 1A is —C 3 H 7 O.
6. The compound of claim 5 , wherein R 1 or R 1A is —CH 2 OCH 2 CH 3 .
7. The compound of claim 1 , wherein R 2A is H or C 1-12 optionally substituted alkyl.
8. The compound of claim 7 , wherein R 2A is C 1-6 alkyl, or —C y H 2y+1 O or an ester thereof, wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
9. The compound of claim 8 , wherein R 2A is CH 3 .
10. The compound of claim 7 , wherein R 2A is H.
11. The compound of claim 7 , wherein R 2A is C 4 H 9 .
12. The compound of claim 1 , wherein R 3 is C 1-30 optionally substituted alkyl.
13. The compound of claim 12 , wherein R 3 is C 1-10 alkyl, or —C w H 2w+1 O or an ester thereof, wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
14. The compound of claim 1 , wherein R 3 is —(C t H 2t O 0−1 )—Ht, wherein t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and Ht is optionally substituted C 3-6 heterocyclyl.
15. The compound of claim 1 , wherein R 3 is —(C u H 2u O 0−1 )—Z—(C v H 2v+1 ), wherein Z is a bond, O, NHSO 2 , or NHCO, u is 0, 1, 2, 3, 4, 5, or 6, and v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.
16. The compound of claim 1 , wherein R 3 is —(C u H 2u O 0−1 )—NR a R b , and u is 1, 2, 3, 4, 5, or 6, wherein R a and R b are independently H or C 1-6 alkyl.
17. The compound of claim 13 , wherein R 3 is C 5 H 11 O.
18. The compound of claim 13 , wherein R 3 is —CH 2 —CH 2 —C(CH 3 ) 2 OH.
19. The compound of claim 16 , wherein R 3 is —CH 2 —CH 2 —CH 2 —NH 2 .
20. The compound of claim 1 , wherein R 4 is H or C 1-6 alkyl.
21. The compound of claim 20 , wherein R 4 is H.
22. The compound of claim 1 , wherein R 5 is R a , F, Cl, —CN, —OR a , —NR a R b , —OCOR a , or —SO 2 R a , —SO 2 NHR a , wherein R a and R b are independently H or C 1-6 alkyl.
23. The compound of claim 22 , wherein R 5 is H.
24. The compound of claim 1 , wherein R 5 is —(C m H 2m O 0−1 )—Z—(C n H 2n+1 ), wherein Z is a bond, O, NHSO 2 , or NHCO, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.
25. The compound of claim 1 , wherein R 6 is R a , F, Cl, —CN, —OR a , —NR a R b , —OCOR a , or —SO 2 R a , —SO 2 NHR a , wherein R a and R b are independently H or C 1-6 alkyl.
26. The compound of claim 25 , wherein R 6 is H.
27. The compound of claim 1 , wherein R 6 is —(C m H 2m O 0−1 )—Z—(C n H 2n+1 ), wherein Z is a bond, O, NHSO 2 , or NHCO, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.
28. The compound of claim 1 , wherein R 7 is R a , F, Cl, —CN, —OR a , —NR a R b , —OCOR a , or —SO 2 R a , —SO 2 NHR a , wherein R a and R b are independently H or C 1-6 alkyl.
29. The compound of claim 28 , wherein R 7 is H.
30. The compound of claim 1 , wherein R 7 is —(C m H 2m O 0−1 )—Z—(C n H 2n+1 ), wherein Z is a bond, O, NHSO 2 , or NHCO, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.
31. The compound of claim 1 , which is:
a salt of any of these compounds, or an ester of any of these compounds having an —OH group.
32. The compound of claim 1 which is optionally substituted 9-methoxy-1H-imidazo[4,5-c]quinolin-4-amine.
33. The compound of claim 32 , which is optionally substituted 1-(4-amino-2-(ethoxymethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-isobutyl-9-methoxy-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 1-(4-amino-9-methoxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol or a salt thereof; optionally substituted 1-(4-amino-2-(2-hydroxyethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol or a salt thereof; optionally substituted 4-((4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methylbutan-2-ol or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-(isopentyloxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 4-((4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butan-2-ol or a salt thereof; optionally substituted 1-((4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propan-2-ol or a salt thereof; optionally substituted 4-((4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methylbutan-2-ol or a salt thereof; optionally substituted 44(4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methylbutan-2-ol or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-(2-isopropoxyethoxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 4-((4-amino-2-(ethoxymethyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methylbutan-2-ol or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-(2-isopropoxyethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 4-(4-amino-2-(ethoxymethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylbutan-2-ol or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-isobutoxy-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-(2-isopropoxyethoxy)-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-(isopentyloxy)-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-isobutoxy-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)methanesulfonamide or a salt thereof; optionally substituted N-(2-(2-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)ethoxy)ethyl)-methanesulfonamide or a salt thereof; optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)acetamide or a salt thereof; optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)methanesulfonamide or a salt thereof; optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)stearamide or a salt thereof; optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)acetamide or a salt thereof; optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)-stearamide or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-methyl-9-(2-morpholinoethoxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-methyl-9-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-methyl-9-(pyrrolidin-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-methyl-9-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)palmitamide or a salt thereof; optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)palmitamide or a salt thereof; optionally substituted 9-(3-aminopropoxy)-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-isopropoxy-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 1-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methylpropan-2-ol or a salt thereof; optionally substituted 2-(ethoxymethyl)-3,4-dihydro-5-oxa-1,2a,9-triazanaphtho[2,1,8-cde]azulen-10-amine or a salt thereof; optionally substituted (R)-2-(10-amino-2-(ethoxymethyl)-3,4-dihydro-5-oxa-1,2a,9-triazanaphtho[2,1,8-cde]azulen-3-yl)propan-2-ol or a salt thereof; optionally substituted (S)-2-(10-amino-2-(ethoxymethyl)-3,4-dihydro-5-oxa-1,2a,9-triazanaphtho[2,1,8-cde]azulen-3-yl)propan-2-ol or a salt thereof; optionally substituted (S)-2-amino-12-(ethoxymethyl)-6-methyl-6,7-dihydro-5H-3,4-(azenometheno)[1,5]oxazocino[4,3,2-de]quinolin-6-ol or a salt thereof; optionally substituted (R)-2-amino-12-(ethoxymethyl)-6-methyl-6,7-dihydro-5H-3,4-(azenometheno)[1,5]oxazocino[4,3,2-de]quinolin-6-ol or a salt thereof; optionally substituted (R)-2-amino-12-(ethoxymethyl)-6,7-dihydro-5H-3,4-(azenometheno)[1,5]oxazocino[4,3,2-de]quinolin-6-ol or a salt thereof; optionally substituted (S)-2-amino-12-(ethoxymethyl)-6,7-dihydro-5H-3,4-(azenometheno)[1,5]oxazocino-[4,3,2-de]quinolin-6-ol or a salt thereof; optionally substituted 2-amino-12-(ethoxymethyl)-5H-3,4-(azenometheno)[1,5]oxazocino[4,3,2-de]quinolin-6(7H)-one or a salt thereof; or optionally substituted tert-butyl 4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)piperidine-1-carboxylate or a salt thereof.
34. A dosage form suitable for administration to a mammal, comprising a compound of claim 1 .