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 S(O) y , wherein y is 2;
R Z is H;
R m′ and R m are each H;
L is a bond or C 1-2 alkylene (optionally substituted by halogen or C 1-2 alkyl);
A is a 5-7 membered monocyclic heterocyclic or 5-6 membered monocyclic heteroaryl ring optionally substituted by one or two substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, and NR′R″;
B is selected from the group consisting of phenyl (optionally substituted by one, two or three substituents represented by R 33 ), 5-6 membered monocyclic heteroaryl optionally substituted by one, two or three substituents represented by R 33 ), and 9-10 membered bicyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 33 );
R′ is selected, independently for each occurrence, from H, methyl, ethyl, 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 2-6 alkynyl, C 2-6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR′R″;
R 33 is independently selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, —C(O)—NR′R″, —C(═NH)—NR′R″, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carboxy, —CHO, NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, C 3-6 cycloalkyl, —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);
q is 0, 1, 2 or 3;
wherein for each occurrence, C 1-6 alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, NR′R″, —NR′—S(O) w — C 1-6 alkyl (where w is 0, 1 or 2), 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 1-6 alkyl, NR′R″, —NR′—S(O) w — C 1-6 alkyl (where w is 0, 1 or 2), and S(O) w —NR′R″ (where w is 0, 1 or 2); and
pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , wherein the compound is represented by:
3. The compound of claim 2 , wherein A is a 5-6 membered monocyclic heteroaryl.
4. The compound of claim 2 , wherein A is pyridinyl.
5. The compound of claim 2 , wherein A is pyrimidinyl.
6. The compound of claim 2 , wherein A is thiadiazole.
7. The compound of claim 2 , wherein 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, methyl, trifluoromethyl, and halogen.
8. The compound of claim 7 , wherein each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is hydrogen.
9. The compound of claim 2 , wherein A is optionally substituted by one substituent selected from the group consisting of halogen, C 1-6 haloalkyl, and C 1-6 alkyl.
10. The compound of claim 2 , wherein R 33 is selected from the group consisting of H, halogen, hydroxyl, cyano, C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, —C(O)—NR′R″, C 1-6 alkoxy, carboxy, CHO, NR′R″, and —C 1-6 alkyl-OH.
11. The compound of claim 2 , wherein L is a bond or a methylene.
12. The compound of claim 2 , wherein LB is a bond.
13. The compound of claim 2 , wherein B is selected from the group consisting of phenyl, indolyl, indazolyl, benzimidazolyl, and pyrimidinyl, each of which may be optionally substituted by one, two or three substituents represented by R 33 .
14. The compound of claim 2 , wherein q is 1.
15. A pharmaceutically acceptable composition comprising a compound of claim 2 , and a pharmaceutically acceptable excipient.
16. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering an effective amount of a compound of claim 2 .