Hepatitis B core protein modulators
The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.
1. A compound represented by:
wherein
Y is O;
R Z is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
R m′ and R m are each independently selected from the group consisting of H, C 1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), and C 2-6 alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl);
R c is selected from the group consisting of H, C 1-6 alkyl and C 2-6 alkenyl;
R 77 is selected from the group consisting of H, halogen, cyano, and C 1-6 alkyl;
R 78 is phenyl (optionally substituted with one, two, three or four substituents each independently selected from the group consisting of R 73 );
X 2 is selected from the group consisting of S(O) w (wherein w is 0, 1, or 2), O, —C(O)— and NR′,
R 79 is selected from the group consisting of H, hydroxyl, halogen, C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, heterocycle (optionally substituted by one or more substituents selected from the group consisting of halogen, NR′R′, —C(O)—O—C 1-6 alkyl, carboxy and C 1-6 alkyl), —C(O)—NR′R″, —C(═NH)—NR′R″, heteroaryl, phenyl (optionally substituted by one or more substituents selected from the group consisting of halogen, NR′R′, —C(O)—O—C 1-6 alkyl, carboxy, C 1-6 alkoxy, and C 1-6 alkyl), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carboxy, NR′R″, —C(O)—C 1-6 alkyl, C 3-6 cycloalkyl, —NR′—C(O)— C 1-6 alkyl, NR′—C(O)— O—C 1-6 alkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), —S(O) w —NR′R″ (where w is 0, 1 or 2), and —NR′—S(O) w — C 1-6 alkyl (where w is 0, 1 or 2));
R 73 is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, oxo, C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, heterocycle (optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, NR′R′, —C(O)—O—C 1-6 alkyl, carboxy and C 1-6 alkyl), —C(O)—NR′—C 1-6 alkyl, —C(═NH)—NR′R″, heteroaryl, phenyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carboxy, oxo, NR′R″, —C(O)—C 1-6 alkyl, —C 3-6 cycloalkyl, NR′—C(O)— C 1-6 alkyl, NR′—C(O)— O—C 1-6 alkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), —S(O) w —NR′R″ (where w is 1, 2 or 3), —NR′—S(O) w — C 1-6 alkyl (where w is 0, 1 or 2), C(O)—NR′— C 1-6 alkyl, C(O)—C 1-3 alkylene-NR′— C(O)—O— C 1-6 alkyl, X 2 — R 79 ; and X 2 —C 1-6 alkylene-R 79 ;
R′ is selected, independently for each occurrence, from H, methyl, ethyl, cyclopropyl, cyclobutyl, and propyl;
R″ is selected, independently for each occurrence, from H, methyl, ethyl, propyl, (optionally substituted by hydroxyl), butyl (optionally substituted by hydroxyl), —C(O)-methyl and —C(O)-ethyl, or R′ and R″ taken together with the nitrogen to which they are attached may form a 4-7 membered heterocycle optionally substituted by one, two or more substituents selected from the group consisting of halogen, hydroxyl, NH 2 , —C(O)—O—C 1-3 alkyl, —C(O)—C 1-3 alkyl, carboxy, oxo, and C 1-3 alkyl;
each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected for each occurrence from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR′R″;
wherein for each occurrence, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, NR′R″, —NR′—S(O) w — C 1-2 alkyl (where w is 0, 1 or 2), NR′—C(O)—C 1-3 alkyl, NR′—C(O)— O—C 1-3 alkyl, and S(O) w —NR′R″(where w is 0, 1 or 2); C 1-6 alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 1-3 alkyl, NR′R″, —NR′—S(O) w — C 1-2 alkyl (where w is 0, 1 or 2), and S(O) w —NR′R″ (where w is 0, 1 or 2); C 1-6 alkylene may be optionally substituted by a substituent selected from the group consisting of C 3-6 cycloalkyl, hydroxyl, cyano, and halogen;
and pharmaceutically acceptable salts and N-oxides thereof.
2. The compound of claim 1 , wherein R 77 is selected from the group consisting of H, CH 3 and CF 3 .
3. The compound of claim 1 , wherein R 7 is H or halogen.
4. The compound of claim 1 , wherein R 10 is H, halogen or methyl.
5. The compound of claim 1 , wherein R m′ and R m are each H.
6. The compound of claim 1 , wherein R Z is H.
7. The compound of claim 1 , wherein each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is H.
8. The compound of claim 1 , wherein R 77 is H.
9. A pharmaceutically acceptable composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
10. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering an effective amount of a compound of claim 1 .
11. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from a compound of claim 1 , and optionally administering one or more additional compounds.
12. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering an amount of a compound of claim 1 , and administering another HBV capsid assembly promoter.