Compounds and methods for treating disease
The invention provides compounds, compositions and methods for treating medical disorders, such as cancer, an autoimmune disorder, and/or a neurological disorder, and inhibiting LINE1 reverse transcriptase and/or HERV-K reverse transcriptase using a compound according to Formula I or a pharmaceutically acceptable salt thereof, or a related compound provided herein.
1. A compound is represented by Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 4 represent independently —C(O)R 5 or hydrogen; provided that at least one of R 1 and R 4 is —C(O)R 5 ;
R 2 is halo;
R 3 is halomethyl which optionally has one or more hydrogen replaced with deuterium;
R 5 represents independently for each occurrence C 1-20 aliphatic, phenyl, —CH 2 -phenyl, or hydrogen; wherein each phenyl is substituted with m occurrences of R 10 ;
R 8 is halo;
R 10 represents independently for each occurrence C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 haloalkyl, or halo;
B 1 is
and
m is 0, 1, or 2.
2. The compound of claim 1 , wherein the compound is represented by Formula II-A:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 4 are —C(O)R 5 ;
R 3 is halomethyl;
R 5 represents independently for each occurrence C 1-20 aliphatic, phenyl, or —CH 2 -phenyl; wherein each phenyl is substituted with m occurrences of R 10 ;
R 8 is halo;
R 10 represents independently for each occurrence C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 haloalkyl, or halo; and
m is 0, 1, or 2.
3. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a carrier, excipient, and/or vehicle.
4. A method of treating an autoimmune disorder selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, and Aicardi-Goutieres Syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , compound 67, or a pharmaceutically acceptable salt thereof, in order to treat the disorder, wherein compound 67 is represented by:
5. The method of claim 4 , wherein the subject has (i) elevated expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) elevated activity of LINE1 reverse transcriptase.
6. The method of claim 4 , wherein the autoimmune disorder is systemic lupus erythematosus or cutaneous lupus erythematosus.
7. The method of claim 6 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
8. The method of claim 6 , wherein the compound is
9. The method of claim 4 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , wherein the autoimmune disorder is systemic lupus erythematosus.
11. The method of claim 9 , wherein the autoimmune disorder is cutaneous lupus erythematosus.
12. The method of claim 9 , wherein the autoimmune disorder is lupus nephritis.
13. The method of claim 9 , wherein the autoimmune disorder is dermatomyositis.
14. The method of claim 9 , wherein the autoimmune disorder is Aicardi-Goutieres Syndrome.
15. A method of inhibiting LINE1 reverse transcriptase activity in a subject, the method comprising contacting a LINE1 reverse transcriptase with an effective amount of a compound according to claim 1 , compound 67, or a pharmaceutically acceptable salt thereof, in order to inhibit the activity of said LINE1 reverse transcriptase, wherein compound 67 is represented by:
16. The method of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
17. The method of claim 15 , wherein the compound is
a pharmaceutically acceptable salt thereof.
18. A compound selected from the following:
or a pharmaceutically acceptable salt thereof.
19. A compound selected from
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 19 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 19 , wherein the compound is
22. A pharmaceutical composition comprising a compound according to claim 21 and a carrier, excipient, and/or vehicle.
23. The compound of claim 19 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 19 , wherein the compound is
25. A pharmaceutical composition comprising a compound according to claim 23 and a carrier, excipient, and/or vehicle.
26. A pharmaceutical composition comprising a compound according to claim 24 and a carrier, excipient, and/or vehicle.