Deuterated baricitinib
The present invention in one embodiment provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula I are as defined in the specification, as well as pharmaceutical compositions comprising the same, and methods of using such compounds and compositions to inhibit at least one of Janus Kinase-1 and -2 and diseases associated with those kinases.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y 1a and Y 1b are the same and are selected from hydrogen and deuterium;
Y 2a , and Y 2b are the same and are selected from hydrogen and deuterium;
each Y 3 , Y 4 , Y 6 and Y 7 is independently selected from hydrogen and deuterium;
Y 5 is deuterium;
X 1 and X 2 are the same and are selected from hydrogen and deuterium;
Z 1 and Z 2 are the same and are selected from hydrogen and deuterium; and
R is selected from —CH 3 and —CD 3 ,
wherein each position designated as “D” or “deuterium” has at least 75% incorporation of deuterium.
2. The compound of claim 1 , wherein X 1 and X 2 are each hydrogen.
3. The compound of claim 1 , wherein X 1 and X 2 are each deuterium.
4. The compound of claim 1 , wherein Y 1a and Y 1b are hydrogen.
5. The compound of claim 1 , wherein Y 1a and Y 1b are deuterium.
6. The compound of claim 1 , wherein Y 2a and Y 2b are hydrogen.
7. The compound of claim 1 , wherein Y 2a and Y 2b are deuterium.
8. The compound of claim 1 , wherein Z 1 and Z 2 are hydrogen.
9. The compound of claim 1 , wherein Z 1 and Z 2 are deuterium.
10. The compound of claim 1 , wherein Y 3 and Y 4 are hydrogen.
11. The compound of claim 1 , wherein Y 3 and Y 4 are deuterium.
12. The compound of claim 1 , wherein Y 6 and Y 7 are hydrogen.
13. The compound of claim 1 , wherein Y 6 and Y 7 are deuterium.
14. The compound of claim 1 , wherein:
Y 1a and Y 1b are hydrogen;
Y 2a and Y 2b are hydrogen;
each of Y 3 , Y 4 , Y 6 and Y 7 is hydrogen;
X 1 and X 2 are each hydrogen;
Z 1 and Z 2 are hydrogen; and
R is —CH 3 .
15. The compound of claim 1 , wherein each position designated specifically as deuterium has at least 90% incorporation of deuterium.
16. The compound of claim 1 , wherein each position designated specifically as deuterium has at least 95% incorporation of deuterium.
17. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
18. A method of inhibiting at least one of JAK1 and JAK2 kinase in a cell, comprising contacting the cell with a compound of claim 1 .
19. A method of treating a disease selected from rheumatoid arthritis, psoriasis, myeloproliferative disorders, lupus, transplant rejection, alopecia and other hair loss disorders, and dry eye, in a subject in need of such treatment, the method comprising administering to the subject in need of such treatment a compound of claim 1 .
20. The method of claim 19 , wherein the disease to be treated is alopecia.
21. The method of claim 19 , wherein the disease to be treated is selected from rheumatoid arthritis and psoriasis.
22. The method of claim 21 , comprising the additional step of co-administering methotrexate to the subject.
23. The method of claim 19 , wherein the myeloproliferative disorders are selected from chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia and primary myelofibrosis.
24. The compound of claim 1 , wherein each position designated specifically as deuterium has at least 82.5% incorporation of deuterium.
25. The compound of claim 14 , wherein each position designated specifically as deuterium has at least 90% incorporation of deuterium.
26. The compound of claim 14 , wherein each position designated specifically as deuterium has at least 95% incorporation of deuterium.