Benzyloxy phosph(on)ate compounds
Provided herein are 2-substituted benzyloxy phosph(on)ate compounds, their preparation and their uses, such as treating liver diseases or conditions.
1 . A compound of Formula I:
wherein:
R 1 is selected from the group consisting of —CH(OR 6 ) 2 , —C(O)N(R 6 ) 2 , —CH 2 OR 7 , CH 2 SR 7 , —CH 2 N(R 7 ) 2 , —CH 2 OCH 2 OR 6 , —COOR 5 , and
each R 2 is independently selected from the group consisting of halogen, an optionally substituted alkyl, and an optionally substituted alkyloxy;
R 3 is selected from the group consisting of H, an optionally substituted aryl, and a therapeutic or diagnostic moiety;
R 4 is selected from a nucleoside or a nucleoside base or analog thereof, or alternatively, R 4 and R 3 together with the atoms to which they are attached form a monocyclic heterocyclyl substituted with a nucleoside base or analog thereof, or R 4 and R 5 together with the atoms to which they are attached form a heterocyclyl substituted with a nucleoside base or analog thereof, wherein the nucleoside base or analog thereof is selected from the group consisting of:
R 5 is H or an optionally substituted alkyl;
each R 6 is independently an optionally substituted alkyl;
R 7 is selected from the group consisting of H, an optionally substituted C 1 -C 10 acyl, an optionally substituted C 1 -C 10 alkyl-OC(O)—, an optionally substituted (C 6-10 aryl)-C(O)—, and an optionally substituted (C 6-10 aryl)-OC(O)—;
R 9 is H, halo, or an optionally substituted C 1 -C 10 alkyl;
R 10 is selected from the group consisting of H, an optionally substituted C 1 -C 10 alkyl, an optionally substituted C 1 -C 10 alkyl-OCH 2 —, an optionally substituted C 1 -C 10 alkyl-NHCH 2 —, an optionally substituted C 1 -C 10 acyl, an optionally substituted C 1 -C 10 alkyl-OC(O)—, an optionally substituted (C 6-10 aryl)-CH 2 OCH 2 —, an optionally substituted (C 6-10 aryl)-OCH 2 —, an optionally substituted (C 6-10 aryl)-C(O)—, and an optionally substituted (C 6-10 aryl)-OC(O)—;
R 11 is selected from the group consisting of OH, NH 2 , NHOR 7 , an optionally substituted C 1 -C 10 alkyloxy, an optionally substituted C 1 -C 10 alkylamino, an optionally substituted C 1 -C 10 acyloxy, an optionally substituted C 1 -C 10 acylamino, an optionally substituted C 1 -C 10 alkyl-OC(O)NH—, an optionally substituted (C 6-10 aryl)-C(O)O—, an optionally substituted (C 6-10 aryl)-C(O)NH—, an optionally substituted (C 6-10 aryl)-OC(O)NH—, an optionally substituted C 1 -C 10 alkyl-OCH 2 NH—, and an optionally substituted C 1 -C 10 alkyl-OCH 2 O—; and
R 12 is selected from a group of H, NH 2 , an optionally substituted C 1 -C 10 alkylamino, an optionally substituted C 1 -C 10 acylamino, an optionally substituted C 1 -C 10 alkyl-OC(O)NH—, an optionally substituted (C 6-10 aryl)-C(O)NH—, an optionally substituted (C 6-10 aryl)-OC(O)NH—, and an optionally substituted C 1 -C 10 alkyl-OCH 2 NH—; and
n is 0, 1, 2, or 3;
or a stereoisomer or pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein the nucleoside base or analog thereof is selected from the group consisting of
3 . The compound of claim 2 , wherein the nucleoside base or analog thereof is
4 . The compound of claim 3 , wherein R 11 is NH 2 .
5 . The compound of claim 3 , wherein R 12 is H.
6 . The compound of claim 2 , wherein the nucleoside base or analog thereof is
7 . The compound of claim 6 , wherein R 9 is H.
8 . The compound of claim 6 , wherein R 11 is NH 2 .
9 . The compound of claim 1 , wherein n is 1.
10 . The compound of claim 1 , wherein R 3 is selected from the group consisting of H and an optionally substituted aryl.
11 . The compound of claim 1 , wherein R 1 is selected from the group consisting of —CH(OR 6 ) 2 , —C(O)N(R 6 ) 2 , and
12 . The compound of claim 1 , wherein the compound of Formula I is represented by Formula (Ia):
or a stereoisomer or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 12 , wherein R 5 is an unsubstituted C 1 -C 6 alkyl.
14 . The compound of claim 13 , wherein R 5 is ethyl.
15 . The compound of claim 13 , wherein R 5 is i-propyl.
16 . The compound of claim 12 , wherein R 5 is H.
17 . The compound of claim 12 , wherein R 3 is an unsubstituted aryl.
18 . The compound of claim 12 , wherein R 3 is phenyl.
19 . The compound of claim 1 , wherein the compound is selected from the group consisting of
20 . A method of treating a liver disease comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.
21 . The method of claim 20 , wherein the subject is a mammal.
22 . The method of claim 21 , wherein the mammal is a human.