Azepane derivatives and methods of treating hepatitis B infections
Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.
1. A compound of Formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
X is C or N;
one of Y or Z is N, and the other is C;
L 1 is —C(O)—, or —C(O)O—;
R x is independently, at each occurrence, halo;
R y is independently, at each occurrence, C 1-6 alkyl, halo, —CN, —NO 2 , -(L 2 ) q -OR 3 , -(L 2 ) q -SR 2 , -(L 2 ) q -S(═O)R 2 , -(L 2 ) q -S(═O) 2 R 2 , -(L 2 ) q -NHS(═O) 2 R 2 , -(L 2 ) q -C(═O)R 2 , -(L 2 ) q -OC(═O)R 2 , -(L 2 ) q CO 2 R 3 , -(L 2 ) q -OCO 2 R 3 , -(L 2 ) q -N(R 3 ) 2 , -(L 2 ) q -C(═O)N(R 3 ) 2 , -(L 2 ) q -OC(═O)N(R 3 ) 2 , -(L 2 ) q -NHC(═O)NH(R 3 ), -(L 2 ) q -NHC(═O)R 2 , -(L 2 ) q -NHC(═O)OR 2 , -(L 2 ) q -C(OH)(R 3 ) 2 , -(L 2 ) q C(NH 2 )(R 3 ) 2 , —C 1-6 haloalkyl, —C 1-6 dihaloalkyl, —C 1-6 trihaloalkyl, C 3-7 cycloalkyl, a C 3-10 heterocycloalkyl, aryl, heteroaryl, —C 1-4 alkylene-(C 3-7 cycloalkyl), —C 1-4 alkylene-(C 3-10 heterocycloalkyl), —C 1-4 alkylene-(aryl), or —C 1-4 alkylene-(heteroaryl);
or:
two R y groups on adjacent carbon atoms are taken together to form a fused ring; or
two R y groups on non-adjacent carbon atoms are taken together to form a bridge of a bridged bicyclic group; or
two R y groups on the same carbon atom, together with that carbon atom, form C(O);
R z is independently, at each occurrence, C 1-6 alkyl, halo, —CN, —NO 2 , -(L 2 ) q -OR 3 , -(L 2 ) q -SR 2 , -(L 2 ) q -S(═O)R 2 , -(L 2 ) q -S(═O) 2 R 2 , -(L 2 ) q -NHS(═O) 2 R 2 , -(L 2 ) q -C(═O)R 2 , -(L 2 ) q -OC(═O)R 2 , -(L 2 ) q CO 2 R 3 , -(L 2 ) q -OCO 2 R 3 , -(L 2 ) q -N(R 3 ) 2 , -(L 2 ) q -C(═O)N(R 3 ) 2 , -(L 2 ) q -OC(═O)N(R 3 ) 2 , -(L 2 ) q -NHC(═O)NH(R 3 ), -(L 2 ) q -NHC(═O)R 2 , -(L 2 ) q -NHC(═O)OR 2 , -(L 2 ) q -C(OH)(R 3 ) 2 , -(L 2 ) q C(NH 2 )(R 3 ) 2 , —C 1-6 haloalkyl, —C 1-6 dihaloalkyl, —C 1-6 trihaloalkyl, C 3-7 cycloalkyl, a C 3-10 heterocycloalkyl, aryl, heteroaryl, —C 1-4 alkylene-(C 3-7 cycloalkyl), —C 1-4 alkylene-(C 3-10 heterocycloalkyl), —C 1-4 alkylene-(aryl), or —C 1-4 alkylene-(heteroaryl);
L 2 is independently, at each occurrence, a bivalent radical selected from —(C 1-3 alkylene)-, —(C 3-7 cycloalkylene)-, —(C 1-3 alkylene) q -O—(C 1-3 alkylene) q -, or —(C 1-3 alkylene) q -NH—(C 1-3 alkylene) q -;
R 1 is H or C 1-6 -alkyl;
R 2 is C 1-6 alkyl, —C 1-6 haloalkyl, —C 1-6 dihaloalkyl, —C 1-6 trihaloalkyl, C 3-7 cycloalkyl, C 3-10 heterocycloalkyl, aryl, heteroaryl, —C 1-4 alkylene-(C 3-7 cycloalkyl), —C 1-4 alkylene-(C 3-10 heterocycloalkyl), —C 1-4 alkylene-(aryl), or —C 1-4 alkylene-(heteroaryl);
each R 3 is independently, at each occurrence, H, C 1-6 alkyl, —C 1-6 haloalkyl, —C 1-6 dihaloalkyl, —C 1-6 trihaloalkyl, C 3-7 cycloalkyl, C 3-10 heterocycloalkyl, aryl, heteroaryl, —C 1-4 alkylene-(C 3-7 cycloalkyl), —C 1-4 alkylene-(C 3-10 heterocycloalkyl), —C 1-4 alkylene-(aryl), or —C 1-4 alkylene-(heteroaryl);
m is 1, 2, or 3;
n is 0, 1, 2, or 3;
p is 1, 2, or 3; and
q is 0 or 1.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is N, and Z is C.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R y is C 1-6 alkyl, halo, -(L 2 ) q -OR 3 , -(L 2 ) q CO 2 R 3 , or —C 1-4 alkylene-(aryl).
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein two R y groups on the same carbon atom, together with that carbon atom, form C(O).
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein two R y groups on adjacent carbon atoms are taken together to form a fused ring, and wherein the ring is C 3-10 -cycloalkyl or phenyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein two R y groups on non-adjacent carbon atoms are taken together to form a bridge of a bridged bicyclic group, and wherein the bridge is a C 1-3 -alkyl chain.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R z is independently, at each occurrence, C 1-6 alkyl, halo, -(L 2 ) q -OR 3 , or C 3-7 cycloalkyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R z is independently, at each occurrence, halo or C 1-6 alkyl.
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
10. A method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to claim 1 .
11. The method of claim 10 , further comprising administering to the individual at least one additional therapeutic agent selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, BAY 41-4109, reverse transcriptase inhibitor, a TLR-agonist, AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide), and AT-130 ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide), and a combination thereof.
12. The method of claim 11 , wherein the therapeutic agent is a reverse transcriptase inhibitor, and is at least one of Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, cidofovir, Efavirenz, Nevirapine, Delavirdine, and Etravirine.
13. The method of claim 11 , wherein the TLR-agonist is selected from the group consisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848 (methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).
14. The method of claim 11 , wherein the therapeutic agent is an interferon, and wherein the interferon is any interferon, which may be optionally pegylated.
15. The method of claim 14 , wherein the interferon is interferon alpha (IFN-α), interferon beta (IFN-β), interferon lambda (IFN-λ) or interferon gamma (IFN-γ).
16. The method of claim 14 , wherein the interferon is interferon-alpha-2a, interferon-alpha-2b, interferon-alpha-n1, pegylated interferon-alpha-2a, or pegylated interferon-alpha-2b.
17. The method of claim 10 , further comprising administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof.
18. The method of claim 17 , wherein the HBV vaccine is selected from the group consisting of Recombivax HB, Engerix-B, Elovac B, GeneVac-B, and Shanvac B.
19. A method of treating an HBV infection in an individual in need thereof, comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a compound according to claim 1 alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutically effective amount of HBV vaccine.
20. The method of claim 10 further comprising monitoring the HBV viral load of the subject, and wherein the method is carried out for a period of time such that the HBV virus is undetectable.