Antiviral agents against HBV infection
The present invention provides novel compounds of formula (I) and methods of use thereof. In certain embodiments, the compounds of the invention are useful as nucleocapsid assembly inhibitors. In other embodiments, the compounds of the invention are useful as pregenomic RNA encapsidation inhibitors of Hepatitis B virus (HBV). In yet other embodiments, the compounds of the invention are useful for the treatment of viral infection, including HBV and related viral infections.
1. A compound of Formula (I), or an enantiomer, diastereomer, pharmaceutically accepted salt, or solvate thereof:
wherein in (I):
A is selected from the group consisting of SO 2 and CO;
R 1 is selected from the group consisting of optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted benzyl, optionally substituted 3-7 membered cycloheteroalkyl, optionally substituted C 2-8 alkenyl, optionally substituted C 2-8 alkynyl, and optionally substituted heterocyclic;
R 2 is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 3-7 cycloalkyl, and optionally substituted heterocyclic;
R 3 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R 4 is selected from the group consisting of hydrogen and optionally substituted C 1-6 linear alkyl;
R 5 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, optionally substituted C 1-6 haloalkyl, OR 9 , cyano, and N(R 9 ) 2 ;
R 6 and R 8 are selected independently at each occurrence from the group consisting of fluoro, C 1-3 alkyl, and C 1-3 alkoxy;
R 7 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, OR 9 , cyano, and N(R 9 ) 2 ;
R 9 is independently at each occurrence selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted benzyl, and optionally substituted heterocyclyl;
wherein a substituted group is substituted with at least one selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-6 cycloalkyl, —F, —Cl, —Br, —I, —CN —NO 2 , —OR 41 , —SR 14 , —N(R 14 ) 2 , —NR 14 C(O)R 14 ,—SO 2 R 14 ,—SO 2 OR 14 —SO 2 N(R 14 ) 2 , —C(O)R 14 , —C(O)OR 14 —C(O)N(R 14 ) 2 , aryl, heterocyclyl, or heteroaryl, wherein each occurrence of R 14 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 3-6 cycloalkyl, or two R 14 units taken together with the atom(s) to which they are bound form an optionally substituted carbocyclyl or heterocyclyl group, wherein the carbocyclyl or heterocyclyl group has 3 to 7 ring atoms,
wherein the heteroaryl is selected from the group consisting of diazolyl, imidazolyl, imidazolyl, triazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolinyl, furanyl, thiophenyl, pyrimidinyl, pyridinyl, tetrazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H -purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-(ijpyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, and isoquinolinyl;
provided that, when A is SO 2 , then the compound is not selected from any of groups (a) through (c):
(a) R 3 is optionally substituted phenyl and R 1 or R 2 , either individually or when taken together, contain a hydroxyl group; or
(b) R 3 is optionally substituted phenyl, and N(R 1 )(R 2 ) is selected from the group consisting of
or
(c) R 3 is optionally substituted phenyl and N(R 1 )(R 2 ) is selected from the group consisting of:
2. The compound of claim 1 , wherein
R 3 is selected from a group consisting of optionally substituted phenyl, optionally substituted benzoisoxazolyl, optionally substituted benzooxazolyl, optionally substituted furyl, optionally substituted imidazolyl, optionally substituted indoyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted oxazolyl, optionally substituted pyrazolyl, optionally substituted pyridin-2-on-yl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted quinolinyl, optionally substituted thiazolyl, and optionally substituted thienyl.
3. The compound of claim 2 , wherein R 3 is
wherein
R s is independently at each occurrence selected from the group consisting of bromo, chloro, fluoro, cyano, hydroxyl, optionally fluorinated C 1-6 alkyl, and —O—(C 1-6 alkyl), or when two are taken form a fused cyclic or heterocyclic moiety;
x is 0, 1, 2, or 3; and
R 4 is hydrogen.
4. The compound of claim 2 , wherein the optional substitution of R 3 comprises at least one halo or C 1-6 alkyl.
5. The compound of claim 1 , wherein R 3 is
6. The compound of claim 1 , wherein R 5 and R 7 are independently at each occurrence H or F.
7. The compound of claim 1 , wherein
R 3 is
and
R 4 is hydrogen.
8. The compound of claim 1 , wherein
R 5 and R 7 are each H; and
R 6 is fluoro or methoxy.
9. The compound of claim 1 , wherein,
R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, optionally substituted benzyl, optionally substituted methylpyridyl,
and
R 2 is H.
10. The compound of claim 9 , wherein R 1 is isopropyl, t-butyl,
and
R 2 is H.
11. The compound of claim 1 , with the proviso that the —N(R 1 )(R 2 ) moiety does not contain hydroxyl.
12. The compound of claim 1 , with the proviso that R 1 is not cyclopentane.
13. The compound of claim 1 , wherein
is
14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
15. A method of inhibiting pregenomic RNA encapsidation in a patient in need thereof, said method comprising administering to the patient an effective amount of at least one compound of claim 1 .
16. The method of claim 15 , wherein the pregenomic RNA is from a Hepatitis B virus.
17. A method of treating a Hepatitis B viral infection in a patient in need thereof, said method comprising administering to the patient an effective amount of at least one compound of claim 1 .
18. The method of claim 17 , wherein the treatment controls or ameliorates a condition associated with liver disease.
19. A method of repressing at least one process selected from the group consisting of viral replication and morphogenesis in a patient in need thereof, said method comprising administering to the patient an effective amount of a compound of claim 1 .