Hepatitis B antiviral agents
Provided herein are compounds useful for the treatment of HBV infection in man.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is selected from:
wherein:
G is N, and Q is CH 2 or NR 3 , or
G is NR 3 , and Q is CH or N, or
G is CH, and Q is NR 3 , or
G is CH 2 , and Q is N; and
represents a single or double bond;
R 1 in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, —OC 1-6 alkyl, and —NO 2 , wherein the C 1-6 alkyl is optionally substituted with one to three halo;
R 2 in each occurrence is independently selected from hydrogen, halo, and C 1-6 alkyl;
R 3 is selected from H and C 1-6 alkyl;
R 4 in each occurrence is independently selected from halo, C 1-6 alkyl, monocyclic 5 to 7-membered carbocyclyl, monocyclic 5 to 7-membered heterocyclyl, —OR 4a , —SR 4a , and —N(R 4a ) 2 , wherein the C 1-6 alkyl, monocyclic 5 to 7-membered carbocyclyl, and monocyclic 5 to 7-membered heterocyclyl are optionally substituted with one or more R 40 ;
R 4a in each occurrence is independently selected from H, C 1-6 alkyl, monocyclic 5 to 7-membered carbocyclyl, and monocyclic 5 to 7-membered heterocyclyl, wherein said C 1-6 alkyl, monocyclic 5 to 7-membered carbocyclyl, and monocyclic 5 to 7-membered heterocyclyl, are optionally and independently substituted with one or more R 40 ;
R 5 is selected from H and C 1-6 alkyl;
R 40 in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, monocyclic 5 to 7-membered carbocyclyl, monocyclic 5 to 7-membered heterocyclyl, —OR 40a , —SR 40a , —N(R 40a ) 2 , NO 2 , —C(O)R 40b , and —C(O) 2 R 40a ;
R 40a in each occurrence is independently selected from H, C 1-6 alkyl, monocyclic 5 to 7-membered carbocyclyl, and monocyclic 5 to 7-membered heterocyclyl;
R 40b in each occurrence is independently selected from C 1-6 alkyl, monocyclic 5 to 7-membered carbocyclyl, and monocyclic 5 to 7-membered heterocyclyl;
w is 0, 1, 2, or 3;
x is 0 or 1; and
y is 0, 1, or 2.
2. The compound of Formula I, as claimed in claim 1 , wherein the compound is a compound of Formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is selected from:
and Q is CH or N, or
Ring A is
and Q is CH 2 or NR 3 .
3. The compound of Formula I, as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is halo.
4. The compound of Formula I, as claimed in claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
R 1 in each occurrence is independently selected from fluorine and chlorine;
R 3 in each occurrence is independently selected from H and methyl;
R 4 is selected from H and methyl; and
w is 0, 2, or 3.
5. The compound of Formula I, as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H, and R 4 is H.
6. The compound of Formula I, as claimed in claim 1 , wherein the compound is a compound of Formula III:
or a pharmaceutically acceptable salt thereof.
7. The compound of Formula III, as claimed in claim 6 , wherein the compound is a compound of Formula IV:
or a pharmaceutically acceptable salt thereof.
8. The compound of Formula I, as claimed in claim 1 , wherein the compound is a compound of Formula V:
or a pharmaceutically acceptable salt thereof.
9. The compound of Formula V, as claimed in claim 8 , wherein the compound is a compound of Formula VI:
or a pharmaceutically acceptable salt thereof.
10. The compound of Formula I, as claimed in claim 1 , wherein the compound is a compound of Formula VII:
or a pharmaceutically acceptable salt thereof.
11. The compound of Formula VII, as claimed in claim 10 , wherein the compound is a compound of Formula VIII:
or a pharmaceutically acceptable salt thereof.
12. A compound of Formula IX:
or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is selected from:
wherein:
G is N, and Q is CH 2 or NR 3 , or
G is NR 3 , and Q is CH or N, or
G is CH, and Q is NR 3 , or
G is CH 2 , and Q is N; and
represents a single or double bond;
R 1 in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, —OC 1-6 alkyl, and —NO 2 , wherein the C 1-6 alkyl is optionally substituted with one to three halo;
R 2 in each occurrence is independently selected from hydrogen, halo, and C 1-6 alkyl;
R 3 is selected from H and C 1-6 alkyl;
R 6 is H or C l-6 alkyl;
R 7 is H or C l-6 alkyl;
n is 1, 2, 3, 4, 5, or 6; and
w is 0, 1, 2, or 3.
13. The compound of Formula IX, as claimed in claim 12 , wherein the compound is a compound of Formula X:
or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is selected from:
and Q is CH or N, or
Ring A is
and Q is CH 2 or NR3.
14. A compound of Formula XI:
or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is selected from:
wherein:
G is N, and Q is CH 2 or NR 3 , or
G is NR 3 , and Q is CH or N, or
G is CH, and Q is NR 3 , or
G is CH 2 , and Q is N; and
represents a single or double bond;
R 1 in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, —OC 1-6 alkyl, and —NO 2 , wherein the C 1-6 alkyl is optionally substituted with one to three halo;
R 2 in each occurrence is independently selected from hydrogen, halo, and C 1-6 alkyl;
R 3 is selected from H and C 1-6 alkyl;
R 6 is H or C l-6 alkyl;
R 7 is H or C 1-6 alkyl, and R 8 is a bond or C 1 -C 3 alkylene, wherein the C 1 -C 3 alkylene is optionally substituted with 1-3 substituents selected from R 10 , or
-R 8 —OR 7 is absent;
R 9 in each occurrence is independently OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, a C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, —C 1 -C 4 alkyl-(C 3 -C 10 cycloalkyl) , —C 1 -C 4 alkyl-(C 3 -C 10 heterocycloalkyl), —C 1 -C 4 alkyl-(aryl) , or —C 1 -C 4 alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R 10 ;
R 10 is independently selected at each occurrence from the group consisting of halo, —CN, —NO 2 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 heteroalkyl, and C(O)—C 1 -C 6 alkyl;
w is 0, 1, 2, or 3;
m is 0, 1, 2, or 3; and
z is 0, 1, 2, or 3.
15. The compound of Formula XI, as claimed in claim 14 , wherein the compound is a compound of Formula XII:
or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is selected from:
and Q is CH or N, or
Ring A is
and Q is CH 2 or NR 3 .
16. A composition comprising a compound according to claim 1 , or a salt, or N-oxide thereof.
17. A composition comprising a compound according to claim 12 , or a salt or N-oxide thereof.
18. A composition comprising a compound according to claim 14 , or a salt or N-oxide thereof.