Imidazo[2,1-f][1,2,4]triazin-4-amine derivatives as TLR7 agonist
An imidazo [2,1-f] [1,2,4] triazin-4-amine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof which are used as a TLR7 agonist in the treatment of cancer are provided. Pharmaceutical compositions comprising the imidazo [2,1-f] [1,2,4] triazin-4-amine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof are also provided.
1 . A compound of Formula (II),
or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
R 1 is —OR 1a or —NHR 1a , wherein R 1a is a branched —C 4-8 alkyl, wherein the branched substituent is at the alpha position with respect to the oxygen or nitrogen atom;
Ring A is pyridyl;
Het is piperidinyl or piperazinyl;
R 5 is C 1-8 alkyl;
p is 0 or 1;
R 6c is hydrogen, —COR 6d , or C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with one, two or three substituents R 6g ;
R 6d is C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with one or two or three substituents R 6g ;
R 6g , at each occurrence, is independently —OR 6h , —SR 6h , or —NR 6h R 6i ,
R 6h and R 6i are independently hydrogen or C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with a substituent selected from hydroxyl or C 1-8 alkylamino.
2 . The compound according to claim 1 , wherein R 1 is —OR 1a or —NHR 1a , wherein R 1a is butan-2-yl, pentan-2-yl, pentan-3-yl, heptan-2-yl, heptan-3-yl, heptan-4-yl, octan-2-yl, octan-3-yl, octan-4-yl, or octan-5-yl.
3 . The compound according to claim 1 , wherein R 5 is —C 1-6 alkyl; and p is 1.
4 . The compound according to claim 1 , wherein R 5 and Het-R 6 are at ortho positions on ring A.
5 . The compound according to claim 1 , wherein Het is piperidinyl, and the piperidinyl is piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, or piperidin-5-yl, or piperazinyl is piperazin-1-yl, piperazin-2-yl, or piperazin-3-yl.
6 . The compound according to claim 1 , wherein R 6c is —COR 6d , wherein R 6d is —C 1-8 alkyl optionally substituted with one or two substituents R 6g , wherein R 6g is —NR 6h R 6i , wherein R 6h and R 6i are each independently hydrogen or —C 1-8 alkyl.
7 . The compound according to claim 1 , wherein R 6c is —COR 6d , wherein R 6d is C 1-6 alkyl or C 1-4 alkyl optionally substituted with one or two substituents Rog, wherein R 6g is —NR 6h R 6i , wherein R 6h and R 6i are each independently hydrogen, C 1-6 alkyl, or C 1-4 alkyl.
8 . The compound according to claim 1 , wherein R 6c is:
acetyl, 2-(dimethylamino)acetyl, aminoacetyl, 2-(methylamino)acetyl, 3-(dimethylamino)propanoyl, 4-(dimethylamino)butanoyl, 5-(dimethylamino)pentanoyl, (2S,3S)-2-amino-3-methylpentanoyl, 2-(methylamino)acetyl, 2-amino-4-methylpentanoyl, 2-amino-3-methylbutanoyl, 2-(dimethylamino)acetyl;
methyl, ethyl, isobutyl, (methylamino)methyl, 2-(dimethylamino)ethyl, (dimethylamino)methyl, 2-aminoethyl, or 2-(methylamino)ethyl; or
dimethylamino or amino.
9 . The compound according to claim 1 , wherein ring A is pyridyl, and the methylene group and Het on the pyridyl are in para positions of the pyridyl, and said pyridyl is further optionally substituted with one R 5 , wherein R 5 is C 1-8 alkyl.
10 . A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:
11 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
12 . A method of modulating TLR7, which comprises administering to an individual the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
13 . A method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof as a TLR7 agonist.
14 . The method according to claim 13 , wherein the disease or disorder is cancer.