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;
R 21 is selected for each occurrence from the group consisting of H, and C 1-6 alkyl;
q is 0, 1, or 2;
R 22 is selected from the group consisting of hydroxyl, nitro, cyano, carboxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, —C(O)—NR′R″, —C(═NH)—NR′R″, X 2 -phenyl (optionally substituted by one, two or three substituents represented by R 63 ), phenyl (optionally substituted by one, two or three substituents represented by R 63 ), 5-6 membered monocyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 63 ), 9-10 membered bicyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 73 ), 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 , (where w is 0, 1 or 2);
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, butyl, —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;
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 63 is selected independently at each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, heterocycle (optionally substituted by halogen or NR′R′), —C(O)—NR′R″, —C(═NH)—NR′R″, heteroaryl, phenyl, benzyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carboxy, 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), —NR′—S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), X 2 —R 69 ;
R 69 is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, heterocycle (optionally substituted by halogen or NR′R′),), —C(O)—NR′R″, —C(═NH)—NR′R″, heteroaryl, phenyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carboxy, 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),
X 2 is selected from S(O) w (wherein w is 0, 1, or 2), O, CH 2 , or NR′;
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, 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(0) w —NR′R″ (where w is 0, 1 or 2);
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , wherein R 22 is selected from the group consisting of NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, —C(O)—NR′R″, —C(═NH)—NR′R″, X 2 -phenyl (optionally substituted by one, two or three substituents represented by R 63 ), phenyl (optionally substituted by one, two or three substituents represented by R 63 ), 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 , (where w is 0, 1 or 2).
3. The compound of claim 1 , wherein R 22 is selected from the group consisting of X 2 -phenyl (optionally substituted by one, two or three substituents represented by R 63 ), phenyl (optionally substituted by one, two or three substituents represented by R 63 ), 5-6 membered monocyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 63 ), and 9-10 membered bicyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 73 ).
4. The compound of claim 1 , wherein R 22 is —X 2 -phenyl (optionally substituted by one, two or three substituents represented by R 63 ).
5. The compound of claim 1 , wherein R 22 is phenyl (optionally substituted by one, two or three substituents represented by R 63 ).
6. The compound of claim 1 , wherein R 22 is a 5-6 membered monocyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 63 ) or a 9-10 membered bicyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 73 ).
7. The compound of claim 1 , wherein q is 0.
8. The compound of claim 1 , represented by:
wherein R 21 is selected from the group consisting of H and C 1-6 alkyl.
9. The compound of claim 1 , wherein the compound is represented by:
wherein R 21 is selected from the group consisting of H and CH 3 .
10. The compound of claim 1 , wherein the compound is represented by:
wherein X 2 is selected from the group consisting of O, CH 2 , and S, and R 21 is selected from the group consisting of H and CH 3 .
11. The compound of claim 1 , wherein R 22 is represented by a substituent selected from the group consisting of:
wherein each R 22 is optionally substituted by one, two or three substituents represented by R 63 .
12. The compound of claim 1 , wherein
R 63 is selected independently at each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1-6 alkyl-OH, —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, 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), —NR′—S(O) w — C 1-6 alkyl (where w is 0, 1 or 2) and —NR′—S(O) w , (where w is 0, 1 or 2) and X 2 —C 1-6 alkylene-R 69 .
13. The compound of claim 1 , wherein
R 63 is selected independently at each occurrence from the group consisting of H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 1-6 alkyl-NR′R″, —O—C 1-6 alkyl-NR′R″, —C 1-6 alkyl-OH, —C(O)—NR′R″, C 1-6 alkoxy, carboxy, NR′R″, and benzyl.
14. A pharmaceutically acceptable composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
15. 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 .