Deuterated JAK inhibitor and uses thereof

1. A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein

Y 1 is selected from hydrogen and deuterium;

each Y 2 is selected from hydrogen and deuterium; and

each Y 3 is selected from hydrogen and deuterium;

provided that at least one of Y 1 , Y 2 , and Y 3 is deuterium; and

wherein each position designated specifically as deuterium has at least 90% deuterium incorporation.

2. The compound of claim 1 , selected from:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , which is Compound 10:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein each position designated specifically as deuterium has at least 95% deuterium incorporation.

5. The compound of claim 1 , wherein each position designated specifically as deuterium has at least 97% deuterium incorporation.

6. The compound of claim 1 , wherein the pharmaceutically acceptable salt is a phosphate salt.

7. A pharmaceutical composition comprising a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein Y 1 is selected from hydrogen and deuterium;

each Y 2 is selected from hydrogen and deuterium;

each Y 3 is selected from hydrogen and deuterium; and

wherein each position designated specifically as deuterium has at least 90% deuterium incorporation; and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7 , further comprising an additional therapeutic agent which is a JAK inhibitor.

9. The pharmaceutical composition of claim 8 , wherein the additional therapeutic agent which is a JAK inhibitor is selected from CTP-543, ruxolitinib, tofacitinib, baricitinib, upadacitinib, fedratinib, filgotinib, momelotinib, pacritinib, itacitinib, peficitinib, PF-06651600, PF-06700841 (brepocitinib), and abrocitinib, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 9 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof, and the JAK inhibitor is CTP-543, or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition of claim 7 , wherein the pharmaceutical formulation is in tablet form.

12. The pharmaceutical composition of claim 7 , wherein the pharmaceutical formulation is in capsule form.

13. A method of inhibiting the activity of one or more of JAK1 or JAK2 in a cell, comprising contacting the cell with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. The method of claim 13 , further comprising contacting the cell with one or more additional JAK inhibitors selected from CTP-543, ruxolitinib, tofacitinib, baricitinib, upadacitinib, fedratinib, filgotinib, momelotinib, pacritinib, itacitinib, peficitinib, PF-06651600, PF-06700841 (brepocitinib), and abrocitinib; or a pharmaceutically acceptable salt thereof.

15. A method of treating a disease or disorder in a human subject that is beneficially treated by inhibiting the activity of a JAK, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein

Y 1 is selected from hydrogen and deuterium;

each Y 2 is selected from hydrogen and deuterium; and

each Y 3 is selected from hydrogen and deuterium

wherein each position designated specifically as deuterium has at least 90% deuterium incorporation;

and a pharmaceutically acceptable carrier.

16. The method of claim 15 , wherein the disease or disorder is a hair loss disorder selected from alopecia areata, alopecia totalis, alopecia universalis, ophiasis, androgenic alopecia, and telogen effluvium.

17. The method of claim 16 , wherein the hair loss disorder is alopecia areata.

18. The method of claim 15 , wherein the pharmaceutically acceptable salt is a phosphate salt.

19. A method of treating a disease or disorder that is beneficially treated by inhibiting the activity of a JAK in a human subject in need thereof, comprising administering to the human subject an effective amount of a pharmaceutical composition comprising: (i) a first JAK inhibitor which is a compound represented by structural Formula (I)

or a pharmaceutically acceptable salt thereof,

wherein,

Y 1 is selected from hydrogen and deuterium;

each Y 2 is selected from hydrogen and deuterium; and

each Y 3 is selected from hydrogen and deuterium

wherein each position designated specifically as deuterium has at least 90% deuterium incorporation; (ii) a second JAK inhibitor; and (iii) a pharmaceutically acceptable carrier.

20. The method of claim 19 , wherein the second JAK inhibitor is selected from CTP-543, ruxolitinib, tofacitinib, baricitinib, upadacitinib, fedratinib, filgotinib, momelotinib, pacritinib, itacitinib, peficitinib, PF-06651600, PF-06700841 (brepocitinib), and abrocitinib, and pharmaceutically acceptable salts thereof.

21. The method of claim 19 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof, and the second JAK inhibitor is CTP-543, or a pharmaceutically acceptable salt thereof.

22. The method of claim 21 , wherein the pharmaceutical composition is administered at 16 mg/day or 24 mg/day of the first JAK inhibitor and the second JAK inhibitor together.

23. The compound of claim 3 , wherein the pharmaceutically acceptable salt is a phosphate salt.

24. The method of claim 21 , wherein the pharmaceutically acceptable salt is a phosphate salt.