Anti-infective agents and uses thereof
View Patent ↗This invention relates to: (a) compounds and salts thereof that, inter alia, inhibit HCV; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions.
1. A compound or salt thereof, wherein the compound corresponds in structure to formula II:
wherein
is selected from the group consisting of single carbon-carbon bond and double carbon-carbon bond;
R 1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group;
R 2 is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and cyclobutyl;
R 3 is selected from the group consisting of hydrogen, halo, oxo, and methyl;
R 4 is selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl, and
(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl, optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl, and
(c) the carbocyclyl and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl;
R 5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo; and
X 2 is halo.
2. The compound or salt of claim 1 , wherein is a single carbon-carbon bond.
3. The compound or salt of claim 1 , wherein is a double carbon-carbon bond.
4. The compound or salt of claim 1 , wherein R 1 is selected from the group consisting of hydrogen and methyl.
5. The compound or salt of claim 1 , wherein R 1 is hydrogen.
6. The compound or salt of claim 1 , wherein R 2 is selected from the group consisting of hydrogen, methyl, and halo.
7. The compound or salt of claim 1 , wherein R 2 is hydrogen.
8. The compound or salt of claim 1 , wherein R 3 is selected from the group consisting of hydrogen and methyl.
9. The compound or salt of claim 1 , wherein R 3 is hydrogen.
10. The compound or salt of claim 1 , wherein R 4 is selected from the group consisting of C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, amino, C 1 -C 4 -alkylsulfonyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl, wherein:
the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl,
the C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, and C 2 -C 4 -alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, and amino, wherein:
the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.
11. The compound or salt of claim 1 , wherein:
R 4 is selected from the group consisting of C 1 -C 4 -alkyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the C 1 -C 4 -alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino.
12. The compound or salt of claim 1 , wherein R 4 is selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl.
13. The compound or salt of claim 1 , wherein R 4 is selected from the group consisting of C 1 -C 4 -alkyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl.
14. The compound or salt of claim 1 , wherein R 4 is selected from the group consisting of tert-butyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl.
15. The compound or salt of claim 1 , wherein R is selected from the group consisting of tert-butyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl.
16. The compound or salt of claim 1 , wherein R 4 is alkyl.
17. The compound or salt of claim 1 , wherein R 4 is tert-butyl.
18. The compound or salt of claim 1 , wherein R 5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo.
19. The compound or salt of claim 1 , wherein R 5 is selected from the group consisting of hydrogen, methoxy, and halo.
20. The compound or salt of claim 1 , wherein R 5 is methoxy.
21. The compound or salt of claim 1 , wherein X 2 is selected from the group consisting of chloro, bromo, and iodo.
22. The compound or salt of claim 1 , wherein X 2 is iodo.
23. The compound or salt of claim 1 , wherein
R 1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group;
R 2 is selected from the group consisting of hydrogen and halo;
R 3 is selected from the group consisting of hydrogen and halo;
R 4 is selected from the group consisting of C 1 -C 4 -alkyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the C 1 -C 4 -alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino;
R 5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo; and
X 2 is selected from the group consisting of chloro, bromo, and iodo.
24. The compound or salt of claim 1 , wherein
is a double carbon-carbon bond;
R 1 is hydrogen;
R 2 is selected from the group consisting of hydrogen and halo;
R 3 is hydrogen;
R 4 is tert-butyl;
R 5 is selected from the group consisting of hydrogen, hydroxy, and methoxy; and
X 2 is selected from the group consisting of bromo and iodo.
25. The compound or salt of claim 1 , wherein
R 1 is selected from the group consisting of hydrogen and methyl;
R 2 is selected from the group consisting of hydrogen and methyl;
R 3 is selected from the group consisting of hydrogen and methyl;
R 4 is tert-butyl;
R 5 is selected from the group consisting of hydroxy and methoxy; and
X 2 is selected from the group consisting of chloro, bromo, and iodo.
26. The compound or salt of claim 1 , wherein
is a double carbon-carbon bond;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is hydrogen;
R 4 is tert-butyl;
R 5 is selected from the group consisting of hydroxy and methoxy; and
X 2 is selected from the group consisting of chloro, bromo, and iodo.
27. The compound or salt of claim 1 , wherein the compound is selected from the group consisting of
28. A process for preparing the compound or salt of claim 1 , wherein the process comprises reacting a compound of formula III with a compound of formula IV in the presence of (i) copper (I) salt catalyst and (ii) nitrogenous heteroaryl ligand
wherein R 1 , R 2 , R 3 , R 4 , R 5 and X 2 are as defined in claim 1 , and X 1 is halo.
29. The process of claim 28 , wherein X 1 is selected from the group consisting of chloro, bromo, and iodo.
30. The process of claim 28 , wherein the process is conducted in the presence of a base.
31. The process of claim 30 , wherein the base is selected from the group consisting of potassium salt, sodium salt, and cesium salt.
32. The process of claim 28 , wherein the nitrogenous heteroaryl ligand comprises a picolinamide compound corresponding in structure to formula V:
and
R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently selected from the group consisting of hydrogen, C 1-4 -perfluoroalkyl, C 1-4 -alkyloxy, C 1-4 -haloalkyl, chloro, and cyano.
33. The process of claim 28 , wherein the nitrogenous heteroaryl ligand is selected from the group consisting of 8-hydroxyquinoline, 2-(2-pyridyl)-benzimidazole, N-(4-cyano-phenyl)picolinamide, and N-(2-cyanophenyl)picolinamide.
34. The compound or salt of claim 1 , wherein the compound is 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.
35. 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.