Pyrrole compounds
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
R 1 is an unsubstituted or a substituted C 2 alkenyl or an unsubstituted or a substituted C 2 alkynyl, wherein when the C 2 alkenyl and the C 2 alkynyl are substituted, the C 2 alkenyl and the C 2 alkynyl are independently substituted with one or more substituents independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an unsubstituted C 1-4 hydroxyalkyl, an unsubstituted monocyclic C 3-6 cycloalkyl and a hydroxy-substituted monocyclic C 3-6 cycloalkyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen, an unsubstituted or a substituted C 1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl, an unsubstituted or a substituted monocyclic 3-6 membered heterocyclyl, an unsubstituted C 1-4 hydroxyalkyl and an unsubstituted C 1-5 alkoxyalkyl, wherein when the monocyclic C 3-6 cycloalkyl and the monocyclic 3-6 heterocyclyl are substituted, the monocyclic C 3-6 cycloalkyl and the monocyclic 3-6 heterocyclyl are independently substituted with one or more substituents independently selected from the group consisting of halogen or hydroxy, and wherein when the C 1-4 alkyl is substituted, the C 1-4 alkyl is substituted with one or more substituents selected from the group consisting of a phosphate, an O-linked α-amino acid and an O-carboxy, and provided that at least one of R 2 and R 3 is not hydrogen; or
R 2 and R 3 are taken together along with the carbon to which R 2 and R 3 are attached to form an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl or an unsubstituted or a substituted monocyclic 3-6 membered heterocyclyl, wherein when the C 3-6 cycloalkyl and 3-6 membered heterocyclyl are substituted, the C 3-6 cycloalkyl and the 3-6 membered heterocyclyl are independently substituted with 1 or 2 substituents independently selected from the group consisting of halogen and hydroxy;
R 4 and R 5 are independently hydrogen, halogen, an unsubstituted C 1-4 alkyl, a deuterated C 1-4 alkyl or an unsubstituted C 2-4 alkenyl;
R 6 is hydrogen, an unsubstituted C 1-4 alkyl, a deuterated C 1-4 alkyl or an unsubstituted C 3-4 alkenyl; and
provided that at least one of R 4 , R 5 and R 6 is not hydrogen; or
R 5 is hydrogen, halogen, an unsubstituted C 1-4 alkyl or an unsubstituted C 2-4 alkenyl; and R 4 and R 6 are taken together to form an unsubstituted or substituted 5-6 membered heterocyclic ring;
X 1 is CR A or N;
R 7a , R 7b , R 7c and R 7d are independently hydrogen, halogen, an unsubstituted C 1-4 haloalkyl, cyano or an unsubstituted C 1-4 alkoxy;
R 8 is —CH 2 OC(═O)-(an unsubstituted C 1-4 alkyl), —CH 2 OC(═O)—O(an unsubstituted C 1-4 alkyl), —CH 2 -(α-amino acid) or —CH 2 -phosphate; and
R A is hydrogen, halogen, an unsubstituted C 1-4 haloalkyl or cyano.
2. The compound of claim 1 , wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl, an unsubstituted or a substituted monocyclic 3-6 membered heterocyclyl, an unsubstituted C 1-4 hydroxyalkyl and an unsubstituted C 1-5 alkoxyalkyl, wherein when the monocyclic C 3-6 cycloalkyl and the monocyclic 3-6 heterocyclyl are substituted, the monocyclic C 3-6 cycloalkyl and the monocyclic 3-6 heterocyclyl are independently substituted with one or more substituents selected from the group consisting of halogen or hydroxy.
3. The compound of claim 1 , wherein R 2 and R 3 are taken together along with the carbon to which R 2 and R 3 are attached to form an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl or an unsubstituted or a substituted monocyclic 3-6 membered heterocyclyl, wherein when the C 3-6 cycloalkyl and 3-6 membered heterocyclyl are substituted, the C 3-6 cycloalkyl and the 3-6 membered heterocyclyl are independently substituted with 1 or 2 substituents selected from the group consisting of halogen and hydroxy.
4. The compound of claim 3 , wherein the monocyclic 3-6 membered heterocyclyl is selected from the group consisting of an unsubstituted or substituted oxetane, an unsubstituted or substituted thietane, an unsubstituted or substituted
an unsubstituted or substituted
an unsubstituted or substituted
an unsubstituted or substituted
an unsubstituted or substituted
and an unsubstituted or substituted
5. The compound of claim 1 , wherein R 4 is an unsubstituted C 1-4 alkyl; R 5 is an unsubstituted C 1-4 alkyl; and R 6 is an unsubstituted C 1-4 alkyl.
6. The compound of claim 1 , wherein X 1 is CR A .
7. The compound of claim 6 , wherein R A is halogen.
8. The compound of claim 1 , wherein R 7a is hydrogen; and R 7d is hydrogen.
9. The compound of claim 1 , wherein R 7b is halogen, an unsubstituted C 1-4 haloalkyl, cyano or an unsubstituted C 1-4 alkoxy.
10. The compound of claim 1 , wherein R 7c is halogen, an unsubstituted C 1-4 haloalkyl, cyano or an unsubstituted C 1-4 alkoxy.
11. The compound of claim 1 , wherein R 1 is an unsubstituted C 2 alkenyl.
12. The compound of claim 1 , wherein R 1 is an unsubstituted C 2 alkynyl.
13. The compound of claim 1 , wherein R 8 is —CH 2 OC(═O)-(an unsubstituted C 1-4 alkyl), —CH 2 OC(═O)—O(an unsubstituted C 1-4 alkyl) or —CH 2 -(α-amino acid).
14. The compound of claim 1 , wherein R 8 is —CH 2 -phosphate.
15. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and excipient.
16. A method for treating hepatitis B in a subject comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, suffering from hepatitis B.
17. A method for treating hepatitis D in a subject comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, suffering from hepatitis D.
18. The method of claim 16 , further comprising administering an additional agent selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence oligonucleotide, a nucleic acid polymer, an entry inhibitor and a small molecule immunomodulator.
19. The method of claim 17 , further comprising administering an additional agent selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence specific oligonucleotide, a nucleic acid polymer, an entry inhibitor and a small molecule immunomodulator.
20. A compound having the structure
or a pharmaceutically acceptable salt thereof.
21. A compound having the structure
or a pharmaceutically acceptable salt thereof.
22. A compound having the structure
23. A compound having the structure
or a pharmaceutically acceptable salt thereof.
24. A compound having the structure
or a pharmaceutically acceptable salt thereof.
25. A compound having the structure
or a pharmaceutically acceptable salt thereof.
26. A compound having the structure
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 1 , wherein:
R 1 is an unsubstituted or a substituted C 2 alkynyl, wherein when the C 2 alkynyl is substituted, the C 2 alkynyl is substituted with one or more substituents independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an unsubstituted C 1-4 hydroxyalkyl, an unsubstituted monocyclic C 3-6 cycloalkyl and a hydroxy-substituted monocyclic C 3-6 cycloalkyl;
R 2 is an unsubstituted C 1-4 alkyl;
R 3 is selected from the group consisting a substituted C 1-4 alkyl and an unsubstituted C 1-4 hydroxyalkyl, wherein when the C 1-4 alkyl is substituted, the C 1-4 alkyl is substituted with one or more substituents selected from the group consisting of a phosphate, an O-linked α-amino acid and an O-carboxy;
R 4 and R 5 are each an unsubstituted C 1-4 alkyl;
R 6 is an unsubstituted C 1-4 alkyl;
X 1 is CR A ;
R 7a , R 7c and R 7d are each hydrogen;
R 7b is halogen, an unsubstituted C 1-4 haloalkyl, cyano or an unsubstituted C 1-4 alkoxy;
R 8 is —CH 2 OC(═O)-(an unsubstituted C 1-4 alkyl), —CH 2 OC(═O)—O(an unsubstituted C 1-4 alkyl), —CH 2 -(α-amino acid) or —CH 2 -phosphate; and
R A is halogen.
28. The compound of claim 1 , wherein:
R 1 is an unsubstituted or a substituted C 2 alkynyl, wherein when the C 2 alkynyl is substituted, the C 2 alkynyl is substituted with one or more substituents independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an unsubstituted C 1-4 hydroxyalkyl, an unsubstituted monocyclic C 3-6 cycloalkyl and a hydroxy-substituted monocyclic C 3-6 cycloalkyl;
R 2 and R 3 are taken together along with the carbon to which R 2 and R 3 are attached to form an unsubstituted or a substituted monocyclic 3-6 membered heterocyclyl, wherein when 3-6 membered heterocyclyl are substituted, the 3-6 membered heterocyclyl is substituted with 1 or 2 substituents independently selected from the group consisting of halogen and hydroxy;
R 4 and R 5 are each an unsubstituted C 1-4 alkyl;
R 6 is an unsubstituted C 1-4 alkyl;
X 1 is CR A ;
R 7a , R 7c and R 7d are each hydrogen;
R 7b is halogen, an unsubstituted C 1-4 haloalkyl, cyano or an unsubstituted C 1-4 alkoxy;
R 8 is —CH 2 OC(═O)-(an unsubstituted C 1-4 alkyl), —CH 2 OC(═O)—O(an unsubstituted C 1-4 alkyl), —CH 2 -(α-amino acid) or —CH 2 -phosphate; and
R A is halogen.
29. The compound of claim 28 , wherein R 2 and R 3 are taken together along with the carbon to which R 2 and R 3 are attached to form an unsubstituted or a substituted oxetane.
30. The compound of claim 29 , wherein R 8 is —CH 2 -phosphate.