UNNATURAL CONFIGURATION NUCLEOTIDE PRODRUG COMPOUNDS
Provided herein am phosphoramidate and cyclophosphate prodrug compounds of unnatural configuration nucleotide, their preparation, and their uses, such as treating liver diseases or nonliver diseases via intervening in the molecular pathways in the liver.
1 . A compound of Formula I, II, III, IV, V or VI, or VII:
or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein:
Y is H or —OR 2 ;
R 1 and R 2 are independently H, an optionally substituted C 1 -C 10 alkyl, an optionally substituted C 5 -C 10 aryl, an optionally substituted C 1 -C 6 alkyl-C(O)—, an optionally substituted five to ten membered heteroaryl, or an optionally substituted —(CH 2 ) x —(C 5 -C 10 aryl); or alternatively, R 1 and R 2 may be taken together with the atoms to which they are attached and intervening atoms to form a four to ten membered heterocycle optionally substituted with between one and four C 1 -C 6 alkyl groups,
R 3a and R 3b are independently H or an optionally substituted C 1 -C 10 alkyl; or
alternatively, R 3a and R 3b may be taken together with the atom to which they are attached form a three to seven membered ring,
R 4 is halo, an optionally substituted C 1 -C 10 alkyl, or an optionally substituted C 1 -C 6 alkyloxy;
R 5a , R 5b , R 6a , and R 6b are independently selected from the group consisting of H, OR A , halo, —CN, and an optionally substituted C 1 -C 10 alkyl;
R A is selected from the group consisting of H, an optionally substituted C 1 -C 6 acyl, an optionally substituted C 1 -C 6 alkyloxycarbonyl; and an optionally substituted C 1 -C 6 carbamoyl;
R 7 is H or an optionally substituted C 1 -C 10 alkyl;
R 8 is selected from the group consisting of an optionally substituted C 1 -C 15 alkyl, an optionally substituted aryl, an optionally substituted benzyl, an optionally substituted phenylethyl, and an optionally substituted phenylpropyl.
n is 0, 1, 2, or 3;
x is 0, 1, or 2; and
Base is a natural nucleoside base or a derivative or analog thereof.
2 . The compound of claim 1 , wherein the compound is of Formula (I):
3 . The compound of claim 1 , wherein the compound is of Formula (IV):
4 . The compound of claim 1 , wherein the compound is of Formula (V):
5 . The compound of any one of claims 1-4 , wherein R 1 is a C 1 -C 6 alkyl.
6 . The compound of any one of claims 1-5 , wherein R 1 is methyl.
7 . The compound of any one of claims 1-5 , wherein R 1 is ethyl.
8 . The compound of any one of claims 1-5 , wherein R 1 is propyl.
9 . The compound of any one of claims 1-5 , wherein R 1 is butyl.
10 . The compound of any one of claims 1-4 , wherein R 1 is H.
11 . The compound of any one of claims 1-4 , wherein aryl is phenyl.
12 . The compound of any one of claims 1-4 and 11 , wherein x is 1.
13 . The compound of any one of claims 1-12 , wherein Y is H.
14 . The compound of any one of claims 1-12 , wherein Y is —OR 2 .
15 . The compound of claim 14 , wherein R 2 is methyl.
16 . The compound of claim 14 , wherein R 2 is ethyl.
17 . The compound of claim 14 , wherein R 2 is propyl.
18 . The compound of claim 14 , wherein R 2 is butyl.
19 . The compound of claim 1 , wherein R 1 and R 2 are taken together with the atoms to which they are attached and intervening atoms to form a four to ten membered heterocycle optionally substituted with between one and four C 1 -C 6 alkyl groups.
20 . The compound of claim 1 , wherein R 1 and R 2 are taken together with the atoms to which they are attached and intervening atoms to form
21 . The compound of claim 20 , wherein R 1 and R 2 are taken together with the atoms to which they are attached and intervening atoms to form
22 . The compound of claim 20 , wherein R 1 and R 2 are taken together with the atoms to which they are attached and intervening atoms to form
23 . The compound of claim 1 , wherein the compound is of Formula (VI):
24 . The compound of claim 1 or 23 , wherein R 8 is C 1 -C 15 alkyl.
25 . The compound of any one of claims 1, 23, and 24 , wherein R 8 is pentyl.
26 . The compound of any one of claims 1, 23, and 24 , wherein R 8 is hexyl.
27 . The compound of any one of claims 1, 23, and 24 , wherein R 8 is heptyl.
28 . The compound of any one of claims 1, 23, and 24 , wherein R 8 is phenyl.
29 . The compound of any one of claims 1, 23, and 24 , wherein R 8 is fluorophenyl.
30 . The compound of any one of claims 1, 23, and 24 , wherein R 8 is benzyl.
31 . The compound of any one of claims 1, 23, and 24 , wherein R 8 is phenylethyl.
32 . The compound of claim 1 , wherein the compound is of Formula (III):
33 . The compound of any one of claims 1-3, 5-22, and 32 , wherein R 3a and R 3b are both H.
34 . The compound of any one of claims 1-3, 5-22, and 32 , wherein R 3a is H and R 3b is methyl.
35 . The compound of claim 1 , wherein the compound is of Formula (VII):
36 . The compound of any one of claims 1 -, 2 , 5 - 22 , and 35 , wherein R 5a is H.
37 . The compound of any one of claims 1 -, 2 , 5 - 22 , 35 , and 36 , wherein R 5b is —OR A .
38 . The compound of any one of claims 1 -, 2 , 5 - 22 , and 35 - 37 , wherein R A is H.
39 . The compound of any one of claims 1 -, 2 , 5 - 22 , and 35 - 37 , wherein R 5b is
40 . The compound of any one of claims 1 -, 2 , 5 - 22 , and 35 - 37 , wherein R 5b is
41 . The compound of claim 1 , wherein the compound is of Formula (II):
42 . The compound of claim 1 or 41 , wherein R 7 is C 1 -C 6 alkyl.
43 . The compound of any one of claims 1, 41, and 42 , wherein R 7 is methyl.
44 . The compound of any one of claims 1, 41, and 42 , wherein R 7 is ethyl.
45 . The compound of any one of claims 1, 41, and 42 , wherein R 7 is propyl.
46 . The compound of any one of claims 1, 41, and 42 , wherein R 7 is i-Pr.
47 . The compound of any one of claims 1, 41, and 42 , wherein R 7 is butyl.
48 . The compound of any one of claims 1, 41, and 42 , wherein R 7 is i-butyl.
49 . The compound of any one of claims 1-48 , wherein R 6a is halo.
50 . The compound of any one of claims 1-49 , wherein R 6a is fluoro.
51 . The compound of any one of claims 1-50 , wherein R 6b is H.
52 . The compound of any one of claims 1, 2, 4-22, and 33-51 , wherein R 4 is halo selected from fluoro and chloro.
53 . The compound of any one of claims 1 -, 2 , 4 - 22 , and 33 - 52 , wherein n is 1.
54 . The compound of any one of claims 1, 2, 4-22, and 33-52 , wherein n is 2.
55 . The compound of any one of claims 1, 2, 4-22, 33-52 and 54 , wherein one R 4 is fluoro and one R 4 is chloro.
56 . The compound of any one of claims 1-55 , wherein Base is selected from the group consisting of
wherein:
R 9 is H, halo, —CD 3 , 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 , NHOH, 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—.
57 . The compound of any one of claims 1-56 , wherein Base is
58 . The compound of any one of claims 1-57 , wherein R 9 is methyl.
59 . The compound of any one of claims 1-58 , wherein R 10 is H.
60 . A compound selected from the group consisting of:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
61 . A pharmaceutical composition comprising the compound of any one of claims 1-60 and a pharmaceutically acceptable excipient.
62 . The pharmaceutical composition of claim 61 , further comprising one or more anti-cancer agents.
63 . A method of treating a disease, disorder or condition comprising administering an effective amount of the compound of any one of claims 1-60 to a subject in need thereof.
64 . The method of claim 63 , wherein the disease, disorder, or condition is a disease, disorder, or condition of the liver.
65 . The method of claim 63 , wherein the disease, disorder or condition is a metabolic, cardiovascular, or hormonal disease in which the liver is involved in the production and/or the homeostasis control of the biochemical end products of the disease, disorder, or condition.
66 . The method of claim 63 , wherein the disease, disorder or condition is selected from the group consisting of hepatitis, cancer, liver fibrosis, fatty liver, malaria, viral infection, parasitic infection, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia, and a hormonal condition.
67 . The method of claim 63 , wherein the disease, disorder or condition is a viral infection, cancer, or other disease in which the prodrug compounds enhance the distribution of an active drug to the target tissue or cell.
68 . The method of any one of claims 63-67 , wherein the subject is a mammal.
69 . The method of any one of claims 63-68 , wherein the subject is a human.
70 . The method of any one of claims 63-69 , further comprising administering an effective amount of at least one additional therapeutic agent to the subject in need thereof.
71 . The method of claim 70 , wherein the additional therapeutic agent is one or more of sorafenib, regorafenib, an immune-oncology agent such as a PD-1 or PD-L1 checkpoint inhibitor.
72 . A compound of any one of claims 1-60 for use in treating a disease or condition in the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver.
73 . Use of a compound of any one of claims 1-60 in the preparation of a medicament for treating a disease or condition in the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver.